Culture

In a review paper published in Frontiers in Plant Science, scientists urge the importance of combining the knowledge harbored by farmers of diverse crop varieties - which is often overlooked by scientists - with high-tech breeding done in laboratories.

Authors argue that farmers' knowledge and high-tech breeding to improve crops can be effectively combined to unlock more resilient and nutritious food supplies in the face of climate threats. They say that involving farmers in crop improvement enhances the chance that new varieties will be adopted, making crop improvement more efficient.

"Modern breeding under a microscope in the lab can speed up breeding of 'elite' varieties able to provide significant yield increase," says Carlo Fadda, a co-author from the Alliance of Bioversity and International Center for Tropical Agriculture. "But are those varieties and traits most important to farmers? Do they plant them? On the other hand, traditional varieties can better withstand changing climatic conditions, but are these varieties high-yielding enough?"

This Seeds for Needs approach, first trialed in Ethiopia to speed up durum wheat breeding, has already yielded surprising results. When scientists took a selection of elite and traditional durum wheat varieties obtained from Ethiopia Biodiversity Institute (EBI) to farmers to get their feedback, traditional varieties outperformed elite ones, producing double the average national durum wheat yield while also resistant to major diseases.

"Rather than mass-producing seed to cope in a broad range of conditions, we need to find varieties for local contexts in order to maximize yields at each site," says Fadda. "Traditionally, farmers grow a portfolio of crops to withstand different conditions and make different products. Some will plant wheat for bread, for local-brewed beer, for injera - the local flatbread - to minimize their risk."

The 'Seeds for Needs' approach further integrates scientific rigor and cutting-edge breeding to fast-track climate-resilient traits and crop varieties. Combined with farmer selection of varieties, which can cope in field conditions, the result is a better-adapted food supply, more resilient to the impacts of the impending climate crisis, say authors.

"Climate change is a shifting target, and to address it we need a dynamic process," says Fadda. "This approach provides a constant injection of new material adapted to a broader set of conditions within one locality. With this approach, as climate change advances, there will always be well-adapted crop varieties for local conditions, bringing together high tech approaches and traditional knowledge."

Matteo Dell'Acqua, a co-author and geneticist at the Institute of Life Sciences, Scuola Superiore Sant'Anna, in Pisa in Italy, adds: "This approach shows the value of combining the most advanced genomics approaches with traditional knowledge of farmer communities. In this framework, modern breeding and crowd-sourcing methods can complement each other in supporting local adaptation of farming systems to the impacts of climate change."

With the advent of digital tools, the researchers say farmer 'citizen scientists' can provide adequate, reliable information identifying varieties with superior traits tolerant to climate-induced stress. Research conducted with farmers in Ethiopia, Honduras and India shows they are keen to be part of trials, to contribute to research or in exchange for advice.

In Ethiopia, two wheat varieties bred using the 'Seeds for Needs' approach have already been released four years faster than the average time required to release new varieties. Now, the approach is being used across Africa, Asia and Latin American and the Caribbean.

A druggable pocket in the SARS-CoV-2 Spike protein that could be used to stop the virus from infecting human cells has been discovered by an international team of scientists led by the University of Bristol. The researchers say their findings, published today [21 Sep] in the journal Science, are a potential 'game changer' in defeating the current pandemic and add that small molecule anti-viral drugs developed to target the pocket they discovered could help eliminate COVID-19.

SARS-CoV-2 is decorated by multiple copies of a glycoprotein, known as the 'Spike protein', which plays an essential role in viral infectivity. Spike binds to the human cell surface, allowing the virus to penetrate the cells and start replicating, causing widespread damage.

In this ground-breaking study, the team headed by Professor Christiane Schaffitzel from Bristol's School of Biochemistry and Professor Imre Berger from the Max Planck-Bristol Centre for Minimal Biology, used a powerful imaging technique, electron cryo-microscopy (cryo-EM), to analyse SARS-CoV-2 Spike at near atomic resolution. Enabled by Oracle high-performance cloud computing, a 3D structure of SARS CoV-2 Spike protein was generated allowing the researchers to peer deep inside the Spike identifying its molecular composition.

Unexpectedly, the research team's analysis revealed the presence of a small molecule, linoleic acid (LA), buried in a tailor-made pocket within the Spike protein. LA is a free fatty acid, which is indispensable for many cellular functions. The human body cannot produce LA. Instead, the body absorbs this essential molecule through diet. Intriguingly, LA plays a vital role in inflammation and immune modulation, which are both key elements of COVID-19 disease progression. LA is also needed to maintain cell membranes in the lungs so that we can breathe properly.

Professor Berger said: "We were truly puzzled by our discovery, and its implications. So here we have LA, a molecule which is at the centre of those functions that go haywire in COVID-19 patients, with terrible consequences. And the virus that is causing all this chaos, according to our data, grabs and holds on to exactly this molecule - basically disarming much of the body's defences."

Professor Schaffitzel explained: "From other diseases we know that tinkering with LA metabolic pathways can trigger systemic inflammation, acute respiratory distress syndrome and pneumonia. These pathologies are all observed in patients suffering from severe COVID-19. A recent study of COVID-19 patients showed markedly reduced LA levels in their sera."

Professor Berger adds: "Our discovery provides the first direct link between LA, COVID-19 pathological manifestations and the virus itself. The question now is how to turn this new knowledge against the virus itself and defeat the pandemic."

There is reason for hope. In rhinovirus, a virus causing the common cold, a similar pocket was exploited to develop potent small molecules that bound tightly to the pocket distorting the structure of the rhinovirus, stopping its infectivity. These small molecules were successfully used as anti-viral drugs in human trials and show promise for treating rhinovirus clinically. The Bristol team, based on their data, is optimistic that a similar strategy can now be pursued to develop small molecule anti-viral drugs against SARS-CoV-2.

Professor Schaffitzel said: "COVID-19 continues to cause widespread devastation and in the absence of a proven vaccine, it is vital that we also look at other ways to combat the disease. If we look at HIV, after 30 years of research what worked in the end is a cocktail of small molecule anti-viral drugs that keeps the virus at bay. Our discovery of a druggable pocket within the SARS-CoV-2 Spike protein could lead to new anti-viral drugs to shut down and eliminate the virus before it entered human cells, stopping it firmly in its tracks."

