Culture

WASHINGTON--Patients hospitalized with COVID-19 have worse outcomes if they have high blood sugar, or hyperglycemia, regardless of whether they have diabetes, a new study finds. The researchers will present their results, of the first known study of the impact of hyperglycemia on a largely Black patient population with the novel coronavirus, at ENDO 2021, the Endocrine Society's annual meeting.

The investigators found that patients with COVID-19 who had hyperglycemia on admission to the hospital were more likely than those with normal glucose (sugar) to require a breathing machine or admission to the intensive care unit (ICU). These patients also were reportedly likelier to have kidney injury and to die in the hospital.

"COVID-19 patients presenting to the hospital with hyperglycemia require closer observation, as they are likely to require more aggressive therapies," said the study's lead investigator, Samara Skwiersky, M.D., M.P.H., an internal medicine resident physician at the State University of New York (SUNY) Downstate Medical Center in Brooklyn, N.Y.

Although a few prior studies have identified hyperglycemia or diabetes as an independent risk factor for worse COVID-19 outcomes, Skwiersky said they did not take place in a predominantly Black population. The virus has disproportionately affected Black people, including higher rates of hospitalization and death than in white people, she noted.

Their study included 708 adults with COVID-19 admitted to SUNY Downstate Medical Center, 89 percent of whom were Black. About half were men, and 54 percent of patients had a history of either type 1 or type 2 diabetes on admission.

The researchers studied patient outcomes by the presence or absence of diabetes and by their blood glucose values on admission. Because guidelines recommend that hospitalized patients with diabetes maintain blood glucose levels between 140 and 180 milligrams per deciliter (mg/dL), the investigators divided patients into groups by glucose levels less than 140 and less than 180 mg/dL.

Patients with diabetes whose blood glucose values on admission exceeded 140 mg/dL had a 2.4-fold increased odds of ICU admission and intubation--needing a breathing machine--versus those whose glucose levels were lower, the researchers reported. Furthermore, patients with diabetes whose admission glucose levels were higher than 180 mg/dL had an approximately twofold increased odds of in-hospital death, their data showed.

However, Skwiersky said the odds of death also were increased twofold for patients who did not have diabetes and whose glucose values exceeded 140 mg/dL. Additionally, these patients had a 3.5-fold raised odds of ICU admission and a 2.3-fold higher odds of intubation and of experiencing acute kidney injury.

According to Skwiersky, patients without diabetes whose blood glucose levels topped 180 mg/dL had a fourfold greater death risk, a nearly threefold increased odds of ICU admission, and a 2.7-fold higher odds of intubation.

"The results from our study," she said, "reiterate the importance of regularly monitoring blood glucose in patients hospitalized with COVID-19, even without a prior diagnosis of diabetes."

It is unclear whether hyperglycemia is the result of or a cause of more severe COVID-19 illness, Skwiersky stated. Still, she said their results suggest the need for intensive glucose control in hospitalized COVID-19 patients with high blood sugar. This is consistent with the current Endocrine Society guidelines, which recommend that all patients with blood glucose above 140 mg/dL be monitored with point-of-care glucose testing and treated with appropriate therapies.

"More frequent glucose monitoring and treatment with insulin therapy to a target glucose value less than 140 mg/dL could improve outcomes in these patients," Skwiersky said.

WASHINGTON--People with type 1 diabetes can improve their blood sugar control while reducing time with low blood sugar, or hypoglycemia, using Insulet Corporation's Omnipod 5 Automated Insulin Delivery System compared to their standard insulin therapy. Results from an industry-sponsored study of the latest Omnipod, the first tubeless, wearable insulin pump, will be presented at ENDO 2021, the Endocrine Society's annual meeting.

The Omnipod 5 System underwent three months of at-home testing in 128 adults and adolescents ages 14 to 70 years and 112 children ages 6 to less than 14 years. All study participants have type 1 diabetes and were first followed for two weeks using their standard therapy, either multiple daily insulin injections or an insulin pump. Using Omnipod 5, participants experienced significant average improvements in both hemoglobin A1c, a measure of blood glucose (sugar) control over the past several months, and the percentage of time the participants stayed within the recommended target glucose range (70 to 180 milligrams per deciliter), the researchers reported.

"These study results represent an advancement in diabetes therapies with a fully wearable device that enables continuous automated insulin modulation. This will expand the available treatment options for people with type 1 diabetes," said the study's senior investigator, Trang Ly, MBBS, FRACP, PhD, Senior Vice President and Medical Director of Insulet Corporation.

Insulet funded this study and manufactures Omnipod 5, which is under review by the U.S. Food and Drug Administration. It is an update to the Omnipod DASH and the original Omnipod System, which are sold in the U.S., Canada, Europe and the Middle East.

The Omnipod 5 System, according to Ly, is the first tubeless automated insulin delivery system integrated with the Dexcom G6 continuous glucose monitoring (CGM) system. She said this commonly used glucose monitor automatically measures glucose levels every five minutes and communicates directly with Omnipod 5. The Pod is now designed with an embedded algorithm that adjusts the pump's insulin delivery automatically to a customizable glucose target, based on the CGM value and trend.

