Culture

Rheumatologists at the University of Alberta are flagging similarities between the deaths of some COVID-19 patients and those with rheumatic illnesses, and are testing proven rheumatic treatments to see whether they help against the pandemic virus.

A substantial proportion of COVID-19 patients admitted to intensive care die of pneumonia due to a cytokine storm, where the body attacks itself rather than fighting off the illness, said Jan Willem Cohen Tervaert, director of rheumatology in the Department of Medicine.

In a new paper published in Autoimmunity Reviews, Cohen Tervaert and his colleagues note that such storms, whether in patients with COVID-19 or rheumatic diseases, are caused by dysfunctional "natural killer" (NK) immune cells.

They say that SARS-CoV-2, the virus that causes COVID-19, might attack NK cells directly by binding to angiotensin converting enzyme 2 (ACE-2), a receptor on the cells that COVID-19 researchers believe attracts and opens the door to the virus.

"This virus is so smart, it kills the cells that are supposed to kill it," Cohen Tervaert said.

Worldwide clinical trials are being carried out to test treatments typically used to treat cytokine storm in patients with juvenile arthritis and other rheumatic diseases.

These include intravenous immunoglobulin, a blood transfusion product prepared from the serum of thousands of healthy or previously infected patients, and rheumatic drugs such as tocilizumab and anakinra. Some researchers in China are even attempting to transplant healthy NK cells.

Cohen Tervaert said the U of A team is collaborating with researchers at the University of Calgary to further study the role of NK cells in COVID-19 patients. There are more COVID-19 patients in southern Alberta than in the Edmonton area.

In a healthy person, natural killer cells are responsible for both turning on and turning off the immune response when a body is attacked by disease, including viruses and even cancer. Unlike other immune cells (T and B cells), natural killer cells don't need to be trained or primed to fight infection.

"They are not thinkers," Cohen Tervaert said. "They immediately do their work without being exposed previously to a virus. As soon as a virus affects the cell and the cell wall changes, NK cells can attack that cell."

After the NK cells kill the virus-infected cells, the T and B immune cells come along and produce cytokines, making the immune reaction stronger and stronger.

"But at a certain time the immune reaction has to end," he said. "Natural killer cells play an important role in finishing that huge attack.

"If they don't work, the cytokine storm goes on and on, and the patient will die."

For those who have not been infected with the virus, Cohen Tervaert recommends regular mild to moderate exercise to boost their NK cells. His own daily routine includes step climbing, walking and weightlifting.

"If you sit the whole day in your room because you have to be isolated, your NK cell activity goes down," he said. "That's the big warning about the isolation of elderly people who are not allowed to go outside of their rooms. Over time they are more and more at risk to die from COVID-19."

A Northwestern University research team has developed a new method to conduct spectroscopic nanoscopy, an approach that could help researchers understand more complicated biomolecular interactions and characterize cells and diseases at the single-molecule level.

The new system, called asymmetrically dispersed spectroscopic single-molecule localization microscopy (SDsSMLM), builds upon existing sSMLM techniques developed at the McCormick School of Engineering to provide more precise spectroscopic single-molecule analysis to study how cells behind certain cancers, or diseases like diabetic retinopathy, function in their localized environments.

While current spectroscopic single-molecule localization microscopy techniques achieve super-resolution imaging and single-molecule spectroscopy simultaneously, current sSMLM designs suffer from reduced imaging resolution and spectral precision. This is caused by the system dividing a finite number of emitted photons -- atomic particles that transmit electromagnetic light -- between two separate channels for spatial and spectral imaging.

"We should not be satisfied to only know where a particular molecule is or where many molecules are without differentiating their properties," said Hao Zhang, professor of biomedical engineering, who led the research. "Our approach enables us to fully use all photons from each emission for both spatial imaging and spectral analyses. As a result, we significantly improved the spatial imaging resolution and spectral precision compared to existing sSMLM techniques."

A paper describing the work, titled "Symmetrically Dispersed Spectroscopic Single-molecule Localization Microscopy," was published May 25 in the journal Light: Science and Applications. Cheng Sun, professor of mechanical engineering, was a coauthor on the paper.

Unlike existing sSMLM approaches, which often use a 1:3 ratio to split photos between the spatial and spectral channels, SDsSMLM commits all available photos to create two mirrored spectral images. This approach extracts spectral information at the highest possible resolution. In addition, because the images are symmetrical, researchers can still identify spatial information by identifying the mid-point between the two spectral images.

When compared to an existing sSMLM using the same number of photos, the researchers found that SDsSMLM improved the spatial precision by 42 percent and spectral precision by 10 percent.

"We realized that the spatial information is totally overlooked in the spectral image in existing sSMLM techniques," Zhang said. "This approach allows us to apply all of the available photons for spectral analysis to push the resolution limit while also acquiring spatial imaging."

When used together with spectroscopic single-molecule imaging techniques, SDsSMLM can be adapted for 3D cellular imaging, an essential tool in cell biology and materials science that allows researchers to track how cells interact in their environments.

"This technique holds true for all molecules, regardless of their emission spectra and minute spectral variations, even among the same species of molecules," Zhang said. "With improved spatial resolution and spectral precision, sSMLM will find broader applications in multi-molecule imaging in cells and three-dimensional tracking for individual nanoparticles in biological and chemistry investigations."