Alison Derbenwick Miller, Vice President, Oracle for Research, added: "Oracle for Research unites researchers and cloud computing to help bring about beneficial change for our planet and its people. SARS-CoV-2 and COVID-19 are causing global devastation, and research efforts to find vaccines and treatments cannot move quickly enough. We are so pleased that Oracle's high-performance cloud infrastructure enabled Professors Berger and Schaffitzel to examine the molecular structures of the coronavirus spike protein and make this powerful and unexpected new discovery that could help curb the pandemic and save lives."

September 21, 2020--(BRONX, NY)--The first study comparing the immune responses of adults and children with COVID-19 has detected key differences that may contribute to understanding why children usually have milder disease than adults. The findings also have important implications for vaccines and drugs being developed to curb COVID-19. The study was published today in Science Translational Medicine and was conducted by scientists at Albert Einstein College of Medicine, Children's Hospital at Montefiore (CHAM), and Yale University.

The study involved 60 adult COVID-19 patients and 65 pediatric COVID-19 patients (less than 24 years old) hospitalized at CHAM and Montefiore Health System between March 13 and May 17, 2020; 20 of the pediatric patients had the novel multi-system inflammatory syndrome (MIS-C). The patients' blood was tested for the presence of several types of immune cells, antibody responses, and the inflammatory proteins, known as cytokines, that immune cells produce.

Children with COVID-19 fared significantly better than adults. Twenty-two adults (37%) required mechanical ventilation compared with only five (8%) of the pediatric patients. In addition, 17 adults (28%) died in the hospital compared with two (3%) of the pediatric patients. No deaths occurred among pediatric patients with MIS-C.

"Our findings suggest that children with COVID-19 do better than adults because their stronger innate immunity protects them against SARS-CoV-2, the novel coronavirus that causes the disease," said co-senior author Betsy Herold, M.D., chief of infectious diseases and vice chair for research in the department of pediatrics at Einstein and CHAM. Kevan C. Herold, M.D., C.N.H. Long Professor of Immunology and of Medicine at Yale School of Medicine, was the other co-senior author on the study.

People have two types of immunity--innate and adaptive. Innate immunity, in which immune cells respond rapidly to invading pathogens of all kinds, is more robust during childhood. Adaptive immunity, the second type of immune response, is more specific and features antibodies and immune cells that target specific viruses or other microbes.

Compared with adult patients, pediatric COVID-19 patients in the study possessed significantly higher levels of certain cytokines associated with the innate immune response. This suggests that young people's more robust innate response protects them from developing acute respiratory distress syndrome (ARDS)--the hallmark of severe and often fatal COVID-19 cases. One cytokine in particular, known as IL-17A, was found at much higher levels in pediatric patients than in adults. "The high levels of IL-17A that we found in pediatric patients may be important in protecting them against progression of their COVID-19," said Dr. K. Herold.

Both pediatric and adult COVID-19 patients were found to make antibodies against the coronavirus' spike protein, which the virus uses to latch onto and infect cells. Those spike-protein antibodies include neutralizing antibodies, which block the coronavirus from infecting cells. Counterintuitively, the researchers found that neutralizing antibody levels in adult COVID-19 patients who died or required mechanical ventilation were higher than in those who recovered--and significantly higher than levels detected in pediatric patients.

"These results suggest that the more severe COVID-19 disease seen in adults is not caused by a failure of their adaptive immunity to mount T-cell or antibody responses," said Dr. K. Herold. "Rather, adult patients respond to coronavirus infection with an over-vigorous adaptive immune response that may promote the inflammation associated with ARDS."

The findings have important implications for COVID-19 therapies and vaccines. "Our adult COVID-19 patients who fared poorly had high levels of neutralizing antibodies, suggesting that convalescent plasma--which is rich in neutralizing antibodies--may not help adults who have already developed signs of ARDS," said Dr. B. Herold. "By contrast, therapies that boost innate immune responses early in the course of the disease may be especially beneficial."

As for vaccines, Dr. B. Herold notes that most vaccine candidates for protecting against SARS-CoV-2 infection are aimed at boosting neutralizing-antibody levels. "We may want to consider assessing vaccines that promote immunity in other ways, such as by bolstering the innate immune response," she said.

New research suggests that the impact of natural and vaccine-induced immunity will be key factors in shaping the future trajectory of the global coronavirus pandemic, known as COVID-19. In particular, a vaccine capable of eliciting a strong immune response could substantially reduce the future burden of infection, according to a study by Princeton researchers published in the journal Science Sept. 21.

"Much of the discussion so far related to the future trajectory of Covid-19 has rightly been focused on the effects of seasonality and non-pharmaceutical interventions [NPIs], such as mask-wearing and physical distancing,", said co-first author Chadi Saad-Roy, a Ph.D. candidate in Princeton's Lewis-Sigler Institute for Integrative Genomics. "In the short term, and during the pandemic phase, NPIs are the key determinant of case burdens. However, the role of immunity will become increasingly important as we look into the future."

"Ultimately, we don't know what the strength or duration of natural immunity to SARS-CoV-2 -- or a potential vaccine -- will look like," explained co-first author Caroline Wagner, an assistant professor of bioengineering at McGill University who worked on the study as a postdoctoral research associate in the Princeton Environmental Institute (PEI).

"For instance, if reinfection is possible, what does a person's immune response to their previous infection do?" Wagner asked. "Is that immune response capable of stopping you from transmitting the infection to others? These will all impact the dynamics of future outbreaks."

The current study builds on Princeton research published in Science May 18 that reported that local variations in climate are not likely to dominate the first wave of the COVID-19 pandemic and included many of the same authors, who are all affiliated with PEI's Climate Change and Infectious Disease initiative.

In the most recent paper, the researchers used a simple model to project the future incidence of COVID-19 cases -- and the degree of immunity in the human population -- under a range of assumptions related to how likely individuals are to transmit the virus in different contexts. For example, the model allows for different durations of immunity after infection, as well as different extents of protection from reinfection. The researchers posted online an interactive version of model's predictions under these different sets of assumptions.

As expected, the model found that the initial pandemic peak is largely independent of immunity because most people are susceptible. However, a substantial range of epidemic patterns are possible as SARS-CoV-2 infection -- and thus immunity -- increases in the population.