Users of Omnipod 5 inject insulin into a single-use Pod, which adheres to their skin for 72 hours of continuous infusion of insulin. At mealtimes, the user administers a bolus dose of insulin which is controlled by the Omnipod 5 app on the user's personal smartphone or a separate wireless controller. Ly said the new system will have the ability to control the Pod from a compatible smartphone, making the wireless controller optional.

Ly reported that the adult/adolescent group's A1c averaged 0.4 percent lower with Omnipod 5 than when they used their standard insulin therapy, an improvement from 7.2 percent to 6.8 percent.

With Omnipod 5, their average time in the glucose range recommended by the American Diabetes Association (70 to 180 milligrams per deciliter) was 2.2 hours a day longer, or 9.3 percent better, Ly stated. Overall, this group was in target range nearly 74 percent of the time when they used Omnipod 5, while the general population with type 1 diabetes is often in target glucose range 60 percent or less of the time.

"Even though many of the study participants had their diabetes well controlled before the study, they still experienced improved time in the target glucose range, regardless of their baseline control. This shows the potential of the technology in the broader population with diabetes," Ly said.

One of their most important findings in the adult/adolescent group, according to Ly, was a reduction of time in hypoglycemia, measured on the sensor as glucose levels below 70 milligrams per deciliter, down to a median of 1.1 percent. Hypoglycemia is a dangerous drop in blood glucose levels. Only two episodes of severe hypoglycemia occurred, reportedly after user-initiated bolus doses.

Most study participants chose to continue using the Omnipod 5 during an extension of the original three-month study, which Ly said suggests a preference over their previous therapy.

Children participating in the study also had improved blood sugar control after using Omnipod 5. The average A1c dropped by 0.7 percent, to 7 percent, and the time in range improved by nearly four hours per day. One event of diabetic ketoacidosis (excessive ketones in the blood due to insufficient insulin) occurred, which Ly attributed to infusion site failure. She said one severe hypoglycemia event occurred that was not attributable to device malfunction.

"Omnipod 5 protects you from both high and low glucose values," Ly said. "It also is simple, intuitive, and easy to use."

Sue Brown, M.D., of the University of Virginia in Charlottesville, Va., will present the data for adults and adolescents during an oral presentation at the meeting. Bruce Buckingham, M.D., of Stanford University, will present the pediatric data in a poster presentation.

The research team led by Prof. ZHANG Jie from the University of Science and Technology of China (USTC) of the Chinese Academy of Sciences made progress on real-time determination of earthquake focal mechanism through deep learning. The work was published in Nature Communications.

Since there are connections between characteristics of the rupture surface of the source fault and seismic wave radiated by the source, it's vital to monitor the earthquake by immediate determination of the source focal mechanism which inferred from multiple ground seismic records.

However, it's hard to calculate the mechanism from the simple records. The parameters about focal mechanism are either merely reported or reported after a few minutes even longer.

In this study, Prof. ZHANG's team applied a novel convolutional neural network to solve this problem effectively, paving the way for the acceleration of the investigation of details about earthquake.

The neural network, named as Focal Mechanism Network (FMNet), was first trained to estimate the source focal mechanism rapidly using full waveforms. Then, the neural network model was trained by comprehensive dataset, which modified the report system. After the earthquake, the real-dataset are introduced into the training system, the estimated parameters about the earthquake source can be calculated within one second with a minimum requirement of computing resources and memory storage.

A large number of practical data tests have proved the effectiveness of the method.

The results of this study are now being translated into practical functions and will soon be put into trial operation on the intelligent ground motion artificial intelligence earthquake monitoring system jointly developed by USTC and China Earthquake Administration.

During the first six months of the pandemic, as people attempted to stay away from hospitals caring for those sick with COVID-19, potentially avoidable hospitalizations for non-COVID-19-related conditions fell far more among white patients than Black patients, according to a new study that looked at admissions to UCLA Health hospitals.

The findings indicate that the COVID-19 crisis has exacerbated existing racial health care disparities and suggest that during the pandemic, African Americans may have had worse access than whites to outpatient care that could have helped prevent deterioration of their non-COVID-19 health conditions, said Dr. Richard Leuchter, a resident physician at UCLA Health and lead author of the study, to be published in the American Journal of Preventive Medicine.

These hospitalizations -- for conditions ranging from diabetes and asthma to hypertension -- disproportionately expose African Americans to the financial burdens of missing work and hospital costs, separate them from their families and increase their risk of hospital-acquired infections, the researchers say.

"At a time when large-scale community activism has brought attention to systemic racial injustices, it's important to bring these inequities to light so that action can be taken," Leuchter said. "While these findings are limited to UCLA Health, these problems represent a systemwide challenge for health care that cannot be addressed through the actions of a single institution.

"It is within our power as a society to reallocate resources to combat these serious health inequities," he added. "We need widespread community action."