In addition to the system's advanced imaging capabilities, SDsSMLM's compact nature allows for easy integration and reliable operation with conventional fluorescence microscope systems. Combined with an open source plug-in the researchers developed called RainbowSTORM, Zhang hopes other members of the biological research community will incorporate this advanced technique within their own work.

"Our design is standalone and can be installed in a majority of microscope systems," Zhang said. "We hope other researchers take advantage of what we've created."

New guidelines for scientists and regulators show how deliberate infection of volunteers for vaccine trials can be done ethically

Peer-reviewed paper by University of Warwick researcher argues that we do not need to lower our ethical standards if appropriate safeguards are in place

Researcher also argues that deliberate infection should be considered to speed up vaccine development

Allowing consenting volunteers to be deliberately infected with COVID-19 for the purposes of developing a vaccine could be done ethically and potentially speed up its development, a University of Warwick researcher has argued in new research.

Dr Adair Richards at the University of Warwick has developed a set of ethical guidelines to guide researchers on an ethical approach to deliberately infecting volunteers who have been given a vaccine candidate with COVID-19.

He argues that this may significantly speed up the process of vaccine development and potentially save many lives. The work has been externally double-blind peer-reviewed and is published today (28 May) in the Journal of Medical Ethics.

Dr Adair Richards is an Honorary Associate Professor in the University of Warwick’s Department of Chemistry and carries out research ethics training for postgraduate researchers in science and medicine. He said: "Currently there are several vaccine candidates that are undergoing human safety testing, but to find out whether they work we need to discover what happens when a vaccinated person is exposed to COVID-19. With new infections dropping in the countries where research is taking place, it may be a long time before many of the volunteers in these experiments naturally come into contact with the disease.

"Deliberately infecting volunteers with a disease as dangerous as COVID-19 has previously been considered to be unethical by the research community. However I believe that the current global situation is so different to those previously faced, that it is ethical in this case.

"In other areas of life it is not unusual for society to allow individuals to do things that put them at personal risk, such as to be a fire fighter or a health professional treating COVID-19 patients. Speeding up vaccine development even by a few weeks or months could result in saving many lives."

The research analyses each of the common arguments against these types of experiments: the risk of harm to volunteers; the risk of no useable vaccine; the validity of a volunteer's informed consent; the reputational risk to research; and that this could be a slippery slope to increasingly unethical research.

Dr Richards demonstrates that these arguments can be overcome and in fact we do not need to lower our ethical standards to permit these types of experiment, and that it is possible to put sufficient ethical safeguards in place.

The article provides guidance for regulators and researchers and poses three key questions for those planning vaccine development studies:

Has reasonable care been taken to maximise the potential benefits of the proposed study and minimise the risks of harm to participants?

Is the informed consent process sufficiently robust?

What do we need to do now to amend our processes to speed up the consideration and approval processes for proposed COVID-19 vaccine candidate phase II and phase III trials?

Dr Richards adds: "My research shows that it is incorrect to rule out human challenge experiments as unethical in relation to COVID-19 vaccine development. I argue that you can apply the same standards of ethics, but that they lead us now to a different conclusion because the facts are different.

"Very large numbers of people globally are affected both directly and indirectly from COVID-19, and the saving of a few weeks or months of time in vaccine development can be expected to result in saving a large number of lives. There are also good ways to minimise the risk of harm to volunteers, and it is ethical, and I argue, admirable to allow a volunteer to choose to take a personal health risk to help serve a greater benefit to humanity."

Survey by researchers at University of Warwick and the University of Edinburgh shows most women's healthcare units have adopted national guidance on COVID-19

Women's healthcare units include services such as maternity, obstetrics and gynaecology

Highlights need for planning to prevent health issues developing in the long-term

The majority of women's healthcare units in the UK, including services such as maternity and gynaecological cancers, have adapted well to the initial COVID-19 outbreak, according to a new survey by University of Warwick researchers.

However, there are concerns that without greater planning for the long-term they could be storing up problems that could adversely affect women's health in the future.

The results of the survey, conducted by Warwick Medical School and the University of Edinburgh, are reported in the BJOG: an International Journal of Obstetrics & Gynaecology today (28 May). They suggest that the rapid implementation of evidence-guidance and re-allocation of NHS resources have been key in adapting to the challenges of COVID-19.

Women's healthcare units provide services such as maternity, antenatal, postnatal and gynaecology, including treatment for women with gynaecological cancers.

95% of women's healthcare units in the UK responded to the survey between 28 March and 7 of April 2020, which aimed to ascertain whether women's healthcare units had adopted guidance from the World Health Organisation and Royal College of Obstetricians and Gynaecologists (RCOG) on the safe management of women with COVID-19.

60.1% of units responded that they had completed specific training drills for obstetric and gynaecological emergencies in women with COVID-19, and 64.9% had provided training in two-persons donning and doffing of Personal Protective Equipment (PPE).

87.8% of units had departmental protocols specific to COVID-19 in pregnancy and 70.8% operated COVID-19 dedicated theatres for obstetrics emergencies. 91.2% of respondents felt that adequate PPE was offered to health professionals.

The majority of units (79.1%) had also reduced face-to-face antenatal clinics and 88.5% had completely stopped elective gynaecology services such as planned caesarean sections and induction of labour among steps to limit the presence of inpatients.

Lead author Dr Bassel Wattar of Warwick Medical School said: "Women require sustainable access to predictable yet essential healthcare services including maternity, contraception and family planning. Our study aimed to provide a rapid snapshot assessment on the current status in providing these service in the NHS within few weeks of implementing the national guidelines in response to COVID-19.