"If immune responses are only weak, or transiently protective against reinfection, for example, then larger and more frequent outbreaks can be expected in the medium term," said co-author Andrea Graham, professor of ecology and evolutionary biology at Princeton.

The nature of the immune responses also can affect clinical outcomes and the burden of severe cases requiring hospitalization, the researchers found. The key question is the severity of subsequent infections in comparison to primary ones.

Importantly, the study found that in all scenarios a vaccine capable of eliciting a strong immune response could substantially reduce future caseloads. Even a vaccine that only offers partial protection against secondary transmission could generate major benefits if widely deployed, the researchers reported.

Factors such as age and superspreading events are known to influence the spread of SARS-CoV-2 by causing individuals within a population to experience different immune responses or transmit the virus at different rates. "Our models show that these factors do not affect our qualitative projections about future epidemic dynamics," said Bryan Grenfell, the Kathryn Briger and Sarah Fenton Professor of Ecology and Evolutionary Biology and Public Affairs and an associated faculty member in PEI. Grenfell is a co-senior author on the paper with C. Jessica Metcalf, associate professor of ecology and evolutionary biology and public affairs and also a PEI associated faculty member.

"As vaccine candidates emerge, and more detailed predictions of future caseloads with vaccination are needed, these additional details will need to be incorporated into more complex models," Grenfell said.

The study authors also explored the effect of "vaccine hesitancy" on future infection dynamics. Their model found that people who decline to partake in pharmaceutical and non-pharmaceutical measures to contain the coronavirus could nonetheless slow containment of the virus even if a vaccine is available.

"Our model indicates that if vaccine refusal is high and correlated with increased transmission and riskier behavior such as refusing to wear a mask, then the necessary vaccination rate needed to reach herd immunity could be much higher," said co-author Simon Levin, the James S. McDonnell Distinguished University Professor in Ecology and Evolutionary Biology and an associated faculty member in PEI. "In this case, the nature of the immune response after infection or vaccination would be very important factors in determining how effective a vaccine would be."

"When so much uncertainty in the underlying processes exists, it can be challenging to make accurate projections about the future," Grenfell said. "We argue in this study that ultimately, a family of both simple and more complex models is the best way to proceed under these circumstances. Comparing the predictions of these models carefully and then coming up with a carefully averaged picture of the future -- as with weather prediction -- can be very helpful."

One of the main takeaways of the study is that monitoring population-level immunity to SARS-CoV-2, in addition to active infections, will be critical for accurately predicting future incidence.

"This is not an easy thing to do accurately, particularly when the nature of this immune response is not well understood," said co-author Michael Mina, an assistant professor at the Harvard School of Public Health and Harvard Medical School. "Even if we can measure a clinical quantity like an antibody titer against this virus, we don't necessarily know what that means in terms of protection."

"Studying the effects of T-cell immunity and cross-protection from other coronaviruses are important avenues for future work," Metcalf said.

Researchers who adapted standard epidemiological models to explore how the COVID-19 pandemic trajectory might unfold in the next five years report diverse scenarios ranging from recurring severe epidemics to elimination. Their work emphasizes how dependent the future course of the pandemic is on the nature of the adaptive immune response to this virus and on the efficacy of future potential vaccines. The duration and severity of future COVID-19 cases will depend on the strength of both natural and vaccine-derived immunity against the SARS-CoV-2 pathogen. However, there is still uncertainty about both. Here, to explore how variations in immune responses could impact the magnitude and timing of COVID-19 cases in the next five years, Chadi Saad-Roy and colleagues adapted a series of standard epidemiologic models of the spread of infection (the SIR and SIRS models, respectively). They used these adapted models to evaluate results of four future scenarios that consider different outcomes for the nature of the adaptive immune response to SARS-CoV-2 infection, the effect of transmission rate seasonality, the adoption of non-pharmaceutical interventions, and the availability and effectiveness of a vaccine. Depending on these variations, dramatically different immunity landscapes and burdens of critically severe cases could emerge, they say, ranging from sustained epidemics to near elimination. The results underscore that understanding the immunology of secondary infection - which impacts the number of those susceptible to the virus - is critical. They also reveal how the pandemic trajectory will be substantially altered by mass deployment of vaccines, though, this is strongly dependent on vaccine efficacy. Their work also shows that relying on the status of infection of an individual as the main "observable" during an ongoing epidemic is not sufficient to characterize the complex immune landscape generated by the pandemic. Regular testing of antibody presence and correlates of protection such as T cell immunity are critical, to accurately characterize population-level natural and vaccinal immunity to this pathogen. The authors note that in order to focus on immune dynamics, they made several simplifying assumptions.

A comparison of children and adults hospitalized with COVID-19 reveals pediatric patients, who had better outcomes and shorter hospital stays, displayed altered immune responses and more limited production of antibodies against infection. While these preliminary findings are descriptive and do not establish a causative relationship, the study hints that these immune differences could help explain why children have consistently developed less severe cases of COVID-19 than adults during the pandemic. COVID-19 has caused more than 29 million cases and 929,000 deaths globally, and high hospitalization rates from the disease have overwhelmed healthcare systems in many cities. Clinicians have noted that children and young people have milder symptoms and rarely progress to life-threatening respiratory complications - the opposite of what has been observed with other viral infections such as respiratory syncytial virus. However, the basis for these clinical differences has been unclear. Carl Pierce and colleagues compared data from 65 children and youths (under 24 years of age) and 60 adults hospitalized with COVID-19 in metropolitan New York. The infected children - including some who had the emerging complication known as multisystem inflammatory syndrome - were less likely to require mechanical ventilation (8% vs 37%) and had lower mortality (3% vs 28%) than the adults. However, adults showed higher antibody production and T cell responses to the viral spike protein, but lower amounts of inflammatory molecules like IL-17A and IFNγ that are involved in innate immunity. "The results provide new insights into potential mechanisms that may contribute to age-related differences in disease resolution ... and may have implications for ongoing efforts with convalescent plasma and the development of therapeutic antibodies," Pierce et al. write.

WASHINGTON, D.C. - September 21, 2020 - Although people of any age can become infected with SARS-CoV-2, the virus that causes COVID-19, elderly patients face a higher risk of severity and death than younger patients. New research comparing the immune response among age groups, published this week in mBio, an open-access journal of the American Society for Microbiology, may help explain why. Older patients with the disease have lower frequencies of the immune cells needed to expel the virus from the body, the researchers found.