Consistent with national trends that emerged as patients avoided hospitals treating individuals with COVID-19, potentially avoidable hospitalizations dropped across UCLA Health hospitals during the pandemic. Research into this phenomenon is ongoing, but the current study suggests that the potential benefits associated with avoiding the hospital were not shared equally among white and Black patients.

The researchers examined records for patients admitted to UCLA Health hospitals between March 1 and Aug. 31, 2020, and compared them with hospitalizations during the same pre-pandemic months of 2019. Patients were admitted for chronic obstructive pulmonary disease, asthma, hypertension, congestive heart failure, community-acquired pneumonia, uncontrolled diabetes and diabetes complications, and urinary tract infections. People with these conditions can often avoid hospitalization with appropriate outpatient treatment.

The researchers found that out of 4,838 hospitalizations during the 2020 time period, 347 (7.2%) were potentially avoidable, compared with 557 out of 6,248 (8.9%) hospitalizations during the same six-month period in 2019. While such hospitalizations dropped by 50% for non-Hispanic whites from 2019 to 2020, they dropped a statistically insignificant 8% for African Americans.

In addition to the wide disparity between white and Black patients, the researchers found that avoidable hospitalizations fell 32.3% for Latinos and 16.1% for Asians over the same periods, although they note that the "relative differences in magnitudes of reduction were only statistically significant between African American and non-Hispanic white patients."

The study has some limitations, the researchers say. For instance, it did not take into account factors like comorbidities or socioeconomic status that could contribute to health disparities. In addition, the sample was confined to a single health system, there was an assumption that the population pools from 2019 and 2020 were similar, and some patients may have received false negative results on COVID-19 tests, leading doctors to admit them for pneumonia, which the study classifies as a potentially avoidable hospitalization.

But the findings could still guide health officials in identifying racial and ethnic groups with these largely treatable conditions and ensuring that they have access to outpatient care that could prevent unnecessary hospitalizations, Leuchter said.

"A campaign to reduce avoidable hospital admissions could have an enormous positive impact on people of color by minimizing the harms to which they are exposed through such hospitalizations," he said.

LA JOLLA, CALIF. - March 19, 2021 - Scientists at Sanford Burnham Prebys Medical Discovery Institute have identified a drug candidate that blocks the uptake of glutamine, a key food source for many tumors, and slows the growth of melanoma. The drug is a small molecule that targets a glutamine transporter, SLC1A5, which pumps the nutrient into cancer cells--offering a promising new approach for treating melanoma and other cancers. The study was published in the journal Molecular Cancer Therapeutics.

"While great strides have been made recently in the treatment of melanoma, many patients' tumors become resistant to therapy, and this has become a major obstacle in the successful treatment of the disease," says Ze'ev Ronai, Ph.D., director of the National Cancer Institute (NCI)-designated Cancer Center at Sanford Burnham Prebys and senior author of the study. "This study describes a promising compound that selectively targets the uptake of glutamine, an amino acid nutrient that tumors rely on for survival. We are hopeful this drug will fill an unmet medical need for people living with this deadly cancer."

More than 7,000 people die from melanoma each year in the U.S., according to the American Cancer Society, and cases continue to increase annually. In the past decade, immunotherapy and personalized treatments have extended survival times for many patients. However, because of the high incidence of cancer recurrence, scientists are increasingly focused on therapeutic strategies to prevent relapse and increase overall survival.

"This is a very important study because many targeted drugs for melanoma treatment have been significantly hindered by the rapid development of treatment resistance, sometimes as quickly as within several months. While immunotherapy approaches are promising, they are only effective in a subset of patients, and treatment resistance can also develop in this setting as well," says M. Celeste Simon, Ph.D., Arthur H. Rubenstein, MBBCh Professor in the department of Cell and Developmental Biology and scientific director of the Abramson Family Cancer Research Institute at the Perelman School of Medicine at the University of Pennsylvania. "The drug candidate identified in Dr. Ronai's study offers an exciting new therapeutic approach for treating tumors addicted to glutamine, which includes a long list of human cancers, and will hopefully lengthen the amount of time that people with melanoma respond to available treatments."

Blocking the tumor's food supply

Researchers know that rapidly growing tumors are able to reprogram their metabolism to generate extra energy to survive and grow. Tumors often achieve this by pumping increasing levels of the amino acid glutamine into their cells, primarily through a pump called SLC1A5. As a result, cancer researchers are working to find drugs that block SLC1A5 and reduce glutamine levels.

In the study, Ronai and his team set out to identify drug(s) that can inhibit glutamine uptake. Working in collaboration with researchers at the Institute's Conrad Prebys Center for Chemical Genomics, the scientists screened 7,000 diverse compounds for their ability to interfere with SLC1A5. This work identified about 20 hits, or promising options, and one was selected based on its superior ability to prevent SLC1A5 from reaching the cell membrane. This drug candidate, IMD-0354, inhibited tumor growth in both cell culture and in mice with melanoma.

"Our study shows that targeting SLC1A5, which stops glutamine from ever entering the cell in the first place, is an effective way to slow cancer cell growth," says Yongmei Feng, Ph.D., staff scientist in the Ronai lab at Sanford Burnham Prebys and first author of the study. "Because many tumor types are dependent upon glutamine for survival, this drug may be able to treat many different types of cancers."