"The majority of NHS hospitals seem to be following established evidence-based guidelines from the Royal College of Obstetricians and Gynaecologists as well as the WHO to provide safe service to women in need. In the acute response phase, many elective gynaecological services were suspended and this could affect women's health on the long-term if these services are not restored rapidly, such as those with chronic pelvic pain and menstrual problems. Additionally, there seems to be an impact on the provision of gynaecological cancer treatment services, but a more detailed assessment is needed to draw an accurate picture."

The survey also highlights concerns about long-term planning for these services as social distancing continues into the next stage of the pandemic.

Dr Wattar adds: "Many units within women's healthcare are starting to use telemedicine technology to provide safe care while upholding the rule of social distancing. These elements need to be explored further and implemented properly into NHS maternity services as we prepare for the 'new normal'. Additionally, there is a need to restore elective gynaecology care rapidly to avoid long-term adverse health outcomes. An example could be to move surgical operation sites into 'clean stand-alone units' which is being trialled by many NHS trusts in collaboration with the private sector.

"In times of major health pandemics, a high level of morbidity is often linked to poor access to healthcare services and depletion of available resources. COVID-19 is presenting an unpresented challenge to medical community worldwide, disrupting access to health services and increasing the strain and demand on medical staff. As we re-allocate resources to deal with the pandemic many groups requiring continuous care, for example maternity, cancer, and trauma care, will be adversely impacted."

CLEVELAND - An international team of researchers co-led by Cleveland Clinic have identified why patients without PTEN mutations may still experience the high cancer risk associated with PTEN hamartoma tumor syndrome (PHTS).

In a new study published in the New England Journal of Medicine, a research team co-led by Charis Eng, MD, PhD, Cleveland Clinic Genomic Medicine Institute, and Pier Paolo Pandolfi, MD, PhD, FRCP, University of Turin, Italy, found that mutations to the gene WWP1 may be an additional genetic driver of PHTS-associated cancer.

PHTS collectively refers to a spectrum of genetic disorders that carry an increased risk for benign growths and tumors (i.e., hamartomas), cognitive and behavioral deficits, macrocephaly and certain cancers and that is defined by carrying a germline PTEN mutations. While germline mutations of the tumor suppressor gene PTEN are an established cause of PHTS, approximately 75% of individuals with typical clinical features have been found to carry no PTEN mutations (termed "wildtype").

"Our findings suggest that WWP1 mutations may account for at least some portion of the large percentage of these patients we see without PTEN mutations," said Dr. Eng. "Importantly, unlike PTEN, WWP1 and the cellular pathway it regulates are druggable targets, a fact that has important implications for cancer prevention and therapy and may open the door for future drug development studies."

In this study, the researchers analyzed a cohort of PTEN wildtype patients for WWP1 variants, as previous studies have found that the enzyme encoded by WWP1 can be overexpressed and/or amplified in multiple types of cancer and can inhibit PTEN function and lead to tumor growth in experimental models.

They identified these variants in a family with a history of oligopolyposis (a condition characterized by abnormal growths on the inner walls of the colon and rectum) and early-onset colon cancers, and an expanded analysis of unrelated patients detected WWP1 germline variants in 4% of PTEN wildtype individuals with gastrointestinal oligopolyposis as a predominant clinical feature. This is significant because oligopolyposis has long eluded causation. In addition, the researchers found that germline WWP1 variants were significantly enriched in patients affected by sporadic cancers, including cancer types associated with PHTS, particularly colorectal adenocarcinoma and thyroid cancer.

On a mechanistic level, they found that in experimental models certain WWP1 variants lead to abnormal activation of the WPP1 enzyme that inhibits PTEN function and ultimately contributes to cancer development and progression by increasing tumorigenesis.

While additional studies are needed, the researchers conclude that PTEN wildtype patients with germline WWP1 variants may benefit from preventative and/or therapeutic measures that modulate WWP1-PTEN axis.

"These findings are extremely exciting because they implicate WWP1 in the genesis of somatic cancers of multiple histology as well as in dictating cancer susceptibility at large, with important prognostic and therapeutic implications since these class of enzymes are druggable and natural compounds that do so are already available," said Dr. Pandolfi.

Researchers from Newcastle University London, Fordham University, and University of Minho published a new paper in the Journal of Marketing that examines how some brands create "sticky" customer journeys that keep customers addicted.

The study forthcoming in the Journal of Marketing is titled "Customer Experience Journeys: Loyalty Loops versus Involvement Spirals" and is authored by Anton Siebert, Ahir Gopaldas, Andrew Lindridge, and Cláudia Simões.

The world's top leisure brands, such as CrossFit, Pokémon Go, and Tinder, have built empires by keeping customers addicted. Athletes don't just work out at CrossFit; they're obsessed with it. Gamers don't just play Pokémon Go for a little while; they're hooked for hours on end. Singles on Tinder don't just hunt for new partners; they're addicted to the hunt itself. And from Netflix to Spotify to TikTok, a new generation of media companies has completely transformed the television, radio, and video industry. Audiences are no longer willing to sit through formulaic shows like NBC's once-beloved Law and Order. They want Game of Thrones-like drama--compelling, polarizing, hard-to-pull-away-from serials that shock, delight, and frequently enrage their viewers.

