Body

An international team of scientists led by microbiologists Professor Alexander Loy from the University of Vienna and Professor David Schleheck from the University of Konstanz has uncovered new metabolic capabilities of gut bacteria. For the first time, the researchers have analyzed how microbes in the gut process the plant-based, sulfur-containing sugar sulfoquinovose. Sulfoquinovose is a sulfonic acid derivative of glucose and is found in all green vegetables such as spinach and lettuce. Their study discovered that specialized bacteria cooperate in the utilization of the sulfosugar, producing hydrogen sulfide. This gas - known for its rotten egg smell - has disparate effects on human health: at low concentrations, it has an anti-inflammatory effect, while increased amounts of hydrogen sulfide in the intestine, in turn, are associated with diseases such as cancer. The study has been published in the current issue of "The ISME Journal".

Diet and the gut microbiome

With the consumption of a single type of vegetable such as spinach, hundreds of chemical components enter our digestive tract. There, they are further metabolized by the gut microbiome, a unique collection of hundreds of microbial species. The gut microbiome thus plays a major role in determining how nutrition affects our health. "So far, however, the metabolic capabilities of many of these microorganisms in the microbiome are still unknown. That means we don't know what substances they feed on and how they process them," explains Buck Hanson, lead author of the study and a microbiologist at the Center for Microbiology and Environmental Systems Science (CMESS) at the University of Vienna. "By exploring the microbial metabolism of the sulfosugar sulfoquinovose in the gut for the first time, we have shed some light into this black box," he adds. The study thus generates knowledge that is necessary to therapeutically target the interactions between nutrition and the microbiome in the future.

Sulfosugars from green plants and algae

Sulfoquinovose is a sulfonic acid derivative of glucose and is found as a chemical building block primarily in green vegetables such as spinach, lettuce, and in algae. From previous studies by the research group led by microbiologist David Schleheck at the University of Konstanz, it was known that other microorganisms can in principle use the sulfosugar as a nutrient. In their current study, the researchers from the Universities of Konstanz and Vienna used analyses of stool samples to determine how these processes specifically take place in the human intestine. "We have now been able to show that, unlike glucose, for example, which feeds a large number of microorganisms in the gut, sulfoquinovose stimulates the growth of very specific key organisms in the gut microbiome," says David Schleheck. These key organisms include the bacterium of the species Eubacterium rectale, which is one of the ten most common gut microbes in healthy people. "The E. rectale bacteria ferment sulfoquinovose via a metabolic pathway that we have only recently deciphered, producing, among other things, a sulfur compound, dihydroxypropane sulfonate or DHPS for short, which in turn serves as an energy source for other intestinal bacteria such as Bilophila wadsworthia. Bilophila wadsworthia ultimately produces hydrogen sulfide from DHPS via a metabolic pathway that was also only recently discovered," explains the microbiologist.

A question of dose: hydrogen sulfide in the intestine

Hydrogen sulfide is produced in the intestine by our own body cells as well as by specialized microorganisms and has a variety of effects on our body. "This gas is a Janus-faced metabolic product," explains Alexander Loy, head of the research group at the University of Vienna. "According to current knowledge, it can have a positive but also a negative effect on intestinal health." A decisive factor, he says, is the dose: In low amounts, hydrogen sulfide can have an anti-inflammatory effect on the intestinal mucosa, among other things. Increased hydrogen sulfide production by gut microbes, on the other hand, is associated with chronic inflammatory diseases and cancer. Until now, mainly sulfate and taurine, which are found in increased amounts in the intestine as a result of a diet rich in meat or fat, were known to be sources of hydrogen sulfide for microorganisms. The discovery that sulfoquinovose from green foods such as spinach and algae also contribute to the production of the gas in the gut therefore comes as a surprise.

"We have shown that we can use sulfoquinovose to promote the growth of very specific gut bacteria that are an important component of our gut microbiome. We now also know that these bacteria in turn produce the contradictory hydrogen sulfide from it," Loy sums up. Further studies by the scientists from Konstanz and Vienna will now clarify whether and how the intake of the plant-based sulfosugar can have a health-promoting effect. "It is also possible that sulfoquinovose could be used as a so-called prebiotic," adds Schleheck. Prebiotics are food ingredients or additives that are metabolized by specific microorganisms and used to explicitly support the intestinal microbiome.

Diet and the gut microbiome

With the consumption of a single type of vegetable such as spinach, hundreds of chemical components enter our digestive tract. There, they are further metabolized by the gut microbiome, a unique collection of hundreds of microbial species. The gut microbiome thus plays a major role in determining how nutrition affects our health. "So far, however, the metabolic capabilities of many of these microorganisms in the microbiome are still unknown. That means we don't know what substances they feed on and how they process them," explains Buck Hanson, lead author of the study and a microbiologist at the Center for Microbiology and Environmental Systems Science (CMESS) at the University of Vienna. "By exploring the microbial metabolism of the sulfosugar sulfoquinovose in the gut for the first time, we have shed some light into this black box," he adds. The study thus generates knowledge that is necessary to therapeutically target the interactions between nutrition and the microbiome in the future.

Sulfosugars from green plants and algae

Sulfoquinovose is a sulfonic acid derivative of glucose and is found as a chemical building block primarily in green vegetables such as spinach, lettuce, and in algae. From previous studies by the research group led by microbiologist David Schleheck at the University of Konstanz, it was known that other microorganisms can in principle use the sulfosugar as a nutrient. In their current study, the researchers from the Universities of Konstanz and Vienna used analyses of stool samples to determine how these processes specifically take place in the human intestine. "We have now been able to show that, unlike glucose, for example, which feeds a large number of microorganisms in the gut, sulfoquinovose stimulates the growth of very specific key organisms in the gut microbiome," says David Schleheck. These key organisms include the bacterium of the species Eubacterium rectale, which is one of the ten most common gut microbes in healthy people. "The E. rectale bacteria ferment sulfoquinovose via a metabolic pathway that we have only recently deciphered, producing, among other things, a sulfur compound, dihydroxypropane sulfonate or DHPS for short, which in turn serves as an energy source for other intestinal bacteria such as Bilophila wadsworthia. Bilophila wadsworthia ultimately produces hydrogen sulfide from DHPS via a metabolic pathway that was also only recently discovered," explains the microbiologist.