As a next step, Ronai and his team will further refine IMD-0354, with a focus on improving biophysical properties that will help accelerate preclinical evaluation of the drug candidate.

Colorectal cancer survivors who maintained a stable body weight but lost muscle and developed fatty deposits in their muscles faced a 40 percent higher risk of premature death than patients who avoided both health issues.

"The conventional wisdom has been that colorectal cancer patients should avoid losing or gaining weight during treatment," said Dr. Justin C. Brown, Assistant Professor and Director of the Cancer Metabolism Program at Pennington Biomedical Research Center. "But maintaining your weight does not mean your body composition remains the same. Muscle can change quite dramatically, and those changes are associated with a much higher risk of death."

The researchers say assessing body composition by computed tomography images may be a vital method of identifying patients at increased risk of death.

This study highlights how body composition can have a powerful impact on long-term health. We at Pennington Biomedical are committed to conducting innovative research to enable cancer survivors around the world to achieve their best possible health," said Dr. John Kirwan, Executive Director.

The study, published in The American Journal of Clinical Nutrition, looked at 1,921 patients with stage I-III colorectal cancer. Skeletal muscle and body weight were measured at diagnosis and an average of 15 months later. Stable body weight was defined as being within plus or minus 5 percent of weight at diagnosis.

Researchers found that stable body weight masks clinically meaningful skeletal muscle depletion. Women were particularly vulnerable to losing muscle. One in five women with stable body weight lost muscle, while less than one in 10 men did.

"More research is needed to determine whether physical activity offers the best solution to prevent muscle loss or fatty deposits in muscle," Dr. Brown said. "But the findings provide colorectal cancer patients with more incentive to engage in physical activity programs that maintain and build muscle."

A team of scientists, led by researchers at Northwestern University, Shirley Ryan AbilityLab and the University of Illinois at Chicago (UIC), has developed novel technology promising to increase understanding of how brains develop, and offer answers on repairing brains in the wake of neurotrauma and neurodegenerative diseases.

Their research is the first to combine the most sophisticated 3-D bioelectronic systems with highly advanced 3-D human neural cultures. The goal is to enable precise studies of how human brain circuits develop and repair themselves in vitro. The study is the cover story for the March 19 issue of Science Advances.

The cortical spheroids used in the study, akin to "mini-brains," were derived from human-induced pluripotent stem cells. Leveraging a 3-D neural interface system that the team developed, scientists were able to create a "mini laboratory in a dish" specifically tailored to study the mini-brains and collect different types of data simultaneously. Scientists incorporated electrodes to record electrical activity. They added tiny heating elements to either keep the brain cultures warm or, in some cases, intentionally overheated the cultures to stress them. They also incorporated tiny probes -- such as oxygen sensors and small LED lights -- to perform optogenetic experiments. For instance, they introduced genes into the cells that allowed them to control the neural activity using different-colored light pulses.

This platform then enabled scientists to perform complex studies of human tissue without directly involving humans or performing invasive testing. In theory, any person could donate a limited number of their cells (e.g., blood sample, skin biopsy). Scientists can then reprogram these cells to produce a tiny brain spheroid that shares the person's genetic identity. The authors believe that, by combining this technology with a personalized medicine approach using human stem cell-derived brain cultures, they will be able to glean insights faster and generate better, novel interventions.

"The advances spurred by this research will offer a new frontier in the way we study and understand the brain," said Shirley Ryan AbilityLab's Dr. Colin Franz, co-lead author on the paper who led the testing of the cortical spheroids. "Now that the 3-D platform has been developed and validated, we will be able to perform more targeted studies on our patients recovering from neurological injury or battling a neurodegenerative disease."

Yoonseok Park, postdoctoral fellow at Northwestern University and co-lead author, added, "This is just the beginning of an entirely new class of miniaturized, 3-D bioelectronic systems that we can construct to expand the capacity of the regenerative medicine field. For example, our next generation of device will support the formation of even more complex neural circuits from brain to muscle, and increasingly dynamic tissues like a beating heart."

Current electrode arrays for tissue cultures are 2-D, flat and unable to match the complex structural designs found throughout nature, such as those found in the human brain. Moreover, even when a system is 3-D, it is extremely challenging to incorporate more than one type of material into a small 3-D structure. With this advance, however, an entire class of 3-D bioelectronics devices has been tailored for the field of regenerative medicine.

"Now, with our small, soft 3-D electronics, the capacity to build devices that mimic the complex biological shapes found in the human body is finally possible, providing a much more holistic understanding of a culture," said Northwestern's John Rogers, who led the technology development using technology similar to that found in phones and computers. "We no longer have to compromise function to achieve the optimal form for interfacing with our biology."

As a next step, scientists will use the devices to better understand neurological disease, test drugs and therapies that have clinical potential, and compare different patient-derived cell models. This understanding will then enable a better grasp of individual differences that may account for the wide variation of outcomes seen in neurological rehabilitation.