The secret behind these breakthrough leisure brands is creating an insanely "sticky" journey that defies all the usual hyperrational rules of marketing. Siebert explains that "It's not at all about creating consistently good customer experiences, but about creating intentionally chaotic, maddening, and unpredictable ones." Lindridge adds, "It's also not about making services convenient, easy, or satisfying, but instead about making them challenging, suspenseful, and thrilling."

"These unpredictable customer journeys are called 'sticky' to emphasize that customers just cannot seem to pull away," explains Gopaldas. "At the heart of these sticky journeys is an 'involvement spiral'--a roller coaster ride of intensely good and bad experiences that keep customers riveted."
How do these leisure brands create such sticky journeys?

The first step is providing customers with "rapid entry." That means giving customers free, quick, and easy access to the service as soon as they express interest, whether in-person or online. These brands don't bore customers with a lot of information. They don't ask too many questions. And they don't pressure customers to sign up for a monthly subscription, at least not at the beginning. Tinder does this first step particularly well. Unlike traditional matchmaking websites that begin with extensive compatibility questionnaires, the Tinder app asks customers for no more than their age, gender, and distance preferences. Customers can also import their photos from Facebook, so they can dive into the Tinder dating pool immediately.

The second step is providing customers with "endless variation" along the user experience journey. Whether we're talking about dating, gaming, working out, or something else, the only way to keep customers excited is by creating unpredictable experiences. Companies create such endless variation using a trio of techniques:

Opening the service system to a massive number of service elements (e.g., the hundreds of possible exercises at CrossFit, virtual creatures in Pokémon Go, or user profiles on Tinder);

Making frequent additions, subtractions, and changes to those elements; and

Offering unique configurations of those elements at each and every service encounter.

For instance, CrossFit changes workouts daily and makes those workouts extraordinarily challenging. Drawing on various sports, fitness regimes, and military drills, no two workouts are ever the same. Once customers are swept up in the endlessly varied customer journey, they are more eager to sign up for monthly subscriptions.

The third step is sparking new customer journeys as soon as the current ones begin to run out of steam. "Leisure brands recognize that all journeys come to an end. Even the most exciting adventures can become familiar, exhausting, or boring after a while. Eventually, brands must offer their customers new journeys," adds Simões. For example, Nintendo, the parent company behind the Animal Crossing gaming franchise, has launched an entirely new generation of the game every few years. CrossFit coaches invite advanced athletes to Barbell Clubs and CrossFit competitions. And recently, Tinder has begun to launch journey offshoots such as Swipe Night, a fun event that matches users based on their responses to an interactive movie.

Wondering how to get un-hooked? Some customers can keep their recreational addictions in check, but many others cannot. Maintaining daily self-discipline is just too hard. For compulsive users, there's only one answer: cancel your subscription, delete the app, and call a friend.

Most customers won't do that. Leisure brands are counting on it.

Although we often think of knowledge as "knowing that" (for example, knowing that Paris is the capital of France), each of us also knows many procedures consisting of knowing how, such as knowing how to tie a knot or start a car. Now a new study has found the brain programs that code the sequence of steps in performing a complex procedure. In a just published paper in Psychological Science, researchers at Carnegie Mellon University have found a way to find decode the procedural information required to tie various knots, with enough precision to identify which knot is being planned or performed. To reach this conclusion, Drs. Robert Mason and Marcel Just first trained a group of participants to tie seven different knots, and then scanned their brains while they imagined tying or actually tied the knots while they were in an MRI scanner. The main findings were that each knot had a distinctive neural signature, so the researchers could tell which knot was being tied from the sequence of brain images collected. Furthermore, the neural signatures were very similar for imagining tying a particular knot and planning to tie it.

Dr. Just noted that "Tying a knot is an ancient and frequently performed human action that is the epitome of everyday procedural knowledge, making it an excellent target for investigation."

The research project was funded by the Office of Naval Research. While naval cadets frequently use nautical knots and naval doctors tie knots in surgical procedures, naval personnel are required to master many other types of procedural skills. Understanding how the brain learns and represents procedural tasks is an important part of the science of learning.

The machine learning algorithm the researchers used succeeded by first processing the fMRI data from trials in which the participants mentally tied a knot like as a bowline or a sheet bend knot, and learned the association between each of the knots and their respective neural signatures.

"Once we identified the neural representations of the procedures of how to tie each specific knot, we were able to predict which knot they were about to tie before they started tying it", said Dr. Mason. That was possible because we have a plan for tying each knot, a plan that becomes activated just before the actual procedure is executed." What distinguishes this finding from previous "brain decoding" studies is that knowing how involves a particular sequence of actions over executed over some time period, and not just a static snapshot of knowing that.

In 1951, Harvard neurophysiologist Karl Lashley proposed that a complex act like playing a tune on a musical instrument requires than a linkage between the successive steps involved in the procedure; he hypothesized that it requires a higher-order mental structure or plan for organizing the sequence of steps. These new findings now confirm the existence of such higher-order mental representations of procedure, and they furthermore identify which procedure is which.

The ability to identify the neural representation of a procedure may useful in developing instructional techniques that teach procedures with high efficiency and in developing brain-computer interfaces that translate a mental procedure into a robotic procedure.

Below please find a summary and link(s) of new coronavirus-related content published today in Annals of Internal Medicine. The summary below is not intended to substitute for the full article as a source of information. A collection of coronavirus-related content is free to the public at http://go.annals.org/coronavirus.