A question of dose: hydrogen sulfide in the intestine

Hydrogen sulfide is produced in the intestine by our own body cells as well as by specialized microorganisms and has a variety of effects on our body. "This gas is a Janus-faced metabolic product," explains Alexander Loy, head of the research group at the University of Vienna. "According to current knowledge, it can have a positive but also a negative effect on intestinal health." A decisive factor, he says, is the dose: in low amounts, hydrogen sulfide can have an anti-inflammatory effect on the intestinal mucosa, among other things. Increased hydrogen sulfide production by gut microbes, on the other hand, is associated with chronic inflammatory diseases and cancer. Until now, mainly sulfate and taurine, which are found in increased amounts in the intestine as a result of a diet rich in meat or fat, were known to be sources of hydrogen sulfide for microorganisms. The discovery that sulfoquinovose from green foods such as spinach and algae also contribute to the production of the gas in the gut therefore comes as a surprise.

"We have shown that we can use sulfoquinovose to promote the growth of very specific gut bacteria that are an important component of our gut microbiome. We now also know that these bacteria in turn produce the contradictory hydrogen sulfide from it," Loy sums up. Further studies by the scientists from Konstanz and Vienna will now clarify whether and how the intake of the plant-based sulfosugar can have a health-promoting effect. "It is also possible that sulfoquinovose could be used as a so-called prebiotic," adds Schleheck. Prebiotics are food ingredients or additives that are metabolized by specific microorganisms and used to explicitly support the intestinal microbiome.

Washington, DC (April 9, 2021) -- The American Society of Nephrology (ASN) and the National Kidney Foundation (NKF) announce the concurrent publication of "Special Article: Reassessing the Inclusion of Race in Diagnosing Kidney Diseases: An Interim Report from the NKF-ASN Task Force" in the Journal of the American Society of Nephrology (JASN) and the American Journal of Kidney Diseases (AJKD).

The publication in JASN and AJKD provides an essential review of the many challenges relative to identifying and implementing alternative methods to diagnosing kidney diseases. Last month, ASN and NKF asserted that race modifiers should not be included in equations used to estimate kidney function. ASN and NKF also stated that current race-based equations should be replaced by a substitute that is accurate, representative, unbiased, and provides a standardized approach to diagnosing kidney diseases.

In its final report, the task force will recommend the best approach to replace the existing equations for estimating kidney function. As a result, the interim report is the second in a three-step process: 1) agree to replace race-based equations; 2) review the many challenges relative to identifying and implementing alternative methods; and 3) recommend the best approach for replacing existing equations) to accomplishing the goal NKF and ASN established in July 2020 "to examine the inclusion of race in the estimation of GFR and its implications for the diagnosis and subsequent management of patients with, or at risk for, kidney diseases."

NKF and ASN urge institutions not to make any changes to how they estimate kidney function until the task force provides its recommendation for the best approach to replace the existing equations for estimating kidney function. The task force plans to include these recommendations in its final report, which is currently being drafted based on considerable input from patients, trainees, health professionals, and other stakeholders. ASN and NKF commend the task force for its thoughtfulness, thoroughness, time, and effort. Both the interim and final reports will guide the kidney community in developing an evidence-based guideline for practice.

"The use of race in clinical algorithms, such as for the estimation of GFR, normalizes and reinforces the misconception of race as a biological determinant of health and disease. This is not to say that clinicians should ignore race and ethnicity. Doing so would blind us to the disparities and inequities present in health and healthcare. But we must not conflate the societal effects of race and racism on health, healthcare and kidney diseases with physiologic and pathophysiologic determinants of health," said NKF President Paul M. Palevsky, MD, FASN, FNKF.

"Beyond the inclusion of race in clinical algorithms like eGFR, ASN and NKF assert that racism manifests in many aspects of health care," said ASN President Susan E. Quaggin, MD, FASN, who added, "Both organizations commit to providing resources and expertise to the essential job of dismantling systemic racism in kidney care, research, and education."

In addition to publishing the interim report, Josephine P. Briggs, MD, and Harold I. Feldman, MD--the Editors-in-Chief of JASN and AJKD respectively--published a joint editorial, "Race and the Estimation of GFR: Getting it Right" (JASN and AJKD). They assert, "As journal editors, we recognize published research that has emphasized race as a biologic construct has contributed to a failure to address core problems." They add that publishing the interim report is an important step "in the pursuit of effective interventions that will lessen race-based disparities in health. It includes being more cognizant of how reporting of science can perpetuate racism. In this spirit, we are grateful for the opportunity to promote and disseminate the work of the task force."

More than 37 million adults in the United States have kidney diseases. A disproportionate number of these people are Black or African American, Hispanic or Latino, American Indian or Alaska Native, Asian American, and Native Hawaiian or Other Pacific Islander. These Americans also face unacceptable health disparities and inequities in healthcare delivery.

When setting SARS-CoV-2 vaccine priorities, Canada should take a more nuanced approach that considers geographic and occupational risk exposures, as 75% of Canadian adults have at least 1 risk factor for severe COVID-19, argues an analysis in CMAJ (Canadian Medical Association Journal).

"Using risk factors for severe COVID-19 in a strategic vaccination strategy may not offer much refinement because of how widespread these conditions are. More detailed weighting of medical, geographic and occupational risks might be required if vaccination is constrained," writes Dr. Finlay McAlister, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, with coauthors. "In particular, since the third wave of the COVID-19 pandemic appears to be disproportionately affecting essential workers in economically disadvantaged neighbourhoods, weighting of such risks may be necessary for equity goals to be met."