"Elderly people have more severe diseases compared to young people, and we found that the cytotoxic part of immune control is not as efficient to respond to the virus in older people," said virologist Gennadiy Zelinskyy, Ph.D., at the University Hospital Essen, in Germany. Zelinskyy led the new study.

He and his colleagues analyzed blood samples from 30 people with mild cases of COVID-19 to observe how T cells, which are necessary for recognition and elimination of infected cells, respond during SARS-CoV-2 infection. Patient ages ranged from the mid-20s to the late 90s. In all patients, the investigators found that acute SARS-CoV-2 infections led to lower numbers of T cells in the blood of the patients, compared to healthy individuals.

This reduction has been one of many unwelcome surprises from COVID-19, said Zelinskyy. Most viruses, once inside the body, trigger an uptick in the immune system's expansion of T cells. These include "killer" T cells, which play a critical role in eradicating virus-infected cells. They produce cytotoxic molecules that destroy infected cells in the body. But if a person's immune system produces fewer of these T cells, said Zelinskyy, it will be less successful at fighting off a viral infection.

In the COVID-19 patient group studied by Zelinskyy and his colleagues, the researchers similarly found that the number of CD8+ T cells producing cytotoxic molecules in response to virus diminished with increased age, and that reduction was significantly higher, on average, in patients over 80. Moreover, the "killer" T cells from patients aged 80-96 produced cytotoxic molecules at a lower frequency than similar cells from younger patients.

The SARS-CoV-2 virus attaches to cells in the nose or mouth. From there, it may spread to the lungs and move on to other organs, triggering a life-threatening infection. "Cytotoxic T cells really fight for control during this acute phase of infection," Zelinskyy said. If an elderly patient's immune system produces fewer killer T cells, and these cells are inadequately armed, he said, they may be mounting an insufficient defense against SARS-CoV-2. The viral particles can continue to spread and, as a result, the infection worsens.

The new data suggest that cytotoxic T cells play a key role in control of early infections, but Zelinskyy cautioned that it's too soon to know if that connection can be harnessed to design an effective immunotherapy that uses these cells. In previous studies on viral infections in mice, his group found that a checkpoint inhibitor--an immunotherapy that activates killer T cells and effectively releases the brakes on the immune system--improved virus control at first but had the potential to later cause damage to the lungs and other organs. Further studies are warranted, he said, to better understand the potential risks and benefits of interfering with T cells as a way to control SARS-CoV-2 and other viruses.

Intolerances to chemicals, foods and drugs impact 8%-33% of individuals, studies suggest, yet few people are screened for it at their doctors’ offices.

To address this and increase awareness of chemical intolerance, researchers at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) developed and validated a three-question, yes-or-no survey that primary care providers, allergists, dermatologists and other specialists can incorporate into patient visits. The survey, called the Brief Environmental Exposure and Sensitivity Inventory, or BREESI, can also be used by researchers and patient groups, and for epidemiological studies in exposed populations.

Sept. 16 in the journal PLOS ONE, the researchers reported that the BREESI accurately predicts scores on a comprehensive 50-question survey called the Quick Environmental Exposure and Sensitivity Inventory (QEESI). The QEESI, which the UT Health San Antonio group introduced online in 2014, is available at no charge to patients and clinicians. Researchers worldwide are using it, making it the new standard for measuring chemical intolerance.

“People who become ill from exposures to chemicals, such as bleach, disinfectants, pesticides, mold, combustion products or volatile organic compounds (VOCs), have higher scores on the QEESI,” said Claudia S. Miller, MD, MS, professor emeritus in the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio. “But the QEESI is a little long for rapid screening.”

Carlos Jaén, MD, PhD, professor and chairman of the Department of Family and Community Medicine at the university, suggested that the team develop and test a brief screening questionnaire.

Predictive value

The BREESI focuses on three different exposure categories: chemical inhalants, drugs/medications and foods/food additives. The research team enrolled 293 volunteers from a university-based primary care clinic and online to complete the BREESI and QEESI.

“The BREESI showed high sensitivity and specificity,” according to the authors.

Of respondents who said “yes” to all three BREESI questions, 90% had scores “very suggestive” of chemical intolerance.
Of those who said “no” to all three BREESI questions, 95% had scores “not suggestive” of chemical intolerance.

Ray Palmer, PhD, professor of family and community medicine at UT Health San Antonio, said the team is currently validating the BREESI in larger, population-based studies in the U.S. and internationally.

“Only a minute or two is required to administer the BREESI, making routine evaluation of chemical intolerance feasible for medical and surgical workups, epidemiological investigations, and before-and-after studies of environmental exposure events such as the Gulf War burn pits or 9/11,” Dr. Miller said.

California wildfires

Currently, Dr. Miller is concerned that misuse of disinfectants to combat COVID-19 may be endangering susceptible individuals. Combustion products from the California wildfires are another concern. Outgassing of volatile organic chemicals (VOCs) from new construction, remodeling and “sick” buildings frequently triggers chemically intolerant individuals’ symptoms.

“Quick screening questionnaires are used routinely in clinics today, e.g., for quality of life or substance abuse, or reactions to antibiotics or latex, and we believe chemical intolerance also needs to be assessed routinely, given its high prevalence,” Dr. Palmer said.

Pregnancy and chemicals

It is especially important for expectant mothers to know whether they are chemically intolerant, so that they can work with their physicians and families to eliminate exposures that may affect them and their babies, Dr. Palmer said.

“We encourage physicians to use the BREESI to identify chemically intolerant mothers whose children may be at increased risk for ADHD and autism,” Dr. Palmer said. ADHD is short for attention deficit hyperactivity disorder.

The Marilyn Brachman Hoffman Foundation, for which Dr. Miller is environmental medicine consultant, funded the research. “Our goal is to improve everyone’s understanding of chemical intolerance through research, education, and outreach,” Dr. Miller said. “Educating health care workers is a top priority. We have now given them a useful tool.”

Both the BREESI and the QEESI are available online at no charge. Researchers should contact the TILT Research Program for permission to use these surveys in their studies. TILT is short for Toxicant-Induced Loss of Tolerance.

