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When taken daily, pre-exposure prophylaxis, or PrEP, is a highly effective way to prevent HIV transmission, according to the Centers for Disease Control and Prevention. Now a new study shows that implementing PrEP distribution within a community-based syringe services program gets the medication into the hands of women who inject drugs -- a population disproportionately impacted by HIV. The results, from researchers at Drexel University's Dornsife School of Public Health, Dornsife School of Public Health, were recently published in the Journal of Acquired Immune Deficiency Syndrome.

In the first demonstration project among women who inject drugs, known as "Project Sexual Health Equity (Project SHE)," the team prescribed up to 24 weeks of daily PrEP, to 95 adult cisgender women -- those whose gender identity matches their sex assigned at birth. The study was based at the largest syringe services program in the mid-Atlantic -- Prevention Point Philadelphia-- located in the Kensington neighborhood, which has been considered the epicenter of the city's opioid crisis.

Although HIV among people who inject drugs has dropped from 40% in the early 1990s to 6% in 2017, recent outbreaks in this population have been reported from coast to coast, including a 115% rise in HIV cases among people who inject drugs in Philadelphia from 2016 to 2018.

Women in particular have been disproportionately represented in these outbreaks, but have been underrepresented in all phases of PrEP research. This study is one of the first to assess how to increase access to PrEP for women who inject drugs.

Participants completed clinical assessments and surveys over the course of 24 weeks and were able to choose whether or not they wanted to take PrEP - in this study, a combination of the drugs emtricitabine and tenofovir disoproxil fumarate sold under the brand name Truvada® -- at three different timepoints (weeks 1, 12, and 24). The majority of women accepted a PrEP prescription at each time, though many failed to consistently achieve prevention effective adherence levels (6 of 7 doses/weekly).

"Despite significant gains in HIV prevention made over the past couple decades, we're seeing a rising number of outbreaks attributable to methamphetamine and fentanyl injection in communities across the United States, some of which have long-standing, harm-reduction programs," said lead author Alexis Roth, PhD, an associate professor in the Dornsife School of Public Health. "This has been met with far too little investment in evidence-based interventions to prevent HIV including studies to optimize PrEP among those who might benefit from it. Now we have strong evidence that there is a demand for PrEP among women who inject drugs when clinical care is provided in tandem with syringe services programs. PrEP has great potential to make a positive difference in this population."

Importantly, to reflect health care in "the real world," participants were required to use their own insurance to pay for PrEP. While 63.4% identified as currently homeless with an annual income less than $4,999 nearly all (90.5%) were insured at enrollment and the rest were helped to sign up for insurance. While only slightly over half of participants reported being aware of PrEP prior to the demonstration, most women (77.5%) went on to accept PrEP at their first return visit (week 1).

Given most of the women in the current study were non-Hispanic white, the authors note that future studies should consider oversampling women of color to contribute to the development of interventions for Black and Latinx women. They also noted that being able to co-locate services within Prevention Point was extremely important.

In addition to serving as a syringe access point, Prevention Point Philadelphia is a trusted community resource for this population, providing many much-needed services, such as case management, access to housing and linkage/provision of medications for opioid use disorder. In a previous study, colleagues from Montefiore Medical Center/Albert Einstein College of Medicine, University of Pennsylvania, and Prevention Point Philadelphia reported that providing buprenorphine maintenance treatment on-site is feasible and provides similar outcomes as other treatment settings which further highlights the potential role syringe services programs could play in addressing gaps in access to treatment and novel prevention services.

"Access to PrEP for women who inject drugs can change survival rates, and therefore providing PreP for women who inject drugs is a critical tool for harm reduction providers," said Silvana Mazzella, associate executive director of Prevention Point Philadelphia. "Prevention Point Philadelphia is thrilled to be able to provide additional resources and programming to help increase access for women who inject drugs to receive prep and additional prevention and social service support."

Barbara Van Der Pol, PhD, a professor at the University of Alabama at Birmingham and a collaborator on this project, noted the importance of co-located services in the context of the global COVID-19 pandemic.

"As SARS-CoV2 has painfully demonstrated, public health resources are limited and underfunded," said Ven Der Pol. "Studies such as this one demonstrate how synergy can be achieved by cross-agency collaboration. Incorporating tools to promote sexual health along with substance use support services is an excellent approach to using resources wisely to support healthy behaviors. We hope to use this model in many other settings around the country."