The authors looked at national data on more than 60 000 people to determine the presence of risk factors for severe COVID-19 in the Canadian population. While age is the most important risk factor for severe illness, three-quarters of adult Canadians have at least one other risk factor, and one-third have two or more. The most common risk factors were hypertension (23.1% of men and 21.1% of women) and obesity (21.7% of men and 20.2% of women). Although risk factors increased with age, the authors note that even in the 18-49 age group, 70.9% of men and 67.9% of women had at least one risk factor and 31% had at least 2 risk factors for severe COVID-19.

The authors acknowledge that vaccine prioritization decisions are as much an ethical question as a scientific one.

"We suggest that transparency in decision-making is important, especially where decisions vary across jurisdictions, to confirm that the rationale for decisions is driven by data and concordant with the shared values of local populations," the authors conclude.

BOSTON -- Videos of people experiencing severe neurological symptoms, including convulsions and difficulty walking, purportedly after receiving a COVID-19 vaccine, have surfaced on Facebook, YouTube and other social media channels. The millions of people watching these videos might conclude that the vaccine is either quite dangerous to produce such symptoms or that the people in the videos are faking their symptoms. Both conclusions are incorrect, according to neurologist and psychiatrist David Perez, MD, MMSc, director of the Functional Neurological Disorders Unit at Massachusetts General Hospital (MGH).

In a JAMA Neurology Viewpoint, the authors explain that the COVID-19 vaccine may precipitate the development of functional neurological disorder (FND), a neuropsychiatric disorder with symptoms such as limb weakness, gait problems, jerky movements, tremor and facial spasms. "The spread of these videos could fuel vaccine hesitancy by giving an overly simplistic impression of potential links between the vaccine and major neurological symptoms," says Perez, the piece's senior author. "Instead, these are symptoms of a real, brain-based disorder that sits at the intersection of neurology and psychiatry."

FND is a disruption in the brain's normal mechanisms for controlling the body and can be triggered by physical or emotional events, including head injury, a medical or surgical procedure, and vaccinations. "Some people with FND have a heightened awareness of their body and increased state of arousal and threat, which may hijack normal neural networks controlling voluntary movements," says Perez. "FND teaches us quite a bit about the complexities of the human brain."

An individual's awareness of motor control may also be impaired with FND, adds first author David Dongkyung Kim, MD, clinical fellow in Behavioral Neurology-Neuropsychiatry at MGH: "The body is moving, but the individual doesn't experience a sense of agency over their movements, such as tremors or movements of the trunk."

Some, but not all, individuals vulnerable to developing FND may have experienced adverse life events or have chronic pain or a range of other medical or psychiatric conditions. "The biopsychosocial model involving an interplay of risk factors, triggering events, and perpetuating factors is how we currently understand FND," says Kim. FND can, however, be treated with education, physical rehabilitation and psychotherapy.

Neurologists and other health care professionals have an obligation to explain FND to the public, say the authors. "Helping people understand FND will bring this disorder into mainstream medical conversations, and transparently addressing concerns will better allow people to make informed decisions for themselves on receiving the COVID-19 vaccine," says Perez.

It's time for a more nuanced approach to prioritizing COVID-19 vaccinations as more contagious variants become prevalent and a third wave of infections threatens to overwhelm hospitals in some provinces, according to an analysis published today in the Canadian Medical Association Journal.

“It’s time to move the debate away from age and medical risk factors,” said lead author Finlay McAlister, professor in the University of Alberta’s Faculty of Medicine & Dentistry.

“The third wave is showing us that the most vulnerable are people in economically marginalized neighbourhoods where people live and work in close proximity—a group that wasn’t prioritized for vaccination before.”

McAlister and three other authors, including U of A professor of medicine Lynora Saxinger, who co-chairs the scientific advisory group for Alberta Health Services’ COVID-19 Emergency Coordination Centre, analyzed data from the Canadian Community Health Survey for 61,000 Canadian adults. They identified how many have conditions that are recognized as risk factors for severe COVID-19 disease, including high blood pressure, obesity, diabetes and smoking.

“At least 75 per cent of Canadian adults have at least one risk factor and one-third have two or more risk factors for severe illness if they contract COVID-19,” McAlister said. “When 75 per cent of people are eligible for prioritization, that’s not really prioritization.”

It was appropriate to give seniors living in communal settings and the very elderly shots first, as they were clearly the most likely to face severe disease and death at the time, McAlister said, but now the focus should also be on neighbourhoods and workplaces facing a higher risk of infection. He applauded the Alberta government’s recent announcement that it will open vaccine clinics at the Cargill meat packing plant in High River as an example of the new direction that should be taken.

McAlister also supports the recommendation from the National Advisory Committee on Immunization to give first doses to as many Canadians as possible, even if it means waiting up to three months to administer second doses while vaccine supplies are limited.
“The science is evolving rapidly, but there is accumulating evidence showing that after the first shot we are getting about 80 per cent efficacy, at least in the short-term, so it looks like delaying second doses while we try to get more first doses into arms is a reasonable approach if we continue to be faced with vaccine shortages,” McAlister said. “Of course, how long that first-dose protection will last, we will only know in retrospect.”

He noted that some groups should be given special consideration to get their second dose more quickly. For example, cancer and transplant patients do not develop the same level of immunity from the first dose as others.

“They seem to get only partial immunity, which means they are at a greater risk for infection, giving the virus another chance to mutate into a variant and get passed on,” McAlister explained. “We want as many people as possible to develop immunity as quickly as possible so there’s less chance for new variants to develop.”

He also reiterated that until we know whether vaccines protect against all of the variants of concern and until the Canadian population has reached herd immunity, thought to be around 70 per cent, we will have to continue public health measures such as wearing masks, socially distancing and washing hands often.

Editor's note: This release is adapted from a press release issued by the American Thoracic Society.

Boston, Mass. - More than 91 percent of the world's population lives in areas that exceed air quality guide-lines recommended by the World Health Organization, and more people are impacted by worsening air quality each year. Ambient air pollution - including potentially harmful pollutants such as small particles and toxic gases emitted by industries, households, cars and trucks - has been shown to worsen viral respiratory infections. Now, new studies are showing a similar association between ambient air pollution and worse COVID-19 outcomes.