"As scientists, our goal is to make laboratory research as clinically relevant as possible," said Kristen Cotton, research assistant in Dr. Franz's lab. "This 3-D platform opens the door to new experiments, discovery and scientific advances in regenerative neurorehabilitation medicine that have never been possible."

It's estimated that an average-sized wastewater treatment plant serving roughly 400,000 residents will discharge up to 2,000,000 microplastic particles into the environment each day. Yet, researchers are still learning the environmental and human health impact of these ultra-fine plastic particles, less than 5 millimeters in length, found in everything from cosmetics, toothpaste and clothing microfibers, to our food, air and drinking water.

Now, researchers at New Jersey Institute of Technology have shown that ubiquitous microplastics can become 'hubs' for antibiotic-resistant bacteria and pathogens to grow once they wash down household drains and enter wastewater treatment plants -- forming a slimy layer of buildup, or biofilm, on their surface that allows pathogenic microorganisms and antibiotic waste to attach and comingle.

In findings published in Elsevier's Journal of Hazardous Materials Letters, researchers found certain strains of bacteria elevated antibiotic resistance by up to 30 times while living on microplastic biofilms that can form inside activated sludge units at municipal wastewater treatment plants.

"A number of recent studies have focused on the negative impacts that millions of tons of microplastic waste a year is having on our freshwater and ocean environments, but until now the role of microplastics in our towns' and cities' wastewater treatment processes has largely been unknown," said Mengyan Li, associate professor of chemistry and environmental science at NJIT and the study's corresponding author. "These wastewater treatment plants can be hotspots where various chemicals, antibiotic-resistant bacteria and pathogens converge and what our study shows is that microplastics can serve as their carriers, posing imminent risks to aquatic biota and human health if they bypass the water treatment process."

"Most wastewater treatment plants are not designed for the removal of microplastics, so they are constantly being released into the receiving environment," added Dung Ngoc Pham, NJIT Ph.D. candidate and first author of the study. "Our goal was to investigate whether or not microplastics are enriching antibiotic-resistant bacteria from activated sludge at municipal wastewater treatment plants, and if so, learn more about the microbial communities involved."

In their study, the team collected batches of sludge samples from three domestic wastewater treatment plants in northern New Jersey, inoculating the samples in the lab with two widespread commercial microplastics -- polyethylene (PE) and polystyrene (PS). The team used a combination of quantitative PCR and next-generation sequencing techniques to identify the species of bacteria that tend to grow on the microplastics, tracking genetic changes of the bacteria along the way.

The analysis revealed that three genes in particular -- sul1, sul2 and intI1-- known to aid resistance to common antibiotics, sulfonamides, were found to be up to 30 times greater on the microplastic biofilms than in the lab's control tests using sand biofilms after just three days.

When the team spiked the samples with the antibiotic, sulfamethoxazole (SMX), they found it further amplified the antibiotic resistance genes by up to 4.5-fold.

"Previously, we thought the presence of antibiotics would be necessary to enhance antibiotic-resistance genes in these microplastic-associated bacteria, but it seems microplastics can naturally allow for uptake of these resistance genes on their own." said Pham. "The presence of antibiotics does have a significant multiplier effect however."

Eight different species of bacteria were found highly enriched on the microplastics. Among these species, the team observed two emerging human pathogens typically linked with respiratory infection, Raoultella ornithinolytica and Stenotrophomonas maltophilia, frequently hitchhiking on the microplastic biofilms.

The team say the most common strain found on the microplastics by far, Novosphingobium pokkalii, is likely a key initiator in forming the sticky biofilm that attracts such pathogens -- as it proliferates it may contribute to the deterioration of the plastic and expand the biofilm. At the same time, the team's study highlighted the role of the gene, intI1, a mobile genetic element chiefly responsible for enabling the exchange of antibiotic resistance genes among the microplastic-bound microbes.

"We might think of microplastics as tiny beads, but they provide an enormous surface area for microbes to reside," explained Li. "When these microplastics enter the wastewater treatment plant and mix in with sludge, bacteria like Novosphingobium can accidentally attach to the surface and secrete glue-like extracellular substances. As other bacteria attach to the surface and grow, they can even swap DNA with each other. This is how the antibiotic resistance genes are being spread among the community."

"We have evidence that the bacteria developed resistance to other antibiotics this way as well, such as aminoglycoside, beta-lactam and trimethoprim," added Pham.

Now, Li says the lab is further studying the role of Novosphingobium in biofilm formation on microplastics. The team is also seeking to better understand the extent to which such pathogen-carrying microplastics may be bypassing water treatment processes, by studying resistance of microplastic biofilms during wastewater treatment with disinfectants such as UV light and chlorine.

"Some states are already considering new regulations on the use of microplastics in consumer products. This study raises calls for further investigation on microplastic biofilms in our wastewater systems and development of effective means for removing microplastics in aquatic environments," said Li.

IIASA researchers worked with local stakeholders from the East African Community to explore and co-develop regional water scenarios that can enhance understanding of the up- and downstream water sector interactions in the extended Lake Victoria Basin to facilitate rational water resource planning.