1. Risk for COVID-19 Resurgence Related to Duration and Effectiveness of Physical Distancing in Ontario, Canada

Researchers from Dalla Lana School of Public Health, University of Toronto, developed an epidemiologic model to explore the effect of physical distancing measures on COVID-19 transmission in the population of Ontario, Canada. Their findings suggest that without intervention, Ontario, which is currently below ICU capacity, would have rapidly exceeded ICU capacity and observed substantially higher mortality. The model also shows the challenges associated with relaxation of physical distancing measures without a concomitant increase in other public health measures. Specifically, when the number of contacts between persons returns to more than 50 percent of normal, disease activity could resurge rapidly and ICUs could quickly reach capacity. Read the full text: https://www.acpjournals.org/doi/10.7326/M20-2945.

Media contacts: A PDF for this article is not yet available. Please click the link to read full text. The lead author, David Fisman, MD, MPH can be reached through Francoise Mbenoun Makanda at francoise.makanda@utoronto.ca or Anna Weigt-Bienzle at anna.weigtbienzle@utoronto.ca.

2. Use of Hydroxychloroquine or Chloroquine in COVID-19

Researchers for the Agency for Healthcare Research and Quality (AHRQ) conducted a living systematic review of published research to summarize evidence about the benefits and harms of using hydroxychloroquine or chloroquine to treat coronavirus disease 2019. They found that evidence was conflicting and insufficient regarding the effect of hydroxychloroquine on such outcomes as all-cause mortality, progression to severe disease, clinical symptoms, and upper respiratory virologic clearance with antigen testing. The evidence for chloroquine was similarly weak. Read the full text: https://www.acpjournals.org/doi/10.7326/M20-2496.

Media contacts: A PDF for this article is not yet available. Please click the link to read full text. The lead authors, C. Michael White and Adrian V. Hernandez, MD, PhD, can be reached at through Karin Burgess at karin.burgess@uconn.edu.

Chemical engineering researchers at the University of Arkansas have developed a device that simulates the blood filtering and ion transport functions of the human kidney. The technology could transform treatment options for people in the final stage of renal disease.

"Basically we created a synthetic nephron - the structure that filters blood to disperse nutrients to the body and remove waste material," said Christa Hestekin, associate professor of chemical engineering and principal researcher. "The system could work as a stand-alone device or in conjunction with peritoneal dialysis to control the chemistry of solutions used in treatment. And, minor modifications to the device could enable it to function as a wearable and potentially implantable artificial kidney."

Hestekin works on a team including Jamie Hestekin, professor of chemical engineering; Ira Kurtz, professor of medicine and chief of nephrology at UCLA Health; and several students in the Ralph E. Martin Department of Chemical Engineering at the University of Arkansas. Funded by the US Kidney Research Corporation, the work was published in Communications Materials, a Nature publication.

The researchers' system simulates the critical ion transport work of the nephron. As the structural and functional unit of the kidney, the nephron regulates blood chemistry through filtration of the blood that delivers ions and organic molecules to the body before generating urine to be excreted.

To simulate the filtration process, researchers inserted platinum porous meshes between two ion-exchange wafers to create a single electrodeionization wafer that uses an electric field to force ions through membranes. The meshes serve as electrodes when voltage is applied. The mesh electrodes enabled independent control of transport chambers within the device, which in turn allowed researchers to select different ions and adjust transport rates independently.

Hestekin's team successfully tested the technology with several physiologically relevant ions, mimicking the specific control of ion transport by the kidney.

Combined with ultrafiltration, nanofiltration or reverse osmosis systems, the researchers' technology could be integrated into an artificial kidney, Hestekin said.

According to the Centers for Disease Control and Prevention, 37 million people in the United States suffer with some form of chronic kidney disease. Of these, about 700,000 people per year will develop end-stage, renal disease, which requires dialysis or, as a last resort, a kidney transplant. The CDC reports that the average duration of patient survival on dialysis is slightly longer than seven years, and patients generally must wait about 10 years to receive a donated kidney. Roughly 100,000 people die each year while waiting for a kidney transplant.

As small businesses reopen after a lengthy pandemic shutdown, one key challenge will be finding working capital to replenish inventories and pay employees until revenue returns to normal, according to a new RAND Corporation perspective based on interviews with a select group of small business owners.

Business owners believe it will take many months to return to normal, and that process can be aided by clear guidance from government or trade organizations about how to reopen safely during the pandemic. This includes how to keep both workers and customers safe.

Small business owners face an array of challenges during the pandemic, which has resulted in sharp reductions in revenue and created an existential threat to their future operation. The RAND paper provides their account of what kinds of policies will help them survive.

The RAND perspective is based on interviews with 21 small businesses from across the country, including owners of restaurants, specialty shops, and even small amusement parks.

Other highlights from the perspective include:

Paying fixed costs such as rent, mortgage, and insurance has been a struggle during the shutdown and such costs represent an existential threat. Business owners report that while existing programs help support payrolls, they do not go far enough in helping businesses with these fixed costs.

For some businesses, it was better to lay off workers so they could receive enhanced unemployment benefits rather than trying to keep paying workers' salaries.

Relaxing rules in the Paycheck Protection Program, the premier federal small-business assistance program, requiring that 75 percent of loans must be used on payroll in order to be forgiven is one possible approach to aid small business owners. Such a change would give business owners more flexibility to meet their other fixed costs such as rent.