In a new commentary reviewing current research on the potential relationships among pollution, respiratory viruses and health disparities, physician-researchers at Beth Israel Deaconess Medical Center (BIDMC) dis-cuss several ways that the COVID-19 pandemic highlights the urgent need to address the global problem of air pollution and improve respiratory health and equity worldwide. The commentary appears in the Annals of the American Thoracic Society.

"A multitude of studies show that exposure to higher long-term ambient air pollution is associated with both increased risk of infection and death from COVID-19," said corresponding author Stephen Andrew Mein, MD, a physician in BIDMC's Department of Medicine. "Historically, air pollution has been linked with worse health outcomes, including higher mortality, due to other respiratory viruses like influenza. Now, new research on COVID-19 adds further evidence of the adverse effects of ambient air pollution and the urgent need to ad-dress the public health crisis of pollution."

In one of the most prominent studies modeling COVID-19 mortality Mein and colleagues reviewed, research-ers at the Harvard T.H. Chan School of Public Health found that each small (1 ?g/m3) increase in long-term fine inhalable particle (PM2.5) exposure was associated with an eight percent increase in mortality during the pandemic, per an examination of county level data. Another study concluded that air pollution has contributed 15 percent to COVID-19 mortality worldwide.

"The studies we reviewed evaluated whether long-term, ambient air pollution exposure that occurred years prior to the pandemic was associated with worse COVID-19 outcomes," said Mein, who is also an Instructor in Medicine at Harvard Medical School.

The exact mechanisms of the association between long-term pollution and poor COVID-19 outcomes are not fully known. However, scientists have suggested that long-term exposure to air pollution may impair the im-mune system, leading both to increased susceptibility to viruses and to more severe viral infections. Higher air pollution exposure -- a burden disproportionately shouldered by communities of color in the Unites States -- is also associated with higher rates of heart disease and metabolic disorders such as diabetes, which are known to be risk factors for severe disease and death from COVID-19. These long-term chronic effects occurred well in advance of the reported reductions in air pollution during the COVID-19 pandemic.

The authors noted that recent models predict that improved air quality (due to less travel and industrial activity) during the pandemic may have reduced morbidity and mortality from non-communicable diseases, but more study is necessary.

"Research evaluating associations between the dramatic reduction in ambient air pollution during global lock-downs and health care utilization for respiratory conditions would further confirm the impact of ambient air pollution on non-communicable diseases and the need to reduce air pollution to improve overall health," said Mary Rice, MD, physician in the Pulmonary, Critical Care & Sleep Medicine Department at BIDMC and senior author of the commentary.

"While the primary association between air pollution and COVID-19 outcomes has been generally consistent, there is still much research to be done," added Rice, who is also Assistant Professor in Medicine at Harvard Medical School. "In particular, there is a need for studies that adjust for individual-level risk factors, since cur-rent studies have been restricted to county or municipal-level exposure and outcome data. Research is also needed to evaluate whether air pollution contributes to the stark differences in COVID-19 outcomes among communities of color.

Racially and ethnically diverse communities are more likely to be located in areas closer to industrial pollution such as PM2.5 and nitrogen dioxide, and to work in types of businesses that expose them to more air pollution. These inequalities in residential and occupational air pollution exposure may be one of the causes of the stark disparities of the COVID-19 pandemic along racial and ethnic lines.

"The COVID-19 pandemic has highlighted the widespread health consequences of ambient air pollution, including acute effects on respiratory immune defenses and chronic effects that lead to higher risk of chronic cardiopulmonary disease and acute respiratory distress syndrome (ARDS)," said Mein. "These chronic health effects likely explain the higher COVID-19 mortality among those exposed to more air pollution. The pandemic has also provided a glimpse into the health benefits of cleaner air. COVID-19 is a wakeup call for the need to adopt stricter air quality standards and end our tolerance for pollution in disadvantaged neighborhoods. As part of our post-COVID-19 recovery, we must clean up the air to improve respiratory health and equality worldwide."

Cycling at moderate intensity during dialysis could drastically improve the heart health of patients with kidney failure and result in significant savings for the NHS, according to new research by the University of Leicester supported by the charity Kidney Research UK and National Institute for Health Research (NIHR) Leicester Biomedical Research Centre.

Patients in the CYCLE-HD study were offered 30 minutes of moderate intensity exercise on a specially adapted bicycle during their regular dialysis sessions. Dialysis can lead to long-term scarring of the heart, which can accumulate over time and lead to heart failure. The study set out to examine whether exercise could reduce these side-effects.

After six months, participants' hearts were assessed with an MRI scan and compared with pre-trial imaging. Patients who had cycled showed improvements in several aspects of heart health - their hearts were more like a 'normal' size, they had less scarring, and there was less stiffness of the major blood vessels.

Analysis of the study also demonstrated a saving in healthcare costs of more than £1,400 per patient which, when balanced against the cost of the exercise equipment, could result in significant savings for the NHS.

James Burton is a Professor of Renal Medicine and Honorary Consultant Nephrologist at the University Hospitals of Leicester NHS Trust, and was chief investigator on the study. He said:

"We know that being more active can help reduce the risk of heart disease, as well as helping to control weight, reduce blood pressure and cholesterol, and improve mental health.

"For all those reasons - but especially because the risk of heart disease is so high - keeping active is particularly important for people on dialysis. Unfortunately, by the time that someone has travelled to and from the dialysis unit, and spent four hours connected up to the dialysis machine, there's very little time to do anything else that day, and the reality is that this happens three times a week for most patients.

"The findings of this study offer significant improvements to the heart health of dialysis patients which may have a major impact on their outlook."

Lord Bethell, Minister for Innovation, said:

"Keeping active has a range of health benefits - both physical and mental - and the importance of exercise has become increasingly apparent over recent months with its impact on COVID-19.