Three questions for identifying chemically intolerant individuals in clinical and epidemiological populations: The Brief Environmental Exposure and Sensitivity Inventory (BREESI)

Raymond F. Palmer, Carlos R. Jaén, Roger B. Perales, Rodolfo Rincon, Jacqueline N. Forster, Claudia S. Miller

First published: Sept. 16, 2020, PLOS ONE

https://doi.org/10.1371/journal.pone.0238296

# # #

The Long School of Medicine at The University of Texas Health Science Center at San Antonio is named for Texas philanthropists Joe R. and Teresa Lozano Long. The school is the largest educator of physicians in South Texas, many of whom remain in San Antonio and the region to practice medicine. The school teaches more than 900 students and trains 800 residents each year. As a beacon of multicultural sensitivity, the school annually exceeds the national medical school average of Hispanic students enrolled. The school’s clinical practice is the largest multidisciplinary medical group in South Texas with 850 physicians in more than 100 specialties. The school has a highly productive research enterprise where world leaders in Alzheimer’s disease, diabetes, cancer, aging, heart disease, kidney disease and many other fields are translating molecular discoveries into new therapies. The Long School of Medicine is home to a National Cancer Institute-designated cancer center known for prolific clinical trials and drug development programs, as well as a world-renowned center for aging and related diseases.

The University of Texas Health Science Center at San Antonio, also referred to as UT Health San Antonio, is one of the country’s leading health sciences universities and is designated as a Hispanic-Serving Institution by the U.S. Department of Education. With missions of teaching, research, patient care and community engagement, its schools of medicine, nursing, dentistry, health professions and graduate biomedical sciences have graduated more than 37,000 alumni who are leading change, advancing their fields, and renewing hope for patients and their families throughout South Texas and the world. To learn about the many ways “We make lives better®,” visit www.uthscsa.edu.

Journal

PLoS ONE

DOI

10.1371/journal.pone.0238296

Boston, Mass. - As electronic medical records (EMR) become ubiquitous in health care settings, scientists are increasingly turning to electronic-based recruitment methods to encourage participation in clinical trials. However, little is known about how this use of technology compares to more traditional clinical trial recruitment strategies, and some researchers worry that an overreliance on technology has the potential to exclude an eligible and interested diverse participant population.

In a new study published in the journal Clinical Trials, researchers led by Stephen Juraschek, MD, PhD, Assistant Professor of Medicine at Beth Israel Deaconess Medical Center (BIDMC) and Hailey Miller, RN, PhD, Postdoctoral Associate at Duke University School of Nursing, compared four electronic-based recruitment methods and four traditional recruitment methods to determine how different strategies may impact enrollment of groups traditionally under-represented in the medical literature.

"Black Americans are under-represented in clinical trials -- something I'm reminded of every time I counsel Black patients using data from largely white adults," said Juraschek. "Electronic medical records hold tremendous promise to offer patients with relevant conditions the opportunity to participate in clinical trials. However, the impact of electronic-based recruitment methods on participant demographics was unknown."

Juraschek and colleagues used a variety of direct recruitment approaches, both electronic and traditional, to identify adults with gout for a clinical trial examining the links between diet and gout. The team used EMR records to identify prospective enrollees, and messaged them through patient portals -- secure online medical messaging services providers use to communicate with patients. They also used non-targeted approaches such as community mailings and advertisements on social media and in newspapers.

After calculating the response rates, cost efficacy and demographic characteristics of eventual enrollees generated by the various strategies, Juraschek and colleagues found important demographic differences in how white and Black adults enrolled in the study. For example, two-thirds of Black participants had been identified through the electronic medical record but did not have an active patient portal. Instead, these enrollees learned about the study through a brochure sent by mail. Black participants otherwise would not have found out about the trial, which was pertinent to their health condition.

These findings build on Juraschek and Miller's previous research that demonstrated that whites disproportionately use patient portals. While the use of patient portals for recruitment may boost overall enrollment in clinical trials, Juraschek said, overdependence on electronic recruitment could perpetuate the underrepresentation of Black patients in clinical research.

Ultimately, the researchers determined that a hybrid strategy using EMRs to identify patients, followed up with postal mailings to potential enrollees yielded the best results. The hybrid outreach method was both cost-effective and increased participation of underrepresented groups, including Black participants and women.

"All patients have the right to be offered medical therapies informed by studies that represent them," said Juraschek, who is also an Instructor of Medicine at Harvard Medical School. "These findings also demonstrate the importance of a range of recruitment approaches to enroll a representative study population."

BOSTON - New research suggests when the COVID-19 pandemic is slowing, low-cost, recurring screening of asymptomatic people - at an expense of approximately $3 or less per test every two weeks - could decrease COVID-19 infections and deaths and be cost-effective. When the pandemic is surging, screening can be cost-effective when done more often, even if tests costs are higher. The report - led by researchers at Massachusetts General Hospital (MGH) - was recently published in Clinical Infectious Diseases.

COVID-19 testing refers generally to testing of people with symptoms of the illness, while screening refers to testing of individuals who do not have symptoms of the infection. In the United States, restricted testing capacity early in the pandemic led states such as Massachusetts to test only severely symptomatic people and those with a known exposure to someone with COVID-19. However, making COVID-19 testing available to all people with symptoms suggestive of the illness, as well as expanding to screening programs for the entire population - including those who are without symptoms - could reduce hospitalizations and deaths, allowing for safe resumption of economic and social activity.

"Massachusetts experienced a major COVID-19 outbreak beginning in March 2020, and while the outbreak is now under reasonably good control, questions remain about how to optimally deploy COVID testing, both in our current situation and in other settings - and communities - where new infections continue to rise," says Anne Neilan, MD, MPH, investigator in the MGH Divisions of General Pediatrics and Infectious Diseases and the Medical Practice Evaluation Center, who led the study. "While some have argued testing must be highly sensitive to be of value, others suggest that sensitivity can be sacrificed if tests are rapid, low-cost, frequent and widely available."

The study used a dynamic transmission model developed by members of the research team (the "CEACOV model") to analyze the outcomes anticipated from several different strategies for COVID-19 testing and screening for the entire population of Massachusetts, using laboratory-based polymerase chain reaction (PCR) tests. The PCR test uses a sample taken from the nose or mouth (usually a nasal swab or a saliva sample), which is then sent to a laboratory that tests for the virus causing COVID-19. The model-based analysis revealed that repeated screening of the entire population would lead to the most favorable clinical outcomes, preventing the greatest number of infections, hospitalizations, and, ultimately, deaths. This was true in a wide range of scenarios, ranging from decreasing to rapidly rising numbers of new cases per day. Such a screening strategy could also be cost-effective, depending on the cost of the test and the frequency of screening.