PISCATAWAY, NJ - When college campuses closed in the spring due to the COVID-19 pandemic, the quantity of alcohol consumed by students decreased significantly if they went from living with peers to living with parents, according to a new report in the Journal of Studies on Alcohol and Drugs.

Leaving home for college is often associated with increases in drinking, and campus closures in spring 2020 formed "the perfect natural experiment" to study changes in drinking behaviors when living situations changed abruptly and unexpectedly for many students, according to lead researcher Helene R. White, Ph.D., distinguished professor emerita with the Center of Alcohol & Substance Use Studies at Rutgers, The State University of New Jersey.

But according to this new study, it might not be just the watchful eye of parents that led to the decrease in quantity of alcohol consumed.

"Drinking is a social behavior for college students, and without social interaction students are less likely to drink heavily," White says. "Living with parents may especially interfere with social interaction with peers and thereby be protective against heavy drinking."

For their research, White and colleagues surveyed 312 emerging adults--mostly college juniors and seniors--approximately 2 months after COVID-19 campus shut-downs in spring 2020. They asked students about their living situations before and after their schools stopped in-person learning, categorizing students into three groups: (a) living with peers before and after closure, (b) living with parents before and after closure and (c) living with peers before closure but with parents after.

The investigators also asked about students' typical weekly drinking before and after closure. From these responses, White and colleagues tallied the number of days of drinking per week, the total number of drinks consumed weekly and the maximum number of drinks consumed in any one day.

Student alcohol users who moved from living with peers to parents significantly decreased the number of days they drank per week, from 3.1 before closure to 2.7 after. However, those who remained with peers significantly increased drinking days per week from 3 to 3.7, and those remaining with parents increased from 2 to 3.3 per week.

Similarly, the total number of drinks per week for students who moved home went from 13.9 to 8.5. Those continuing to live with peers proceeded to drink essentially the same amount (10.6 drinks per week before compared with 11 per week after closure), whereas those who continued living at home drank almost three drinks per week more (6.7 weekly before versus 9.4 drinks per week after closure).

Those who moved from living with peers to living with parents also saw a decrease in the maximum number of drinks in a day--a maximum of 5.4 drinks per day before closure to 2.9 after. But also seeing a decrease were those who remained with peers (4.4 versus 3.7) and those remaining with parents (3.5 versus 3.2) from before to after campus closures.

"[C]ontext is an important correlate of pandemic-related drinking," the authors conclude. "The COVID-19 pandemic is a time of increasing social isolation," which, for college students who move home, "provides fewer social opportunities for drinking."

December 16, 2020, OAKLAND, Calif. -- Kaiser Permanente physicians and therapists now have the ability to refer their patients to evidenced-based mental health and wellness apps through the organization's electronic health record system. With a simple referral to an app, Kaiser Permanente patients can begin using it on their own or under the guidance of a clinician -- at no cost.

A new case study shows that patients are more receptive to using mental health and wellness apps and feel better when referred by a clinician. These are among the takeaways published in the January 2021 issue of NEJM Catalyst Innovations in Care Delivery. This case study provides important learnings to support the integration of mental health apps in care and expand patient engagement with digital tools as part of their overall treatment plan.

"What we're tapping into is the existing relationship people have with their Kaiser Permanente therapist. We know that our patients are more likely to use these digital resources if their provider refers them," said Don Mordecai, MD, national leader for mental health and wellness at Kaiser Permanente. "Digital therapeutics such as mental health apps have a clear place in a care plan and it's very exciting to be on the forefront of this."

In 2018, Kaiser Permanente began providing patients access to apps by simply signing in to their kp.org account. The organization also trained clinicians on the use of the apps, workflow, documentation, and evidence-based best practices. Following the rapid expansion of the app referral effort earlier this year, clinicians referred 44,000 mental health care patients to the digital tools. More recent data shows app referrals have increased to 115,000, and the number continues to grow.

The role apps play in an overall treatment plan

The pandemic is taking a toll on Americans' emotional well-being. The prevalence of depression symptoms in U.S. adults is 3 times higher than before the COVID-19 pandemic began. When mental health issues are left untreated, they can get worse. Digital apps for mindfulness, meditation, and cognitive behavioral therapy can offer significant help for patients with mild-to-moderate anxiety or depression.