"We have long been aware of the impact of exercise on other diseases and this research by the University of Leicester is testament to the ways we're constantly looking to improve people's health - through better understanding of conditions, faster diagnosis and improving treatment.

"Not only does this research show we can reduce the side effects of dialysis, but it could also mean a significant saving for the NHS."

Professor Jeremy Hughes, kidney doctor and chair of trustees at Kidney Research UK said:

"We are delighted to have supported this fascinating study, which shows how exercising while on dialysis can have so many benefits. Cycling can keep patients active and help to pass the long periods of time they spend attached to their dialysis machines.

"However, this study demonstrates that this simple intervention keeps their hearts healthy and offsets the major heart risk associated with kidney failure. We hope this research will lead to other studies examining how to roll it out to other dialysis units across the country."

Dialysis is a life-saving procedure for people living with kidney failure, removing waste products from the body. More than 24,000 patients in the UK typically undergo haemodialysis therapy three times a week at four hours each time.

A quarter of deaths among haemodialysis patients in the UK between 2009 and 2018 were as a result of cardiovascular disease, according to the UK Renal Registry.

Researchers will now examine the possibilities of a wider rollout of the scheme to benefit patients across the UK, and now forms part of The Renal Association's haemodialysis guidelines.

The CYCLE-HD study was undertaken by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre and supported by Kidney Research UK, with findings published in Kidney International.

As SARS-CoV-2 continues to spread in France, a thorough characterization of hospital care needs and of the trajectories of hospital patients, as well as how they have changed over time, is essential to support planning. This led scientists from the Mathematical Modeling of Infectious Diseases Unit at the Institut Pasteur and the University of Cambridge to develop a probabilistic model that can be used to analyze detailed patient trajectories based on 198,846 hospitalizations in France during the first nine months of the pandemic (from March to No-vember 2020). These findings were published in The Lancet Regional Health Europe on March 20, 2021.

This model takes into account variations in the age and sex of the patients over time, and explores changes in probabilities of ICU admission, death and hospital discharge, as well as variations in the length of hospital stays.

The scientists observed major changes in the age and sex of the patients hospitalized during the study period. In particular, the proportion of hospitalized patients aged over 80 varied be-tween 27% and 48% during the epidemic and was lower during the two waves. The proportion of women among the hospitalized patients varied between 45% and 53% during the epidemic.

The scientists also demonstrated that the outcome of hospitalized patients varied substantial-ly during the pandemic. For example, the probability of hospitalized patients being admitted to an ICU fell from 25.4% (24.4%-26.4%) to 12.6% (11.6%-13.6%) during the first four months (from March to June) in parallel with the decrease in case numbers, before rising to 19.3% (18.9%-19.7%) during the second wave. The probability of death followed a similar path, fall-ing from 24.9% (24%-25.9%) to 10% (8.7%-11.3%) after the first wave before increasing again to 18.6% (18.1%-19%) during the second wave. These trends were similar for both men and women.

"These major variations in the probabilities of ICU admission and death need to be taken into account when planning hospital care needs", explains Simon Cauchemez, Head of the Math-ematical Modeling of Infectious Diseases Unit at the Institut Pasteur and last author of the study.

"The reasons for these large-scale changes in patient mortality since the start of the pandem-ic remain unclear but are likely to represent a combination of changes in healthcare seeking behaviour by patients, changing strains on healthcare centres, as well as improvements in treatments as physicians have learnt more about the disease", concludes Noémie Lefrancq, a PhD student in the Department of Genetics at the University of Cambridge and first author of the study.

Heart failure and stroke are unusual diagnoses among younger people. But they are now clearly on the rise in men below the age of 40, according to a University of Gothenburg study. The scientists have found links to obesity and low fitness in the upper teens.

The present study, published in Journal of Internal Medicine, includes data on 1,258,432 men who, at an average age of 18.3 years, enlisted for military service in Sweden between 1971 and 1995.

Particulars of the men's weight, height and physical fitness on enlistment were merged with data in the National Board of Health and Welfare's National Patient Register and Cause of Death Register for the period 1991-2016. From when they enlisted, the men were thus monitored over a period exceeding 20 years.

The proportion of participants who were overweight at the time of enlistment, i.e. with a body mass index (BMI) of 25-30, increased from 6.6 to 11.2 percent between 1971 and 1995, while the proportion with obesity (BMI over 30) rose from 1.0 to 2.6 percent. During the same period, their fitness level at the time of enlistment also declined slightly.

"These factors -- that is, overweight, obesity and low fitness -- partly explain the large increase in heart failure we see in the study, and the rise in stroke as well," states David Åberg. An Associate Professor at Sahlgrenska Academy, University of Gothenburg, and specialist doctor at Sahlgrenska University Hospital, Åberg is the study's first author.

"It's pleasing to see, despite rising obesity, a fairly sharp fall in heart attacks among these younger men, and also their reduced mortality from cardiovascular diseases," he continues.

Heart-failure cases within 21 years of enlistment rose, according to the study, by 69 percent -- from 0.49 per 1,000 of the men who had enlisted in the first five years (1971-75) to 0.83/1,000 of those who enlisted in the last five (1991-95).

The number of stroke cases -- cerebral infarction and cerebral hemorrhage -- showed a similar trend. The increase for cerebral infarction was 32 percent, from 0.68 for the first five-year cohort to 0.9 per 1,000 for the last. For cerebral hemorrhage the rise was 20 percent, from 0.45 to 0.54 per 1,000.

In contrast, heart attacks within 21 years of enlistment fell by 43 percent, from 1.4 to 0.8 per 1,000, of the cohorts enlisting first and last respectively. The proportion of deaths from all cardiovascular disease also decreased, by 50 percent -- from 1.5 to 0.74 per 1,000.

The fact that the trends for cardiovascular diseases move in differing directions over time suggests that other, unknown factors are involved as well. According to the researchers, post-enlistment weight trends may be one such factor, but stress and drug use may be others. Especially for heart attacks, researchers believe that a sharp fall in smoking underlies the decline. The fact remains, however, that overweight and obesity are influential.