ANN ARBOR, Mich. - After experiencing an ACL injury, a common sports injury involving ligaments in the knee, many athletes find they can't return to play with the same vigor as before their injury. But, a new study, published in The American Journal of Sports Medicine, finds human growth hormone treatment after ACL reconstructive surgery may prevent the loss of muscle strength in the knee.

"While modern surgical techniques can reconstruct ACLs in a minimally invasive way, the associated muscle atrophy can be a greater challenge to overcome," says Asheesh Bedi, M.D., senior author of the study, chief of sports medicine and shoulder surgery at Michigan Medicine and director of the Michigan Center for Human Athletic Medicine and Performance (MCHAMP).

"Residual atrophy can slow or limit the safe return to the prior level of competition, and contribute to risk of re-injury and even arthritis."

HGH, a hormone within the body, helps cells and tissues grow and regenerate. HGH supplements are banned by the World Anti-Doping Agency, and in collegiate and professional sports.

"When you hear of athletes taking HGH drugs when they are healthy, it's considered doping because they are essentially trying to overproduce the hormone and bulk their muscles and tissues as a competitive advantage," says Christopher Mendias, Ph.D., ATC, the lead author of the study, an adjunct associate professor of orthopaedic surgery at Michigan Medicine and an associate scientist in the Arthritis and Tissue Degeneration Program at the Hospital for Special Surgery.

Bedi and Mendias hypothesized that administering HGH supplements to injured athletes may activate HGH within the body to target the ACL tear and prevent the knee muscles from losing strength.

"Even after rehabilitation, many patients have muscles that are 30 to 40% weaker when they return to sports compared to their pre-surgery strength," Mendias says.

Trial criteria

The researchers examined 19 male athletes, ages 18 to 35, with ACL tears who were scheduled for ACL reconstruction surgery at Michigan Medicine. The study participants were randomly assigned to self-inject HGH or a placebo solution into their lower abdominal muscles twice daily over a six-week period, beginning one week prior to surgery. The research team excluded collegiate, professional or elite athletes from the study because of the substance ban, as well as patients with diabetes, as developing type 2 diabetes is a side effect of HGH supplements.

Prescription HGH is only available for treating growth hormone deficiency syndromes and can't be used off-label without approval from the U.S. Food and Drug Administration. By obtaining an investigational new drug exemption from the FDA, the research team was able to administer the drug to study enrollees.

Other Michigan Medicine faculty and graduate students contributing to the study include Tariq Awan, D.O., an assistant professor of orthopaedic surgery, Ariel Barkan, M.D., a professor of internal medicine, James Carpenter, M.D., a professor and former chair of orthopaedic surgery, Joel Gagnier, N.D., Ph.D., an associate professor of orthopaedic surgery, Jonathan Gumucio, Ph.D., a graduate student in molecular and integrative physiology, and Jon Jacobson, M.D., a professor of radiology. The multidisciplinary team assured a rigorous scientific approach and the highest level of safety to the study.

The research team found the HGH injections did appear to have an effect after measuring knee muscle strength and volume, patient-reported outcomes, such as pain and symptoms, and analyzing biomarkers in blood samples from the injured athletes versus individuals without an ACL tear.

"While HGH did not appear to affect muscle volume or our patient-reported outcome scores, we found a 29% higher knee extension strength in our patients that had performed the HGH injections compared to those in the placebo group," Bedi says.

Examining the blood analyses revealed other signs of muscle and cartilage change. Patients who performed the HGH treatments had a 2.1-fold increase in circulating insulin-like growth factor 1 (IGF1), a protein similar to insulin that plays an important role in muscle growth. In addition, their blood samples indicated a 36% lower level of matrix metalloproteinase-3 (MMP3), an enzyme that breaks down proteins during growth processes in the body. MMP3 was an indirect biomarker of cartilage wear down in the study.

"We observed a consistent reduction in MMP3 in the HGH group from the first through the 12th post-operative weeks," Mendias says. "This finding suggests a potential protective effect of HGH after ACL reconstruction and that we should look more closely at its potential for cartilage healing in further studies."

Future use in sports?

Bedi and Mendias hope the results of this study allow for revisiting reevaluation of the World Anti-Doping Agency and sports agencies' ban on HGH.

"Perhaps athletes could petition for a Therapeutic Use Exception, which allows a banned substance for a medically-appropriate reason, to prevent loss of muscle strength after ACL reconstruction," Mendias says. "Treatment occurs during a time when athletes are not playing due to their injuries. The goal is to prevent muscle weakness, not make athletes stronger than they were before their injuries. Any small performance-enhancing effects of human growth hormone seem to wear off quickly after stopping the medication, and does not offer a competitive advantage."

The research team notes that further studies into HGH are needed.

"We hope to build upon this research with future studies that include larger cohorts of athletes with broader demographics," Bedi says.

Mendias adds, "Further studies would also allow us to petition the FDA to approve the addition of orthopedic injuries as an on-label indication for the drug."

Nearly half of individuals who contract COVID-19 experience changes in their sense of taste, a new analysis led by a University of Toledo researcher has found.

The systematic review, published in the journal Gastroenterology, could provide yet another diagnostic hint for clinicians who suspect their patients might have the disease.

"Earlier studies didn't note this symptom, and that was probably because of the severity of other symptoms like cough, fever and trouble breathing," said Dr. Muhammad Aziz, chief internal medicine resident at UToledo and the paper's lead author. "We were beginning to note that altered or lost sense of taste were also present, not just here and there, but in a significant proportion."