The case study showed promising results that more patients use the apps when referred by a clinician than if they had to seek out apps on their own. The apps Kaiser Permanente offers in clinical settings include Calm, Headspace, and Whil -- mindfulness and meditation apps aimed at reducing stress and anxiety, and improving sleep -- and myStrength, SilverCloud, and Thrive -- cognitive behavioral therapy apps providing higher-touch guided support through interactive activities and/or coaching. All of these apps are secure and confidential and available to Kaiser Permanente members at no cost to them. Adult members can access Calm and myStrength through kp.org without a clinician's referral.

"I suffer from anxiety. I cannot stop thinking," said Kaiser Permanente member Rosa Salguero-Rodriguez. "So, I started using Calm. I practice the sessions like breathing and gratitude, and morning exercises and stretching. Now, I can relax more and sleep better."

While Kaiser Permanente digital self-care resources do not replace treatment or clinical guidance, they provide additional support.

"It's been amazing to watch patients' progress just by using the apps in between sessions," said Leigh Miller, a Kaiser Permanente clinical social worker who offered feedback during early testing. "We found that these tools really enhanced how we support our patients' mental health and we are thrilled to see the positive changes in our patients."

Ongoing commitment to mental health and wellness

Kaiser Permanente's focus on encouraging members to use self-care apps is part of its ongoing commitment to addressing the mental health and wellness needs of its members and communities. Kaiser Permanente offers mental health care focused on early intervention, personalized treatment, patient empowerment and support, and the latest innovations in care delivery, including virtual care.

BOSTON - (December 02, 2020) - A lipid metabolite called 12,13-diHOME is in human breast milk and appears to be associated with beneficial infant weight gain and body composition in the early postnatal period. Moreover, maternal fitness, specifically exercise, appears to boost levels of the metabolite in breast milk and so might benefit their offspring. This finding was published online by The Journal of Clinical Endocrinology and Metabolism.

The authors of the study propose that 12,13-diHOME, as well as linked pathway metabolites from breast milk, have a protective effect against obesity development in offspring. They also suggest that a single bout of maternal exercise may boost levels of the metabolite in breast milk and that may translate into benefits for offspring in terms of healthy growth and development.

The metabolite is derived naturally from diet directly from linoleic acid, an essential fatty acid (Omega-6) found in many plant-derived oils as well as nuts and seeds.

The research was led by Elvira Isganaitis, MD, from Joslin Diabetes Center, staff physician at Joslin Diabetes Center and Assistant Professor of Pediatrics at Harvard Medical School; and David Fields PhD, who is Associate Professor and the CHF Chickasaw Nation Endowed Chair in Pediatric Diabetes at the University of Oklahoma Health Sciences Center.

"Although breast milk has long been promoted as a way to lower the risk of childhood obesity, the data have not been entirely consistent," said Dr Isganaitis. "The literature is contradictory, and in many cases the protective effects of breastfeeding disappear after controlling for maternal factors such as education, obesity, smoking or socioeconomic status."

"We propose that variations in milk composition between mothers may account for some of the discrepancies that have been observed in terms of childhood obesity and diabetes risk. In other words, some mothers may have greater amounts of protective factors in their milk."

The main focus of the overall study was a prospective cohort study that involved initially 58 mother-singleton infant pairs recruited over the period of 2015-2019. The infants were assessed for various anthropometric parameters related to growth and body composition over a six-month period of follow-up.

The mothers meanwhile provided breast milk samples over the same period of assessment and these were analyzed with a variety of techniques including targeted mass spectrometry, lipidomics and metabolomics approaches. In a separate part of the study, as a pilot, the authors also recruited 16 mother-infant pairs to assess the effects of a mild session of exercise on milk abundance of 12,13-diHOME.

As well as identifying 12,13-diHOME in human breast milk, potentially for the first time, the authors report that the abundance of the metabolite was positively associated with BMI at birth but negatively associated with various measures of adiposity, BMI and fat mass six months post-partum. Crucially, they also identify largely the same patterns in metabolites in the same biosynthetic pathway, backing up the observations with respect to 12,13-diHOME.

All of the metabolites they identify are involved in the so-called 'browning' or 'beigeing' of fat cells, which is a process linked with increased energy expenditure in adipose tissue, and so, the thinking that infants receiving higher levels of the metabolites should benefit in terms of healthier growth patterns (and potentially avoid childhood obesity).

For the smaller pilot study, which was supported by the Harold Hamm Diabetes Center, the authors found that at 1-month postpartum, the overall increase in 12,13-diHOME in milk was 1.39-fold following a 90-minute period of acute exercise. The eight volunteers included who were normal weight experienced a 1.50-fold increase, while the eight individuals with obesity experienced a 1.32-fold increase following exercise.