"We see that heart attacks would have decreased even more if it hadn't been for the rise in overweight and obesity. Our results thus provide strong support for thinking that obesity and, to some extent, low fitness by the age of 18 affect early-onset cardiovascular disease. So at societal level, it's important to try to get more physical activity, and to have already established good eating habits by adolescence, while being less sedentary," David Åberg concludes.

The full assembly of human chromosome 8 is reported this week in Nature.  While on the outside this chromosome looks typical, being neither short nor long or distinctive, its DNA content and arrangement are of interest in primate and human evolution, in several immune and developmental disorders, and in chromosome sequencing structure and function generally.

This linear assembly is a first for a human autosome - a chromosome not involved in sex determination. The entire sequence of chromosome 8 is 146,259,671 bases. The completed assembly fills in the gap of more than 3 million bases missing from the current reference genome.  

The Nature paper is titled "The structure, function and evolution of a complete chromosome 8."

One of several intriguing characteristics of chromosome 8 is a fast-evolving region, where the mutation rate appears to be highly accelerated in humans and human-like species, in contrast to the rest of the human genome.

While chromosome 8 offers some insights into evolution and human biology, the researchers point out that the complete assembly of all human chromosomes would be necessary to acquire a fuller picture.

An international team of scientists collaborated on the chromosome 8 assembly and analysis.  The lead author of the paper is Glennis Logsdon, a postdoctoral fellow in genome sciences at the University of Washington School of Medicine in Seattle. 

The senior author is Evan Eichler, professor of genome sciences at the UW School of Medicine and a Howard Hughes Medical Institute investigator. His group is noted for developing better methods for sequencing DNA and for analyzing mutational trends that may be important in research on primate evolution and neurological disorders.

In addition to the human chromosome 8 assembly, the project researchers also created high quality draft assemblies of the linking site at the waist of the chromosome, the centromere, in the chimpanzee, orangutan and macaque.  The data allowed the scientists to begin to chart the evolutionary history of the chromosome 8 centromere.

Almost like inspecting the depths of a geological site, the researchers observed, on a molecular scale, a layered, mirrored symmetry in how this centromere structure evolved from great ape ancestors. More ancient parts were pushed to the periphery, similar to making room for new material in the middle of a factory production line.

Other research institutions involved in the chromosome 8 assembly project include the Development Therapeutics Branch of the National Cancer Institute, the Genome Informatics Section of the National Human Genome Research Institute, the University of Bari, Italy; the Center for Algorithmic Biology at St. Petersburg State University, Russia; University of California, San Diego, Washington University in St. Louis, University of Pittsburgh, and the University of California, Santa Cruz.  Data were also generated with Oxford Nanopore Technologies and Pacific Biosciences long-read sequencing to resolve gaps in the telomere-to-telomere, or end-to-end, assembly of the chromosome.

Earlier research by a number of scientists had pointed to regions of chromosome 8 as being important both in the normal formation of the brain, as well as to some developmental variations, such as small head size or skull and facial differences.  Mutations on this chromosome have also been implicated in some heart defects, certain forms of cancer, premature aging syndromes, immune responses, and immune disorders like psoriasis and Crohn's disease.

However, the full sequencing of this and most other human chromosomes could not be attempted until recently because the technology and methods to wade through large areas of duplication and identical repeats had not become available. Putting together the puzzle accurately from short reads of DNA, for instance, would have been extremely difficult.

The chromosome 8 assembly achievement benefited from advances in long-read technologies, as well as from the availability of DNA material from hydatidiform moles. These are rare, abnormal growths in the placenta.

The full sequencing of chromosome 8 now provides information that might improve, for example, the understanding of what predisposes specific parts of the chromosome's DNA to microdeletions suspected in certain forms of developmental delay, brain and heart malformations, and autoimmune problems.

The researchers were also able to obtain more information on a part of chromosome 8 that contains some of the greatest copy-number variability among people.  The repeat unit can vary from 53 to 326 copies.

With the chromosome 8 assembly finished, researchers look forward to the world scientific community completing other human chromosome assemblies, and to new challenges in applying what has been learned to further studies of human genome sequencing.

Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis

Human dihydroorotate dehydrogenase (DHODH) is a viable target for the development of therapeutics to treat cancer and immunological diseases, such as rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS).

The authors designed and synthesized a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents. 2-Acrylamidobenzoic acid analog 11 was identified as the lead compound for structure-activity relationship (SAR) studies. The replacement of the phenyl group with naphthyl moieties improved inhibitory activity significantly to double-digit nanomolar range. Further structure optimization revealed that an acrylamide with small hydrophobic groups (Me, Cl or Br) at the 2-position was preferred. Moreover, adding a fluoro atom at the 5-position of the benzoic acid enhanced the potency. The optimization efforts led to potent compounds 42 and 53?55 with IC50 values of 41, 44, 32, and 42 nmol/L, respectively.

The most potent compound 54 also displayed favorable pharmacokinetic (PK) profiles and encouraging in vivo anti-arthritic effects in a dose-dependent manner.

ITHACA, N.Y. - Research shows people turn to religion in times of fear and uncertainty - and March 2020 was one of those times.

To find the impact of religion during the early days of the COVID-19 pandemic in the United States, Landon Schnabel, the Robert and Ann Rosenthal Assistant Professor of Sociology in the College of Arts and Sciences, analyzed responses from 11,537 Americans surveyed March 19-24, 2020, shortly after the World Health Organization declared COVID-19 a global health pandemic.

Religion protected mental health of members of several faith groups, Schnabel reports in the Journal for the Scientific Study of Religion, but also constrained crisis response among some of the same groups, ultimately undercutting the overall effectiveness of public health efforts to contain the virus.