Aziz and his research collaborators analyzed data from five studies conducted between mid-January and the end of March. Of the 817 patients studied, 49.8% experienced changes to their sense of taste. Researchers suspect the true prevalence could be even higher because some of the studies were based on reviews of patient charts, which may not have noted every symptom.

"We propose that this symptom should be one of the screening symptoms in addition to the fever, shortness of breath and productive cough. Not just for suspected COIVD patients, but also for the general population to identify healthy carriers of the virus," Aziz said.

Prior research has found that a significant number of people who have COVID-19 don't know they've been infected and may be spreading the virus.

Aziz and his research collaborators suspect an altered sense of taste is more prevalent in patients with minor symptoms, though more studies are needed to validate that suspicion. Even so, changes in an individual's sense of taste could be a valuable way to identify carriers who are otherwise mostly asymptomatic.

Taste disorders are tied to a variety of viral illnesses. The review did not attempt to identify the reason that COVID-19 is causing changes in patients' sense of taste; however, researchers theorize it could be COVID-19's ability to bind to what's known as the ACE-2 receptor, which is expressed in epithelial cells on the tongue and mouth.

Because the novel coronavirus was unknown prior to its emergence in January, scientists have been moving rapidly to learn more about both the virus and the disease it causes.

Aziz said the drip of new information shows the need for more scientists to dig into the impacts of COVID-19.

"A lot of things are being missed, which is why I think researchers from every field should try to look into this and see if it's affecting their specialty in one way or another," he said. "Who knows what systems this virus is affecting. If we can catch it earlier in the disease course, we can prevent the spread of the virus and potentially have ways of managing it."

Having a faulty gene linked to dementia doubles the risk of developing severe COVID-19, according to a large-scale study.

Researchers at the University of Exeter Medical School and the University of Connecticut School of Medicine analysed data from the UK Biobank, and found high risk of severe COVID-19 infection among European ancestry participants who carry two faulty copies of the APOE gene (termed e4e4). One in 36 people of European ancestry have two faulty copies of this gene, and this is known to increase risks of Alzheimer's disease up to 14-fold* and also increases risks of heart disease.

Now, the research team has found that carrying these gene mutations doubles the risks of COVID-19 - even in people who had not developed these diseases.

The team has previously found that people with dementia are three times more likely to get severe COVID-19, yet they are not one of the groups advertised to shield - or shelter in place - on health grounds. Part of the increased risk effect may have been exposure to the high prevalence of the virus in care homes. However, the new study, published in the Journal of Gerontology: Medical Sciences, indicates that a genetic component may also be at play. The team found that people with the APOE e4e4 genotype were at double the risk of developing severe COVID-19, compared to those with the common e3e3 form of the APOE gene. The team used data from the UK Biobank study, which collects health and genetic data on 500,000 people.

The majority of people in the population and in the sample size have not yet been exposed to the virus. In this analysis, 2.36% (n=9,022) of participants with European ancestries (n=382,188) had the ApoE e4e4 faulty gene, but 5.13% (n=37) of those who tested positive for COVID-19 (n=721) had this gene variant, suggesting the risk is doubled compared to e3e3 (410 per 100,000 versus 179 per 100,000).

Co-author Dr. Chia-Ling Kuo, of the UConn School of Medicine, said: "This is an exciting result because we might now be able to pinpoint how this faulty gene causes vulnerability to COVID-19. This could lead to new ideas for treatments. It's also important because it shows again that increasing disease risks that appear inevitable with ageing might actually be due to specific biological differences, which could help us understand why some people stay active to age 100 and beyond, while others become disabled and die in their sixties."

Professor David Melzer, who led the team, said: "Several studies have now shown that people with dementia are at high risk of developing severe COVID-19. This study suggests that this high risk may not simply be due to the effects of dementia, advancing age or frailty, or exposure to the virus in care homes."

Melzer stresses: "The effect could be partly due to this underlying genetic change, which puts them at risk for both COVID-19 and dementia."

Shea yields are likely to benefit from a diversity of trees and shrubs in parkland habitats in West Africa, according to a new study led by scientists from Trinity College Dublin. The findings have important implications for managing a crop that is typically harvested and sold by women in rural areas, and which helps finance education for children.

Shea trees (Vitellaria paradoxa) grow in dryland savanna, forest and parkland ecosystems across an estimated 1 million km2 between western Senegal and north-western Uganda. Shea is an important agroforestry crop providing fruit near the end of the dry season; the nuts are processed into a nutritious butter that helps sustain an estimated 80 million people, as well as providing an income from local and global trade.

Shea trees benefit from bees moving pollen between their flowers to produce fruit, but the new study - just published in the Journal of Applied Ecology - found that in sites with low tree and shrub diversity, fruit production was severely limited by a lack of pollination. In higher-diversity sites, more honeybees were observed, and other bees visited flowers in greater numbers, boosting pollination services.

The shea parklands are a long-established traditional food and fuel wood production system, but with growing population pressure and the introduction of the tractor, management has moved away from a shifting cultivation and pastoralist system to more intensive 'permanent' agriculture. This has resulted in a loss of fallow land and contributed to a degraded and fragmented landscape with a lower diversity of plants, which makes life hard for insect pollinators in the Sahel.

The study recommends that when areas are cleared for cultivation, shrubs and trees that are beneficial to the local pollinators should be retained. Furthermore, measures to conserve pollinators in the region should target both honeybees and other bee species.