"Although the underlying biological mechanisms are currently unclear, it seems that metabolites in breast milk associated with increased energy expenditure are present, but are also influenced by a single bout of exercise - this is inescapably exciting for this field" said Dr. Fields.

In terms of implications, Dr. Isganaitis added, "The fact that exercise resulted in measurable differences in breast milk composition adds to the growing literature about the multitude of effects that exercise has on the human body. The exciting implication for new parents is that when a mother exercises, it has the potential to improve not only her own health but may also result in metabolic benefits for her child."

The authors do point towards some limitations with the study, not least, that the design precludes definitively proving causality between 12,13-diHOME and adiposity levels in infants.

With only 1% difference, the human and chimpanzee protein-coding genomes are remarkably similar. Understanding the biological features that make us human is part of a fascinating and intensely debated line of research. Researchers at the SIB Swiss Institute of Bioinformatics and the University of Lausanne have developed a new approach to pinpoint, for the first time, adaptive human-specific changes in the way genes are regulated in the brain. These results open new perspectives in the study of human evolution, developmental biology and neurosciences. The paper is published in Science Advances.

Gene expression, not gene sequence

To explain what sets human apart from their ape relatives, researchers have long hypothesized that it is not so much the DNA sequence, but rather the regulation of the genes (i.e. when, where and how strongly the gene is expressed), that plays the key role. However, precisely pinpointing the regulatory elements which act as 'gene dimmers' and are positively selected is a challenging task that has thus far defeated researchers (see box).

Marc Robinson-Rechavi, Group Leader at SIB and study co-author says: "To be able to answer such tantalizing questions, one has to be able identify the parts in the genome that have been under so called 'positive' selection [see box]. The answer is of great interest in addressing evolutionary questions, but also, ultimately, could help biomedical research as it offers a mechanistic view of how genes function."

A high proportion of the regulatory elements in the human brain have been positively selected

Researchers at SIB and the University of Lausanne have developed a new method which has enabled them to identify a large set of gene regulatory regions in the brain, selected throughout human evolution. Jialin Liu, Postdoctoral researcher and lead author of the study explains: "We show for the first time that the human brain has experienced a particularly high level of positive selection, as compared to the stomach or heart for instance. This is exciting, because we now have a way to identify genomic regions that might have contributed to the evolution of our cognitive abilities!"

To reach their conclusions, the two researchers combined machine learning models with experimental data on how strongly proteins involved in gene regulation bind to their regulatory sequences in different tissues, and then performed evolutionary comparisons between human, chimpanzee and gorilla. "We now know which are the positively selected regions controlling gene expression in the human brain. And the more we learn about the genes they are controlling, the more complete our understanding of cognition and evolution, and the more scope there will be to act on that understanding," concludes Marc Robinson-Rechavi.

Box - Positive selection: a hint of the functional relevance of a mutation

Most random genetic mutations neither benefit nor harm an organism: they accumulate at a steady rate that reflects the amount of time that has passed since two living species had a common ancestor. In contrast, an acceleration in that rate in a particular part of the genome can reflect a positive selection for a mutation that helps an organism to survive and reproduce, which makes the mutation more likely to be passed on to future generations. Gene regulatory elements are often only a few nucleotides long, which makes estimating their acceleration rate particularly difficult from a statistical point of view.

Communication, serendipity and an enzyme called DOT1L have all combined to produce some exciting findings into the immune system's B cells and T cells by two groups of Monash Biomedicine Discovery Institute (BDI) scientists. These could result in further studies into a target for asthma and allergies, and fundamental work exploring the formation of immunity itself.

Two papers on DOT1L by teams led by Professor Colby Zaph and Associate Professor Kim Good-Jacobson - whose labs are next door to each other - were each published in Cell Reports today.

Professor Zaph found that the enzyme was critical in controlling how T cells - white blood cells critical for immunity to infections - make the choice to develop into distinct subsets.

T cells have the ability to adopt a variety of fates that depend on the type of infection they face. Type 1 T cells (Th1) for example are critical for clearing viral infections, while type 2 T cells (Th2) are required for immunity to worm parasites. Critically, dysregulated Th1 cells can cause diseases such as inflammatory bowel disease, diabetes and arthritis, and uncontrolled Th2 cell responses can lead to asthma and allergies.