"Based on the prices that most laboratories are now charging for the PCR test, with our current levels of new COVID-19 cases in Massachusetts, the most cost-effective strategy remains testing only people with symptoms of COVID-19. Importantly, for Massachusetts as of now, this includes testing all people with symptoms, and not only people whose symptoms are severe," says study co-senior author Andrea Ciaranello, MD, MPH, investigator in the Division of Infectious Diseases at MGH. "However, in locations where cases are rising, regular screening of the entire population, while expensive, will actually be of very good value. This is true even at current testing costs around $50 and will be truer if test costs can be brought down substantially. There are creative ways to bring tests costs down; for example, using emerging techniques such as less expensive reagents, pooling of specimens in the lab, or carefully allocating unused testing capacity across cities or regions."

"When the pandemic is slowing, if testing costs can come down to $5 or less, repeat screening of people without COVID symptoms would decrease infections and deaths, and be cost-effective," adds Neilan. "Our data suggest that even now, expanding testing and screening capacity must remain a focus of national efforts." Because the study modeled the use of the laboratory-based PCR tests, the investigators did not evaluate the possible use of even less sensitive and less expensive tests, such as rapid tests used on-site at healthcare facilities (like urgent care locations), schools, or places of employment. Several such tests have been brought to market but are not yet widely available for use in these settings.

Adds Ciaranello, "It is important to note that these strategies involve repeated screening. Screening a group of people just one time, while an interesting snapshot, is an approach that will miss many people who will become able to infect others in the future. Because of this, we also found that screening just once was a less efficient use of healthcare resources under most circumstance than strategies using repeat testing."

"There is also a price to not being able to rapidly deploy testing," says Nielan. "Early in the pandemic, we struggled to provide testing even for people with symptoms of COVID-19. If expanded PCR testing had been widely available in Massachusetts from April to May 2020, our model suggests that more than 100,000 infections and approximately 100 deaths would have been averted during that month alone."

"Expanding testing and screening capacity will require careful logistical planning, and also responsiveness to changes in the numbers of new infections that we are seeing. This needs to be a priority for policymakers seeking to utilize available resources in the most efficient way," says Ciaranello.

It is well understood that mortality rates increase with age. Whether you live in Tokyo, rural Tennessee or the forests of Papua, New Guinea, the older you are, the more likely you are to succumb to any number of different ailments.

But how, exactly, do our bodies weather with age, and to what extent do people around the word experience physiological aging differently?

In a paper published in a special issue of the journal Philosophical Transactions of the Royal Society B, a team of anthropologists that includes Michael Gurven, a professor of anthropology at UC Santa Barbara and chair of the campus's Integrative Anthropological Sciences Unit, and Thomas Kraft, a postdoctoral researcher in the same department, construct and compare a composite measure of "physiological dysregulation" among human populations and other species. The themed issue explores the evolution of aging among primates.

Physiological dysregulation refers to the wearing down of the body's ability to bounce back from stress, damage or other adversity. Examples include how one's body might gradually become less able to properly regulate blood sugar, or it might more likely mount an inappropriate immune response that doesn't dissipate when the threat is gone (thereby damaging the body's own cells). This decline in resilience is often considered fundamental to aging.

"We're only now able to start piecing together what physiological aging looks like holistically in subsistence populations of foragers and farmers," said Kraft, the paper's lead author. "We first built a comprehensive metric of physiological dysregulation in humans, then compared it to other primates. It's not just the case that adult mortality rates are lower in humans; rates of physiological dysregulation are much slower in humans, too."

For nearly two decades, the Tsimane Health and Life History Project has been collecting a large number of measures of health and aging (referred to as biomarkers) among the Tsimane, an indigenous population of forager-horticulturists in the Bolivian Amazon. These range from the typical measures that might be taken during a regular physical exam -- blood pressure, cholesterol and blood glucose level -- to indicators such as grip strength, various immune markers for inflammation and bone mineral density.

Overall, the current study includes 40 biomarkers among 5,658 adults spread across 22,115 observations. "This makes it one of the only comprehensive longitudinal studies of health in a population living a vastly different lifestyle than the urban, industrialized countries, where most studies occur," said Kraft.

"While any single biomarker gives a snapshot of just one small part of health, what we did was to combine information from many biomarkers simultaneously -- both the levels of these markers and the extent to which they are linked together -- into a single metric," he continued. "This summary metric gives a holistic portrait of one's 'biological age,' by measuring how 'strange' one's combined biomarkers are relative to a healthy subset of the population."

Noted Gurven, co-director of the Tsimane Health and Life History Project, "In the U.S. and many other countries today, we're more likely to die of heart disease, cancer, diabetes and other 'chronic diseases of aging.' But among the Tsimane and other populations living similar lifestyles, these chronic diseases are rare. Does physiological dysregulation occur at the same rate in this very different context?"

To answer this question, the team compared Tsimane with other human populations. "Where adult mortality rates are high, we might expect that aging of our bodies occurs more quickly, tracking closely the higher increase in mortality with age," Gurven explained. "Another possibility -- and a goal for many of us -- is to maintain healthy bodies for as long as we can, and then have everything fall apart close to the eventual timing of our demise."

The researchers found that despite a lifestyle vastly different from that of urban, post-industrialized populations such as those in the United States and Italy, and despite higher mortality rates throughout adulthood, Tsimane adults show only marginally higher rates of increase in physiological dysregulation among the Tsimane.

"Our first glimpse suggests a broad species-typical pattern of physical aging across environments and cultures," said Gurven. "That's a little surprising because the Tsimane have very low levels of late-age chronic diseases. But the Tsimane are exposed to harsher conditions, including strenuous labor tending fields, tropical diseases and minimal access to health care."

Added Kraft, "We also found similarities in physiological dysregulation among Tsimane women and men, despite evidence in many populations showing that men typically age faster and are more likely to die than women at most ages."