East Africa is the world's fastest growing region outside of Asia, with an estimated growth of 5% and above over the last decade. Part of this success can likely be attributed to the East Africa Vision 2050, which was launched in 2015 by the Heads of States of the East African Community (EAC) - an intergovernmental organization composed of six countries in the African Great Lakes region in eastern Africa. If the region's rapid development were to continue in a sustainable manner, it will have beneficial impacts for the entire African continent. The region's dynamic socioeconomic development - which is characterized by rapid economic and population growth, along with a growing rate of urbanization - will lead to increased water demand and put pressure on water quality. As the water sector is a lever for development, understanding the up- and downstream linkages in hydrological processes and human water use is essential for water resources planning in river basins.

To contribute to and facilitate such understanding, IIASA researchers undertook a quantitative modeling analysis for the transboundary headwaters of the Nile - the extended Lake Victoria Basin, which incorporates parts of seven countries and the basins of all inflows into Lake Victoria, as well as the basins of the Victoria and Albert Niles. Guided by the basin approach (a key principle in integrated water-resource management) the researchers worked with local stakeholders from the EAC and the Lake Victoria Basin Commission to explore and co-develop regional water scenarios that could be used to explore possible development pathways up to 2050 against the background of uncertain futures. Co-development of scenarios such as the researchers undertook in this study are rare, as is the combined modeling of socioeconomic and biophysical (climate change, land use change, and environmental constraints) aspects, which makes the contribution of this novel work quite significant.

"Together with local stakeholders, we assessed upstream and downstream water sector interactions in the extended Lake Victoria Basin to determine the best approach for rational water resource planning," explains Sylvia Tramberend, a researcher with the IIASA Water Security Research Group and first author of the study published in the journal One Earth. "Scenarios are an essential part of sustainability research as they help make the long-term consequences of near-term decisions understandable. In this case, the scenarios we co-developed in close collaboration with stakeholders in East Africa, aids in the identification of sustainable water-development pathways to leverage development opportunities and contribute to development. By using scenarios to portray alternative plausible development pathways, we can pursue sustainable, long-term water security."

The study's scenario assessments suggest that water use and withdrawal will increase significantly (at least fourfold) due to population and GDP growth, coupled with ambitions to significantly increase irrigation for agricultural purposes, which is currently almost non-existent in the region. Furthermore, climate change is likely to increase variability, marked by a seasonal shift in rainfall and more pronounced dry and wet periods, although this scenario is subject to a high degree of uncertainty. In addition, respecting environmental flow requirements - in other words, making sure that enough freshwater is retained in rivers and lakes throughout the year to sustain water ecosystem services - will require a significant proportion of water infrastructure in the region to rely on advanced technologies to ensure efficient water use, which are often more costly.

In light of the above, the researchers urge that the ongoing regional integration of East Africa requires that harmonization of water policy be a priority in the urgently needed development of water infrastructure, which makes interconnected analyses over time and guided by co-developed scenarios, indispensable for planning sustainable water-development pathways. The analyses of water systems must bridge the gap from the local to the regional and global scales, making cooperation and co-development of strategies and approaches to achieve this critical. Although there are still many challenges that need to be overcome in this regard, the researchers point out that the co-development of scenario narratives worked reasonably well. They however note that significantly more resources are needed to achieve true co-development between modeling exercises, which usually require input from experts and researchers, while also taking into account what stakeholders need.

"Water is a pivotal sector for sustainable development and requires smart investment strategies. Similarly important is that we foster co-development initiatives and analyses that respect both upstream and downstream interactions. This requires institutions whose mandate covers entire watersheds like the Lake Victoria Basin Commission who we worked closely with on this assessment. Strengthening these institutions is critical for water security enabled by effective implementation of sustainable development pathways," concludes Hilda Luoga, Projects Development Officer with the East African Community in the Lake Victoria Basin Commission.

A new research study at the University of Chicago Medicine has found that when it comes to COVID-19, having vitamin D levels above those traditionally considered sufficient may lower the risk of infection, especially for Black people.

The study, published March 19 in JAMA Open Network, retrospectively examined the relationship between vitamin D levels and likelihood of testing positive for COVID-19. While levels of 30 ng/ml or more are usually considered "sufficient," the authors found that Black individuals who had levels of 30 to 40 ng/ml had a 2.64 times higher risk of testing positive for COVID-19 than people with levels of 40 ng/ml or greater. Statistically significant associations of vitamin D levels with COVID-19 risk were not found in white people. The study looked at data from over 3,000 patients at UChicago Medicine who had had their vitamin D levels tested within 14 days before a COVID-19 test.

The research team is now recruiting participants for two separate clinical trials testing the efficacy of vitamin D supplements for preventing COVID-19.

This research is an expansion of an earlier study showing that a vitamin D deficiency (less than 20 ng/ml) may raise the risk of testing positive for COVID-19. In the current study, those results were further supported, finding that individuals with a vitamin D deficiency had a 7.2% chance of testing positive for the virus. A separate study recently found that over 80% of patients diagnosed with COVID-19 were vitamin D deficient.