Professor Zaph said the fundamental research began with a collaboration with the Structural Genomics Consortium, a public-private partnership that creates and freely distributes chemical inhibitors of enzymes.

"It was a classic fishing experiment," he said. "We just thought we'd see what changed when we put the inhibitor with the T cells. For a lot of these enzymes nothing changed at all but the DOT1L inhibitor really changed the function of the T cells making them hyper-functional.

"What we found for the first time was that this protein DOT1L was critical for T cell differentiation and activating T cell function," he said.

In this new study, the researchers found that genetically eliminating DOT1L in preclinical models led to the naïve T cells all becoming type 1 cells, which meant the cells were unable to clear worm infections but were good in countering viral infections.

"DOT1L is now a potential target not only to promote type 1 immune responses for vaccine responses for viruses but could also be a good way to reduce type 2 response, which is good for clearing worms," Professor Colby said.

"We also showed that in the absence of DOT1L you don't get asthma developing in preclinical models or the lung inflammation that causes allergies, making DOT1L a nice target to look at in future studies in asthma pathways."

DOT1L is already in clinical trials for human patients mostly for cancer, especially lymphoid cancers.

First author on the paper was Dr Sebastian Scheer.

The findings highlighted the fact that the same protein could have multiple effects under different conditions suggesting that care be taken in clinical trials. Associate Professor Good-Jacobson's research also underscored this and, like Professor Colby's, emphasised the importance of DOT1L.

"There are a number of drugs in early clinical trials to target DOT1L for acute lymphoblastic leukaemia, but there is little known about how turning DOT1L off would effect the ability of B cells to form antibodies," she said.

Associate Professor Good-Jacobson said earlier work by her team had found that certain types of B cells expressed DOT1L. "That finding, combined with early work that Colby had done into the specific role of T cells, gave us impetus to investigate whether it was essential for B cells," she said.

B cells are critical in protecting us from viral infections. Their protective power comes from producing antibodies to help clear an infection, and immune memory cells that respond rapidly to prevent illness if you are reinfected. The formation of antibodies underpins the vast majority of vaccines.

Research by Associate Professor Good-Jacobson's team revealed that DOT1L was critical to turning on an effective B cell response during infection or in response to immunisation.

"What we found was that if B cells didn't have DOT1L they were able to be turned on by infection but the engine would sputter out, they'd get to a certain point in forming an antibody response but couldn't go any further - they are completely shut down before productive antibody and immune memory can be formed," she said.

"If you're going to use a drug that stops DOT1L from functioning it's really important to know what it's actually regulating because it's critical for the body to mount an effective antibody response to infection. You're going to have problems fighting off infection down the track if you're using these drugs."

Understanding how B cells are regulated during the early part of the immune response was critical from a fundamental biological perspective, Associate Professor Good-Jacobson said.

"Our next step is to look at this molecule in the formation of immunity itself," she said.

Associate Professor Good-Jacobson's team will also interrogate DOT1L for its role in driving oncogenic genes in a number of B cell-derived cancers.

Researchers at the University of Eastern Finland and Kuopio University Hospital have discovered several new biomarkers that are associated with incident heart failure. In a new study, several inflammatory biomarkers and cell energy metabolites were linked to an increased risk of incident heart failure.

The study used a random selection of 10,106 men participating in the Metabolic Syndrome in Men (METSIM) study, who at baseline did not have a diagnosis of incident heart failure. Elevated levels of inflammatory biomarkers and several biomarkers associated with heart metabolism, which were measured by NMR analysis, were associated with the development of incident heart failure in a follow-up that lasted for 8.8 years. These new biomarkers included adiponectin, high?sensitivity C?reactive protein, the chronic inflammation biomarker GlycA, the amino acids alanine and phenylalanine, as well as glycerol and pyruvate, which the heart muscle uses for energy. After adjustment for age, BMI, diabetes and statin medication, adiponectin, pyruvate and urinary albumin excretion rate were associated with the development of incident heart failure.

In this study, the most common heart diseases underlying incident heart failure were elevated blood pressure, coronary artery disease and especially previous myocardial infarction. More rarely, incident heart failure was caused by cardiomyopathy or valvular heart disease. Diabetes, systolic blood pressure, age, overweight, high insulin levels, declining kidney function and microalbuminuria, which are well?established risk factors for heart failure, were also associated with the development of incident heart failure.