As Gurven noted, it's impossible to understand dysregulation and aging without knowing how different parts of the body function over time. "And to date, we have had little understanding of what that looked like in a population like the Tsimane," he said. "Yet the conditions we find ourselves in today, where over half of the global population lives in cities, is just a minor blip in the long history of our species. Groups like the Tsimane offer some of the best insight for our understanding of aging prior to industrialization and urbanization."

All that being said, the researchers are quick to acknowledge that their index is still just a statistical composite. "It's not a complex network model showing how everything is related to everything else," Gurven said. What's amazing, he added, is that our global estimates of physiological dysregulation don't change much once the information from roughly 15 biomarkers are integrated.

"Additional biomarkers tell you little, and it may not even matter which biomarkers you look at once you hit about 20. That seems to suggest that we're capturing something about the whole system," he explained. "And any single biomarker is only weakly correlated with our global index. But we'll learn much more about what it means and how important it might be once we can link dysregulation to useful outcomes, like functional performance, disease states and the likelihood of dying."

The reactive and piecemeal approach historically used to manage beaches in Hawai'i has failed to protect them. If policies are not changed, as much as 40% of all beaches on O'ahu, Hawai'i could be lost before mid-century, according to a new study by researchers in the Coastal Geology Group at the University of Hawai'i (UH) at Mānoa School of Ocean and Earth Science and Technology (SOEST).

In an era of rising sea level, beaches need to migrate landward, otherwise they drown. Beach migration, also known as shoreline retreat, causes coastal erosion of private and public beachfront property. Shoreline hardening, the construction of seawalls or revetments, interrupts natural beach migration--causing waves to erode the sand, accelerating coastal erosion on neighboring properties, and dooming a beach to drown in place as the ocean continues to rise.

The team of scientists, led by graduate researcher in the SOEST Department of Earth Sciences Kammie Tavares, assessed the shoreline around O?ahu that would be most vulnerable to erosion under three scenarios of sea level rise--all estimated to occur before, and shortly after mid-century.

They identified the location and severity of risk of shoreline hardening and beach loss, and a potential timeline for the increase in erosion hazards. The most threatened properties fall into an "administrative erosion hazard zone," an area likely to experience erosion hazards and qualify for the emergency permitting process to harden the shoreline.

"By assessing computer models of the beach migration caused by 9.8 inches (0.25 meters) of sea level rise, an amount with a high probability of occurring before mid-century, we found that emergency permit applications for shoreline hardening to protect beachfront property will substantially increase," said Tavares.

According to co-author Dr. Tiffany Anderson, Assistant Researcher in the Department of Earth Sciences, "We determined that almost 30 percent of all present-day sandy shoreline on O'ahu is already hardened, with another 3.5 percent found to be so threatened that those areas qualify for an emergency permit today. Our modeling indicates that, as sea level rises about 10 inches (0.25 meters) by mid-century, an additional nearly eight percent of sandy shoreline will be at risk of hardening--meaning at that point, nearly 40% of Oahu's sandy beaches could be lost in favor of hardened shorelines."

"In another study published in 2018, we showed that accelerated erosion on neighboring properties, called flanking, usually leads to additional shoreline hardening, and condemnes entire beaches," said co-author Dr. Chip Fletcher, Associate Dean and Professor in SOEST. "It is clear that management decisions made today, and during the careers of most of today's natural resource managers, will be critical in determining if future generations will inherent a healthy shoreline, or one that has been ruined by seawalls, and other types of shoreline hardening."

Coastal erosion is inevitable when sea level is rising and global mean sea level has been rising for decades and is accelerating. The Intergovernmental Panel on Climate Change has projected continued sea level rise for many centuries, even if greenhouse gas emissions are reduced or stopped altogether. However, economists are projecting that greenhouse gas emissions will likely continue into mid-century and we will see more years like 2019 when the use of fossil fuels rose faster than the use of renewable forms of energy.

"Despite these facts, we continue to see shoreline hardening as the preferred policy choice, largely because management agencies have failed to develop assisted transition plans for beachfront landowners who are caught in a tightening vice because of accelerating sea level rise," said Fletcher. "In fact, directly to the contrary, beachfront lands continue to be sold to unwitting buyers with no appreciation for the expensive and frustrating situation they are entering into."

"Because coastal zone management laws continue to allow hardship variances in this era of rising sea level, despite widespread knowledge that seawalls kill beaches under these conditions, the same legal system designed to protect public trust lands, is responsible for destroying them," according to Fletcher. "Government agencies must develop creative and socially equitable programs to rescue beachfront owners and free the sandy ecosystem so that it can migrate landward as it must in an era of rising seas. It is urgent that options are developed soon for beachfront landowners and resource managers to avoid further destructive management decisions."

"Beaches are critical ecosystems to native plants and animals, offer protection from storms, are an essential cultural setting, and attract tourists, who are important for Hawai'i's current economy," added Tavares. "This research shows that conversations on the future of our beaches and how we will care for them must happen now rather than later, if we are to protect our sandy beaches."

Indigenous self-determination, leadership and knowledge have helped protect Indigenous communities in Canada during the coronavirus disease 2019 (COVID-19) pandemic, and these principles should be incorporated into public health in future, argue the authors of a commentary in CMAJ (Canadian Medical Association Journal)
.

Indigenous communities in Canada have experienced lower rates of infection and lower death rates from COVID-19 than the general population despite significant differences in social determinants of health, such as adequate housing, access to clean water and healthy food as well as income disparities. First Nations people living on reserve had a COVID-19 case rate 4 times lower than the general population, 3 times fewer deaths and a 30% higher recovery rate.

"Governments, policy-makers and public health providers must embrace the knowledge, expertise and strong leadership of Indigenous communities to face COVID-19," write Dr. Lisa Richardson, a physician at University Health Network and Dr. Allison Crawford, a psychiatrist at Centre for Addiction and Mental Health, Toronto, Ontario.

Public health approaches in Canada were shaped by repressive colonial practices, which outlawed traditional Indigenous cultural and healing practices, forced Indigenous Peoples to seek health care far from their communities and had other negative effects.

The lower incidence of COVID-19 in Indigenous communities may be due to Indigenous ownership of practices to stem the spread of the virus.

"During COVID-19, many Indigenous communities have shown self-determination by articulating and enforcing rules on who can enter their communities, often implementing far stricter measures than those enacted by local municipalities, such as closures and checkpoints," write the authors.