"These new results tell us that having vitamin D levels above those normally considered sufficient is associated with decreased risk of testing positive for COVID-19, at least in Black individuals," said David Meltzer, MD, PhD, Chief of Hospital Medicine at UChicago Medicine and lead author of the study. "This supports arguments for designing clinical trials that can test whether or not vitamin D may be a viable intervention to lower the risk of the disease, especially in persons of color."

Meltzer was inspired to investigate this topic after seeing an article in early 2020 that found people with vitamin D deficiency who had randomly been assigned to receive vitamin D supplementation had much lower rates of viral respiratory infections compared to those who did not receive supplementation. He decided to examine data being collected at UChicago Medicine on COVID-19 to determine the role that vitamin D levels might be playing.

"There's a lot of literature on vitamin D. Most of it has been focused on bone health, which is where the current standards for sufficient vitamin D levels come from," Meltzer explained. "But there's also some evidence that vitamin D might improve immune function and decrease inflammation. So far, the data has been relatively inconclusive. Based on these results, we think that earlier studies may have given doses that were too low to have much of an effect on the immune system, even if they were sufficient for bone health. It may be that different levels of vitamin D are adequate for different functions."

Vitamin D can be obtained through diet or supplements, or produced by the body in response to exposure of the skin to sunlight. Meltzer noted that most individuals, especially people with darker skin, have lower levels of vitamin D; roughly half of the world's population has levels below 30ng/ml. "Lifeguards, surfers, those are the kinds of folks who tend to have more than sufficient vitamin D levels," he said. "Most folks living in Chicago in the winter are going to have levels that are well below that."

While vitamin D supplements are relatively safe to take, excessive consumption of vitamin D supplements is associated with hypercalcemia, a condition in which calcium builds up in the blood stream and causes nausea, vomiting, weakness, and frequent urination. If left unchecked, it can further lead to bone pain and kidney stones.

"Currently, the adult recommended dietary allowance for vitamin D is 600 to 800 international units (IUs) per day," said Meltzer. "The National Academy of Medicine has said that taking up to 4,000 IUs per day is safe for the vast majority of people, and risk of hypercalcemia increases at levels over 10,000 IUs per day."

One of the challenges of this study is that it is currently difficult to determine exactly how vitamin D may be supporting immune function. "This is an observational study," said Meltzer. "We can see that there's an association between vitamin D levels and likelihood of a COVID-19 diagnosis, but we don't know exactly why that is, or whether these results are due to the vitamin D directly or other related biological factors."

Prompted by the evidence that people with vitamin D deficiency are more likely to test positive for COVID-19 and experience significant symptoms, a team at the University of Chicago and Rush University is conducting two studies to learn whether taking a daily vitamin D supplement can help prevent COVID-19 or decrease the severity of its symptoms.

What The Study Did: This analysis examined how patients with multiple sclerosis who have COVID-19 fare and what patient and disease characteristics are associated with worse outcomes.

Authors:  Amber Salter, Ph.D., of  Washington University in St Louis, is the corresponding author.

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

(doi:10.1001/jamaneurol.2021.0688)

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

What The Study Did: Researchers examined if differences in vitamin D levels greater than levels traditionally considered sufficient (30 ng/mL) are associated with having test results positive for COVID-19 in White and in Black individuals.

Authors:  David O. Meltzer, M.D., Ph.D., of the University of Chicago, is the corresponding author.

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

(doi:10.1001/jamanetworkopen.2021.4117)

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

A multinational research team led by Dr. Adnan Sljoka (RIKEN), Prof. R. Scott Prosser (Univ. of Toronto) with collaborations with Dr. Duy Phuoc Tran and Prof. Akio Kitao (Tokyo Tech) and Prof. Roger K. Sunahara (Univ. of California San Diego) has carried out experimental and computational studies, revealing key steps associated with the activation of the human adenosine A2A receptor (A2AR). A2AR is a member of superfamily of receptors called G protein-coupled receptors (GPCRs) (major drug targets) which engage the G protein and initiates cell signaling. The research team discovered that A2AR is represented by at least two inactive conformations and three active conformations whose populations are dependent on ligands and activation states of G protein, and that communication between receptor and G-protein is important for activation and signalling. This study is expected to allow researchers to reach new level of insight in GPCR activation and disease mechanism.

Background

GPCRs affect almost every aspect of human physiology, where 35% of all approved drugs act on GPCRs. In most cases, GPCRs are situated in the plasma membrane that surrounds the cell while the drug or ligand (such as hormones and neurotransmitters) that acts on the GPCR binds to an extracellular pocket. Activation is then transduced across the receptor, resulting in complexation with proteins on the cell interior. Since input arrives at the cell exterior and initiates signalling pathways inside the cell, this makes GPCRs useful in pharmacology as the drug in many cases need not enter the cell. However, GPCRs activations relate to dynamic events and key intermediate states that arise between the time that a ligand binds and when the G protein is activated. Capturing conformational dynamics of GPCRs and description of intermediate states and its role in activation and signalling has been a formidable challenge, which has hampered progress in understanding activation mechanisms of GPCRs.