The researchers used principal component analysis to classify incident heart failure associated risk factors and biomarkers into components that could possibly be linked to different courses of the disease. Four of these components were statistically significant for the development of incident heart failure. Three of the components contained a different inflammatory biomarker and one contained cell energy metabolites.

"Incident heart failure is typically associated with changes in heart metabolism as well as with low-grade, chronic inflammation. Based on our study, these changes are present even years before any sign of heart failure," Professor Johanna Kuusisto from the University of Eastern Finland says.

Earlier studies conducted in animal models have shown that disturbed metabolism of the heart muscle precedes, initiates and maintains unfavourable changes in the heart. However, the newly published study is the first to show that biomarkers of energy metabolism predict the development of incident heart failure in humans.

By measuring biomarkers indicative of heart failure, it could be possible to better identify people with an elevated risk of developing incident heart failure.

"Despite the treatments we have today, the prognosis of incident heart failure is still very poor, and this is why it is important to identify and treat high-risk patients already before the disease develops," Professor Kuusisto says.

Further research is needed to analyse whether drugs targeting inflammatory and metabolic pathways could be used to prevent the development of incident heart failure.

A new paper released by Columbia University Mailman School of Public Health reports a strong association between a high number of adverse childhood experiences (ACEs) and contact with the U.S. justice system. Analyzing data from eleven studies, the researchers found that results were consistent across multiple types of justice system contact and across diverse geographic regions of the country. The findings are published in Pediatrics.

"We found consistent evidence that higher ACE scores are associated with greater risks of juvenile justice system contact in the United States," said Gloria Graf, a doctoral student in epidemiology at Columbia Mailman School, and first author.

ACEs are a set of childhood adversities, including household dysfunction, various forms of abuse and neglect, peer victimization and exposure to community violence occurring before the age of 18.

The researchers reviewed five databases for all observational studies conducted through January 2020 that assessed associations between ACE score and justice system contact. Databases included PubMed, PsycINFO, ProQuest, Web of Science, and Google Scholar.

A total of 11 studies were selected for inclusion in the final review based on their relevance. In 10 of 11 studies, the researchers found elevated scores were associated with increased risk of connection with the juvenile justice system.

For the 11 studies three reported juvenile arrest as their primary outcome of interest, two examined sexual offending, two examined juvenile re-offending, and one each examined serious, violent, and chronic delinquency as a juvenile, early juvenile offending, juvenile gang involvement, early adulthood felony charge, and adult incarceration.

"Over the past two decades, ACEs have emerged as an important risk factor for a broad range of health problems across the lifespan. Justice system contact appears to be a major pathway underlying the profound impact of ACEs on health outcomes and health disparities," said Guohua Li, MD, DrPH, Columbia Mailman School professor of Epidemiology, and senior author.

Of particular interest to public health is the relationship between childhood trauma and justice system involvement given the wide-ranging individual and community impacts of incarceration and policing. At the community level, incarceration destabilizes family structures and hampers employment and economic opportunity, political participation, and neighborhood cohesion. Graf and Li make the point that given the concentration of childhood trauma and justice system involvement in disadvantaged communities, evidence regarding the association of ACEs with justice system contact is potentially helpful for policymakers, those working with justice-involved persons, and public health practitioners alike.

"There is no question that research examining longer-term outcomes of ACEs is needed" noted Graf. 'Life-course epidemiology is well suited for understanding ACE-related adverse health consequences in adulthood and later life."

Researchers have developed a way to use a simple home aroma diffuser to test whether N95 and other types of sealing masks, such as KN95 and FFP2 masks, are properly fitted, a result which could be used to help protect healthcare workers and the public from contracting or transmitting COVID-19.

The researchers, from the University of Cambridge, tested a variety of materials to construct a new inexpensive and reliable method for assessing the fit of masks. Commercial testing equipment has been in extremely short supply since the outbreak of the COVID-19 pandemic, forcing many healthcare institutions to abandon regular fit-testing of their staff.

Their results, published in the journal Disaster Medicine and Public Health Preparedness, found that widely-available alternatives, such as aroma diffusers and extra-large freezer bags, can be used to make a qualitative fit-testing setup which performs at a similar level to commercial solutions.

While commercial kits typically cost several hundred pounds, the Cambridge setup can be made for under £35. In addition to its potential benefits to the healthcare industry, this inexpensive setup can be used by anyone who wants to test the fit of their mask at home.