Indigenous self-determination must shape public health approaches during future waves of COVID-19, they urge.

"Anticipating further waves of COVID-19, it is important that the design, implementation and leadership of public health by First Nations, Inuit and Métis communities continue in Canada. At its foundation, Indigenous public health must be self-determined: adapted for the needs of specific nations and grounded in local Indigenous language, culture and ways of knowing; developed, implemented and led by Indigenous Peoples; and informed by ongoing monitoring of data as governed by appropriate data sovereignty agreements."

All levels of governments in Canada must work to address the social determinants of health to improve health in the short-term as well as lay the foundation for longer-term improvements.

College students with physical and cognitive disabilities use illicit drugs more, and have a higher prevalence of drug use disorder, than their non-disabled peers, according to a Rutgers study.

The study, published in the journal Disability and Health Journal, gives new understanding to the risk factors for substance use in students with disabilities and will help develop more effective prevention and treatment strategies.

An estimated 41 percent of college students have used an illicit drug, most widely marijuana. The American College Health Association estimates that 54 percent of students have a disability, including psychiatric disorders, attention deficit hyperactivity disorder, attention deficit disorder, learning disabilities and chronic illnesses like cancer, diabetes or autoimmune disorders.

The researchers looked at 6,189 college or university students in the 2017 National Survey on Drug Use and Health, 15 percent of whom had a disability that affected their hearing, seeing, mobility or mental or emotional functioning. The illicit drugs included marijuana, cocaine, heroin, hallucinogens, inhalants, methamphetamine and prescription medications such as pain relievers, tranquilizers, stimulants and sedatives.

They found that students with a disability had nearly twice the odds than their peers of misusing prescription pain relievers in the past month and were three times more likely to meet the criteria for past-year dependence or abuse of any illicit drug. In the sample, 40 percent of students with any disability reported having used illicit drugs versus 30 percent of their non-disabled peers. Close to 3 percent of students with a disability reported having used heroin versus less than 1 percent of their peers.

"The odds of past-year misuse of prescription pain relievers, in general, was almost twice as high for students with any disability. In fact, students with any disability were two-and-a-half times more likely to have misused OxyContin specifically," said lead author Myriam Casseus, a graduate student at Rutgers School of Public Health. "This may be due, in part, to these students self-medicating for pain and stress management."

Most of the students reporting a disability had a cognitive limitation. The study noted that young adults with ADHD are more likely to become dependent on or abuse nicotine, alcohol, marijuana, cocaine or other substances.

"Our findings suggest that health care providers be aware of the risk of drug misuse when treating college students with disabilities, particularly when prescribing medications that may lead to abuse or dependence," said Judith Graber, associate professor at Rutgers School of Public Health. "Also drug prevention and treatment programs should include interventions for college students with disabilities, especially cognitive."

A study of approximately 200,000 blood samples from the UK Biobank has identified more than 2,000 undiagnosed cases of type 2 diabetes. The study, presented at this year's Annual Meeting of the European Association for the Study of Diabetes (EASD), also shows that, because UK Biobank data is not reported back to participants, patients found to have undiagnosed diabetes waited on average more than two years for a clinical diagnosis, and around a quarter remained undiagnosed five years later.

The study, by Dr Katherine Young and colleagues at the University of Exeter and the Royal Devon and Exeter NHS Foundation Trust, UK, used a test for monitoring blood glucose control and diagnosing diabetes, known as HbA1c, or 'glycated' haemoglobin. In the UK, type 2 diabetes is predominantly diagnosed through HbA1c testing.

Dr Young said: "As people can have type 2 diabetes for many years without symptoms, diagnosis may be delayed, increasing the risk of complications. Our study shows that population-level screening could identify cases of type 2 diabetes far earlier and potentially reduce complications."

The UK Biobank is a cohort of around half a million participants aged 40-70 at recruitment, with primary care records (clinical codes and prescription data) available for nearly half of participants. In the UK Biobank, all participants were in effect screened for diabetes, as their HbA1c levels were measured in the blood samples collected from them at recruitment, but results were not reported back to them or their healthcare professionals. This is perfectly normal, since volunteers consenting to take part in the UK Biobank project consent that they will not receive feedback of results.

The authors analysed how many additional people with diabetes can be identified by population screening using HbA1c, and how much screening would reduce the time to receive a diagnosis of diabetes compared to present approaches.

The authors defined participants without a diagnosis of diabetes at recruitment as those who: a) did not self-report diabetes; and b) had no indications of diabetes in their primary care records prior to recruitment (clinical codes for diabetes, HbA1c measurements of 48 mmol/mol or higher, or prescriptions for glucose lowering medication).

Undiagnosed diabetes was defined as those with a UK Biobank HbA1c measurement of 48 mmol/mol or higher. For participants with undiagnosed diabetes, the authors then looked up the time that it took to actually receive a clinical diagnosis in their primary care records, defined as the first occurrence of any of: a diagnosis code for diabetes, HbA1c of 48 mmol/mol or higher, or a prescription for glucose lowering medication.

Of the 201,465 UK Biobank participants with primary care records available and an HbA1c measured at recruitment, and no prior diagnosis of diabetes, 2,022 (1.0%) had undiagnosed diabetes on screening by HbA1c.

Individuals with undiagnosed diabetes on screening were older (61 vs 58 years), more likely to have obesity (BMI 31.0 vs 26.6), and more frequently male (60% vs 45%) than those without diabetes. Statistical modelling showed these participants took on average 2.3 years following UK Biobank recruitment to be diagnosed with diabetes, and that 23% still had not been diagnosed at five years follow-up.

Dr Young concludes: "We identified that screening by HbA1c would have identified an extra 1.0% of a population aged 40-70 years as having undiagnosed diabetes. This screening diagnosis would have been approximately two years before a clinical diagnosis was made. 23% had still not received a diagnosis at five years. The identification of these patients for whom primary care records are available in UK Biobank gives us a unique opportunity to study the impact of this delay on the risk of developing complications in the future."

She adds: "While preliminary results suggest that delays in receiving a diagnosis for those with undiagnosed diabetes did not significantly impact diabetes-related complications in this group of people, further research is required to ascertain whether screening for diabetes in this age group would reduce diabetes-related complications."

The research is funded by Professor Andrew Hattersley's Novo Nordisk Foundation Diabetes Prize for Excellence.