The researchers involved in this new study - funded by a Darwin Initiative grant - came together from Trinity and INGOs, BirdLife International and the RSPB, and conducted the work with local farmers, NGOs and academics in Burkina Faso, West Africa. The findings will be used to inform local conservation.

Jane Stout, Professor in Botany at Trinity, and a senior author of the study, said:

"In the face of a global biodiversity crisis, studies like this are crucial for demonstrating the everyday importance of biodiversity. We have shown that more biodiverse parklands support more pollinators, and this makes crops more productive - benefitting local peoples' livelihoods and well-being."

Dr Aoife Delaney, lead researcher, said:

"Shea plays a special economic role in Burkina Faso. It is generally harvested and sold by women in rural areas and generates an income that is particularly linked to funding children's education, bringing wider societal benefits. The fruits ripen at a time of year when both food and money are scarcest, helping to tide families over.

"Nutritionally, shea provides essential nutrients and fats that are in short supply during the dry season, and safe-guarding the shea crop in the long-term is important for food security. Supporting pollinators and diverse plant communities in shea parklands also has secondary benefits as the majority of the trees and shrubs there benefit from pollination, including other fruit crops and species that are important for maintaining soil fertility."

Already, BirdLife International and the Burkinabe partner Naturama are working to change the way shea resources are managed within the landscape and are promoting a farmer-led approach built on simple, low cost changes in land management to enhance biodiversity on-farm. This includes natural regeneration and planting of native trees and shrubs with multiple benefits for people, livestock, insects and birds; replacing agrochemicals with locally produced mulch and compost; and introducing apiculture for pollination and food / income.

Together, the international team has produced biodiversity guidelines for Parkland Management that were adopted by the Global Shea Alliance, a 500-strong member organisation, which aims to increase sustainability across the shea value chain, both in the food and cosmetic industries. And, together with local partners, the team has been educating and increasing awareness around the important role of pollinators and undertaking training and capacity building with Burkinabe communities and in schools throughout the region.

Elaine Marshall, project manager, said:
"Our work supports the theory that when we improve plant diversity on farms we see an increase in pollinators and shea yield. We believe a landscape approach which protects these ecosystem goods and services also reduces the vulnerability of human populations across the shea belt. This work demonstrates the potential for ecosystem restoration to deliver healthier and more resilient stocks of natural capital, enhanced pollination services and improved capacity for adapting to the impacts of climate change. Restoring 'nature' should be considered as a core component of successful development aid strategy."

Professor Juliet Vickery, RSPB's Centre for Conservation Science, said:
"Retaining shrubs and trees can have multiple other benefits. It can help combat desertification in an area extremely vulnerable to the impact of climate change and provide vital habitat for many of Europe's summer migrant birds that winter or stop over in the Shea zone on their way to and from sub-Saharan Africa."

Diving as a lifestyle has evolved many times in the animal kingdom, and the ecology of all diving animals is essentially shaped by how long they can hold their breaths.

According to new research, the world's diving animals - from small insects to giant whales - are all governed by a number of similar principles.

Using the largest dataset ever compiled, an international team of scientists has examined how metabolic constraints govern the diving performance of air-breathing aquatic species, all of which have evolved to maximise the amount of time they can spend underwater.

They discovered that maximum dive duration increases predictably with body mass in all animals, but the rate at which this happens depends on metabolic mode.

Ectotherms - cold-blooded creatures such as amphibians, reptiles and insects - can remain submerged for longer at a given body mass, but the impact of an increase in body mass on dive duration in warm-blooded endotherms - including birds and mammals - is far more pronounced.

Writing in Proceedings of the Royal Society B, scientists say their findings constitute a new fundamental principle of evolutionary physiology, showing that the same 'rules' govern the evolution of diving in animals as different as water beetles and walruses.

They also say it may partly explain why many warm-blooded diving animals - including modern whales but also extinct reptiles such as ichthyosaurs and plesiosaurs - evolved relatively large body sizes, as increases in size led to greater relative increases in dive duration.

The research was completed at the University of Plymouth (UK), and led by an international team of scientists now based at Radboud University (Netherlands), Université du Québec à Rimouski (Canada) and Plymouth's School of Biological and Marine Sciences.

They compiled and analysed 1,792 records for 286 species, including 62 ectotherms and 224 endotherms, and tested whether the globally recognised oxygen store/usage hypothesis - which suggests that larger animals are able to dive for longer and deeper - applies to all diving animals, irrespective of their evolutionary origin and metabolic mode.

Lead author Dr Wilco Verberk, an Assistant Professor at Radboud University, said: "Our work provides an unprecedented analysis of the ecology of diving behaviour from a metabolic perspective, with far-reaching implications. It demonstrates that body mass and temperature affect dive duration in a similar manner in species as evolutionarily distant as insects, reptiles, birds and mammals. This shows the same general physical and physiological principles have shaped the evolution of diving in all animal groups, both ancient and modern, constituting a new fundamental principle for evolutionary physiology."

Senior author David Bilton, Professor of Aquatic Biology at the University of Plymouth and a world renowned expert on aquatic beetles, added: "Our results change our understanding of diving in animals significantly, and help us better disentangle what shapes the ecology and evolution of both extant and extinct divers. It shows that large body size and the increased oxygen storage capacity that goes with it, permit longer dives, opening many previously inaccessible aquatic ecosystems to large bodied air breathers and provides a possible explanation as to why many warm-blooded diving animals tend to be relatively large."