Overview of Research Achievement

Using Fluorine-nuclear magnetic resonance (19F-NMR), mathematical rigidity theory, and molecular dynamics simulations, the international research team has discovered the key mechanism of activation of the human adenosine A2A receptor (A2AR) as it proceeds through signaling pathway. A2AR (also known as caffeine receptor as it is deactivated by caffeine) is a well-known GPCR that is distributed in the nervous system, platelets, immune cells, lungs, heart, and the vasculature. A2AR drugs have been developed to address wound healing, vascular diseases, including atherosclerosis, restenosis, and platelet activation, in addition to inflammation and cancer. Thus, understanding its functional states associated with receptor signaling can yield new opportunities in pharmacology and general understanding of GPCR activation mechanisms. The researchers focused on biasing key conformational states of A2AR by complexing it with G protein and different ligands to better understand signal transduction and receptor activation. F-NMR showed that A2AR is represented by at least two inactive conformations and three active conformations associated with signaling pathway whose populations are dependent on ligands engagement and G protein interactions (Fig2). Research team also used Molecular Dynamics simulations to create a structure of A2AR bound to heterotrimer G-protein complex (performed by Kitao lab), where rigidity theory methods of Sljoka identified an activation pathway where A2AR initiates communication with the G-protein which traverses the receptor's ligand binding site and G-protein (Fig3). Gβγ subunit was discovered to serve as a critical domain for facilitating signaling and activation. Understanding the activation mechanism and functional states of A2AR signaling may provide new opportunities for drug discovery.

Future Development

While the current study provides unprecedented resolution of key functional states associated with receptor signaling, future studies will no doubt focus on other key domains, providing a more comprehensive picture of the activation process.

An important function of the grant peer review process is to provide constructive feedback to applicants for their resubmissions. However, little is known about whether review feedback achieves this goal.

The American Institute of Biological Sciences (AIBS), in collaboration with Washington State University, has published findings on a multi-methods analysis of responses from grant applicants regarding their perceptions of the usefulness and appropriateness of peer review feedback they received from grant submissions.

The analysis focused on responses from a survey sent to over 13,000 scientists concerning the feedback from their recent funding applications (largely from NIH and NSF). The results suggested that only 56-60% of applicants determined the feedback to be appropriate (fair, well-written, and well-informed), although their judgments were more favorable if their recent application was funded. Importantly, independent of funding success, women found the feedback better written than men, and more White applicants found the feedback to be fair than non-White applicants.

Less than 40% of applicants found the feedback to be very useful in informing their research and improving grantsmanship and future submissions. Overall, these results suggest that more effort is needed to ensure that appropriate and useful feedback is provided to all applicants. This investigation is in line with the AIBS commitment to increasing diversity, equity, and inclusion in the biological sciences.

The results showed that several psychological well-being measures gradually increased within participants from the beginning to the end of the course. That was especially true for life satisfaction, perceived well-being, self-awareness and emotional self-regulation. The participants in the study also reported a significant decrease in anxiety, perceived stress, negative thoughts, rumination and anger tendencies. The researchers observed, simultaneously, improvements in the positive aspects and a reduction of negative emotions, both in the short term and longitudinally throughout the program.

Nicola De Pisapia, researcher of the Department of Psychology and Cognitive Sciences of the University of Trento and scientific coordinator, explained the fundamental principles of the study: "The training that we proposed to the participants was inspired by the idea - present in both Western and Eastern philosophical traditions - that happiness is inextricably linked to the development of inner equilibrium, a kinder and more open perspective of self, others, and the world, towards a better understanding of the human mind and brain. In this training process we need on the one hand the theoretical study of philosophy and science, and on the other meditation practices".

The study was conducted over nine months (with seven theoretical/practical weekends and two meditation retreats) at the Lama Tzong Khapa Institute of Tibetan culture in Pomaia (Italy). For the theoretical part, the participants attended a series of presentations and watched some video courses, and took part in open discussions on topics of psychology, neuroscience, the history of Western thought and the philosophy of life of Buddhism. The scientific topics included neuroplasticity, the brain circuits of attention and mind wandering, stress and anxiety, pain and pleasure, positive and negative emotions, desire and addiction, the sense of self, empathy and compassion. For the practical part, a series of exercises were proposed, taken from different, Buddhist and Western, contemplative traditions (for example, meditation on the breath, analytical meditation, personal journal).

In recent years, excluding the "recipes" that mistake happiness for hedonism, and the New Age obsession with positive thinking, research has shown that meditation practices have important benefits for the mind, while studies on happiness and wisdom have been scarce. De Pisapia therefore concluded: " I believe that in times like these, full of changes and uncertainties, it is fundamental to scientifically study how Western and Eastern philosophical traditions, together with the most recent discoveries on the mind and the brain, can be integrated with contemplative practices in secular way. The goal is to give healthy people the opportunity to work on themselves to develop authentic happiness, not hedonism or superficial happiness. With this study we wanted to take a small step in this direction".