"Religion limited the negative mental health impacts of the COVID-19 pandemic in March, with highly religious Americans and especially evangelicals experiencing less distress than more secular Americans," Schnabel wrote. "However, that mental health benefit came at the cost of less concern about and support for addressing an important real-world problem: saving lives during a pandemic."

According to Schnabel, "the most obvious explanation for this pattern is the politicization of the pandemic and the fact that ... Republicans and conservatives simply were not as concerned about the pandemic and less likely to think they needed to worry about social distancing, etc."

Intensely religious white people tend to hold conservative values and embrace Republican politics, Schnabel wrote - the same political positions that downplayed the threat of the virus, especially in the early days of the pandemic.

Schnabel based his conclusions on data from Pew Research's American Trends Panel (ATP), made available by the Cornell Roper Center for Public Opinion Research as part of a growing collection of public opinion data related to COVID-19.

The survey asked questions about mental distress, perceived health and economic threats posed by the pandemic, and opinions on public health restrictions and social distancing behaviors. It also collected data about religious affiliation and behavior, and about political party affiliation.

Schnabel's analysis confirmed a documented benefit of religion: increased mental health.

"Regularly attending and evangelical Americans did not experience as much increased distress during the early stages of COVID-19 as Americans who attended less regularly or who were not evangelical," he wrote. "This suggests that religion, typically implicated in rates of distress, mitigated the increased anxiety most Americans were feeling in the early days of the pandemic."

Schnabel's analysis also confirmed previous research documenting the close alignment of religion and politics in the U.S. "In the contemporary United States, religion has become politicized and is now viewed as entangled with conservative politics," he wrote.

"In sum, religion therefore could paradoxically buffer the hardship caused by the pandemic yet structure attitudes and orientations about public health and science in ways that ultimately increase it," Schnabel wrote.

It is within the power of religious people and faith organizations to glean mental health benefits of religion without endangering public health, Schnabel said.

"Religious organizations should consider how they can promote the things that are helpful for mental health and not promote anything harmful for physical health," Schnabel said, such as building community through virtual gatherings and providing virtual tools to provide psychological resources without risk of exposure. "The ideal scenario would be to figure out how to get the mental health benefits while avoiding the things that were unhelpful for containing the pandemic," he said.

The data for this study came from early in the pandemic, Schnabel wrote. "It remains to be seen the exact extent to which religion will continue to protect mental health as we enter the second year of the pandemic."

JUPITER, FL -- Damage to the autism-associated gene Dyrk1a, sets off a cascade of problems in developing mouse brains, resulting in abnormal growth-factor signaling, undergrowth of neurons, smaller-than-average brain size, and, eventually, autism-like behaviors, a new study from Scripps Research, Florida, finds.

The study from neuroscientist Damon Page, PhD, describes a new mechanism underlying the brain undergrowth seen in individuals with Dyrk1a mutations. Page's team used those insights to target the affected pathway with an existing medicine, a growth hormone. It restored normal brain growth in the Dyrk1a mutant mice, Page says.

"As of now, there's simply no targeted treatments available for individuals with autism spectrum disorders caused by DYRK1A mutations," Page says. "This represents a first step in evaluating a potential treatment that could be used in the clinic."

Their study appears Thursday in the journal Biological Psychiatry.

To track the effects of missing Dyrk1a genes, Jenna Levy, the paper's first author and a graduate student in Page's lab, engineered mice to have one or two broken copies of Dyrk1a in their developing brain tissue. The brains of both sets of mice developed abnormally, she found, displaying decreased brain size and number of neurons, as well as reduced number of other brain cells.

Downstream effects

The scientists also conducted "unbiased" proteomic studies, to see if the mutant mice had abnormally high or low levels of other unknown proteins that might impact brain development. Using a technique called "high-resolution tandem mass spectrometry coupled to liquid chromatography," they found that the Dyrk1a mutant mice had reduced levels of 56 cellular proteins, and increased levels of 33. Many of those were known autism risk genes, some implicated in sending growth signals, Levy says.

"The specific signaling cascades we found altered in Dyrk1a mutants are implicated in multiple causal mechanisms of autism," Levy says.

A computational biology technique called Ingenuity Pathway Analysis helped them find altered proteins. There were changes to those involved in nerve signaling, creation of synapses, and growth of axons, the long, insulated extensions that give neurons their distinct shape. Also, multiple forms of the protein Tau were depleted in the Dyrk1a mice.

"These data implicate signaling cascades that were previously not known to be altered by Dyrk1a mutations," Page says.

Many autism genes

At least 200 different high-confidence risk genes for autism spectrum disorders have been identified, Page says, but little has been known about their roles and relationships, complicating diagnosis and treatment development efforts.

Page estimates that fewer than 1 percent of people diagnosed with autism spectrum disorder carry Dyrk1a mutations. Half of those show autistic behavioral traits, and about 70 percent have short stature. But many more people with autism diagnoses display microcephaly, or smaller-than-average head circumference, around 1 in 20, he says.

"Importantly for treatment considerations, this study suggests there may be a point of convergence for multiple autism causes," Page says. "Abnormal activity of this pathway appears to be shared across various genetic causes of autism, pointing to the possibility of common molecular target for therapeutics."

Previously, Page's lab has found autism-linked mutations to a gene called Pten can cause an opposite effect, brain overgrowth, or macrocephaly.

"What we didn't know before is that the signaling disruptions that cause microcephaly, brain undergrowth, appear to be the flip side of the coin of the signaling disruptions that cause macrocephaly, brain overgrowth," Page says.

Because of that, they hypothesized that restoring growth signaling at a high level, using a known growth hormone, might rescue the brain undergrowth.

"We thought that treating with insulin-like growth factor 1, IGF-1, should increase the activity of the downstream signaling cascade, which should result in increased growth," Levy says. After treating Dyrk1a mice from birth to day 7, she found that was the case. The observed microcephaly improved, and under the microscope, the brain tissue showed normalized neuron growth.

Toward targeted treatments

Based on those results, more investigation is warranted on the potential for growth hormone treatment to benefit a minority of children with autism, those with Dyrk1a mutations, or related downstream mutations and manifestations, including microcephaly, Page says.

Many questions remain. Whether IGF-1 treatment in the newborn Dyrk1a mice might also improve autism-like behaviors in the mice is still under investigation, Levy adds. Also, it's still unclear whether there is a critical treatment window during mouse brain development, and if so, how large that window may be.

In humans, neural progenitor cells begin forming in the third week of pregnancy. By the seventh week, actual neuron production starts. It's a short window--neuron production in the billions is mostly finished by around the 20th week of gestation. As neurons are made, each migrates to its final destination in the forming brain. Once there, it starts making connections with other neurons, elongating and branching out, literally wiring the developing brain. Rapid brain development continues with experience and growth after birth.

Autism is a constellation of disorders with multiple causes, meaning that targeted, individualized treatments will be needed to assist people who seek them, Page says. Prevalence of autism diagnoses has been rising steeply since the 1990s. Research from the U.S. Centers for Disease Control and Prevention now estimates 1 in 59 children have an autism spectrum disorder. The mutations to Dyrk1a that cause autism appear to be sporadic, meaning they aren't typically inherited, but rather appear randomly, Page says.

Page stresses that the study is preliminary, not grounds for off-label use of IGF-1 as a possible autism treatment. He's often asked by families what they can do for their children diagnosed with autism. He suggests asking their doctor for a genetic testing as a first step.

"It helps with understanding of what's going on, it allows them to connect and find support, and also to be aware if clinical trials begin," Page says. "It's too soon for affected families to go to their pediatrician and say, 'Give my child this.' This is a first step in evaluating whether a potential treatment could be used in the clinic."

When you think of ways to treat opioid use disorder, you might think methadone clinics and Narcotics Anonymous meetings. You probably don't imagine stretches and strengthening exercises.

But Anne Swisher--professor at the West Virginia University School of Medicine--is working to address opioid misuse in an unconventional way: through physical therapy. She and her colleagues have enhanced physical therapy instruction at WVU to emphasize the profession's role in preventing and treating opioid use disorder.

"Students have different interests and passions within the profession, and they find their niche," said Swisher, a researcher and director of scholarship in the Division of Physical Therapy. "No matter what their passion is, there is a way they can make a difference, whether it's by preventing people from starting down the road of opioids--by minimizing pain medication and doing movement interventions--or whether it's by helping people in the recovery process become healthier overall."

Swisher and her team devised a model to show doctor of physical therapy students how key topics in their curriculum--such as women's health, pediatric care and sports therapy--could all address opioid use disorder in various ways.

Their model--which was published in prestigious rehabilitation journal Physical Therapy--is innovative because it goes beyond musculoskeletal issues and addresses how physical therapists can assist people across the lifespan, from neonatal to hospice settings. It also illustrates how physical therapists can help improve human movement across what Swisher calls the "whole addiction spectrum."

"In our curriculum, our students learn about all of these different aspects--what to do with somebody who's critically ill, the appropriate developmental milestones for children, how to help older people stay active--but it was really just a matter of connecting it all together," she said.

For instance, by making it easier for pregnant women to manage their aches and pains without opioids, physical therapists can help prevent neonatal abstinence syndrome in newborns. By combining special exercises with pharmacological treatment, they can reduce opioid use in patients after spinal surgery. And by promoting healthy physical activity in general, they can support people as they recover from opioid use disorder.

"I think it comes back to movement," Swisher said. "One of the catchphrases we like to use is, 'Motion is lotion for the joints.' And we know that regular physical activity releases the body's own opioid chemicals. That's the so-called 'runner's high' that makes us feel good. Physical therapists can partner with people to work through their barriers to becoming more physically active."

What are some of those barriers? Well, it depends. An overweight patient may find movement difficult because he has knee pain. A patient recovering from hip surgery may fear the pain of exercise so much that she avoids attempting it. And a new mom may find caring for her baby so overwhelming that even a walk around the block feels herculean.

"Pain is always a perception," Swisher said. "It is always influenced by your own experiences, your motivation. If you get a tattoo to celebrate something monumental, you're causing tissue damage, but you don't perceive that as painful as putting your hand on the stove accidentally. We're educating our students--and our colleagues--to understand that whole context working with pain."

As described in the article, she and her team also incorporated their model into the clinical rotations that DPT students complete in rural Appalachian communities. As part of their rotations, the students choose a topic to develop into an educational program for a specific population in their community. They research issues specific to that community and consider those issues when designing the program.

"So, you get a small group of students who love women's health," Swisher said. "Maybe they develop an exercise program for women who have had babies that might have chronic pelvic pain."

All of the programs are stored electronically so that as the students make their way through their rotations, they can access each other's programs and work with their own clinical supervisors to tailor them to the communities they're serving.

"I think when we're looking at any kind of healthcare provider going into these rural communities that are really struggling with addiction, you have to look at those psychosocial and emotional reasons why people might find a desire to escape some pain, whether they perceive it as physical pain or whether it becomes more of an emotional pain," Swisher said. "We have to consider how we as physical therapists interact with people as complex, bio-psychosocial individuals."

The complex, bio-psychosocial individuals who call Appalachia home have been disproportionately affected by the opioid crisis. Appalachians are more likely to die prematurely than people who live elsewhere in the United States, and opioid-related deaths are a main reason for this disparity, reports the Appalachian Regional Commission.

West Virginia, in particular, has been hit hard. In 2018, the state had the nation's highest rate of opioid-involved overdose deaths, according to the National Institutes of Health. That same year, healthcare providers in the state wrote 69.3 opioid prescriptions for every 100 West Virginians. The national average? Just 51.4.

Preparing the next generation of physical therapists to deal with opioid use disorder is important because "there's such a huge issue here in Appalachia, especially in rural communities," Swisher said.

"If you're a physical therapist, you don't need a special certification in opioid recovery to influence something across this whole addiction spectrum," she said. "Just do the things that you do as a physical therapist, in your area."