The researchers caution, however, that their setup will only test the fit of sealing masks with high filtration ability, such as N95, FFP3, KN95 or FFP2 masks. The method cannot be used to test the fit of surgical or fabric masks, as these do not typically offer the fit or filtration necessary to pass a qualitative fit-test.

Sealing masks offer the wearer a high level of protection, but only if they fit properly, with no gaps between the mask and the wearer's face. Previous studies have found that even if the mask material is highly efficient at filtering fine particles, the effectiveness of the mask is hampered by an imperfect seal.

"So far, there has not been an inexpensive, accessible, and reliable way of testing the fit of sealing masks," said Eugenia O'Kelly from Cambridge's Department of Engineering, the study's first author. "Shortages of the fit-testing equipment that healthcare facilities normally use have left some of them unable to test their workers. And those who do not work in healthcare have had no reliable way to ensure their masks fit."

Most healthcare facilities use qualitative fit-testing methods on their staff, as these are faster and cheaper than quantitative methods. Qualitative fit-testing requires three key pieces of equipment: a testing solution, a diffuser to atomise the solution, and a testing hood.

To carry out a typical fit-test, a user places the hood over their head while wearing a mask, and the solution is aerosolised into the enclosure as a fine mist. The solution is usually sweet or bitter. The fit of the mask is assessed by how well the user can taste the solution while nodding their head or speaking. If the mask fits the wearer, they will not be able to taste the solution.

When COVID-19 struck, the increase in demand for fit-testing supplies, combined with breakdowns in manufacturing and supply chains, meant it became very difficult to get qualitative test equipment, with wait times extending weeks or even months.

"Solving the fit-testing supply crisis is critical to enable hospitals and businesses to properly protect their workers," said O'Kelly.

Meanwhile, those outside of healthcare facilities who use non-sealing face masks are left with no reliable way to determine the fit of their masks. "Many people are using KN95 or FFP2 masks," said O'Kelly. "While these masks can offer high levels of protection, they do not fit everyone. We also wanted to offer a way for the public, particularly those who are at high risk, to evaluate the fit of these masks for themselves."

Previous research has assessed the safety and efficacy of homemade testing solutions; however, no effective alternatives to the atomising equipment or enclosures had yet been identified.

Now, the researchers have identified alternatives to these pieces of the testing apparatus which are around a quarter of the cost of commercial equipment and are readily available from many retailers, including Amazon.

To diffuse the solution, the researchers tested an aroma diffuser, humidifier, mist maker and spray bottle. For the enclosure, they tested a plastic bag, testing hood, a clear storage cube and no enclosure. Testers first underwent quantitative fit-testing to assess the fit on their faces before the qualitative methods. Quantitative testing measures the number of particles inside and outside the mask and is highly accurate. However, it is also time-consuming and expensive, which is why qualitative testing is more frequently used in healthcare settings.

Using an N95 mask from 3M and a KN95 mask from a Chinese manufacturer, the testers then assessed the alternative devices and enclosures. A solution of sodium saccharin - an artificial sweetener - was aerosolised for 60 seconds at a time, and testers were asked whether they could taste the sweetener or not. The test was then repeated with the tester causing an intentional gap in the fit by placing the tip of a finger between the mask and their face.

They found that the combination of an aroma diffuser and a small container, such as a large plastic bag, provided the most accurate and most sensitive setup, with results comparable to commercial qualitative fit-testing solutions.

"Our homemade replacement requires further testing for safety and efficacy: in particular, the use of a plastic bag to concentrate the vapour remains a safety concern," said O'Kelly. "However, we were happy to find an inexpensive setup to assess the fit of masks when used in combination with homemade fit-testing solution. Given the importance of masks in slowing the spread of COVID-19 and other airborne viruses, it's essential that they fit properly, especially in healthcare settings."

AURORA, Colo. (Dec. 15, 2020) - Researchers at the University of Colorado Anschutz Medical Campus have discovered that fructose stimulates the release of vasopressin, a hormone linked to obesity and diabetes. They also found that water can suppress the hormone and alleviate these conditions in mice.

"The clinical significance of this work is that it may encourage studies to evaluate whether simple increases in water intake may effectively mitigate obesity and metabolic syndrome," said the study's lead author Miguel A. Lanaspa, PhD, an associate professor at the University of Colorado School of Medicine specializing in renal disease and hypertension.

The study was published today in the journal JCI Insight.

Lanaspa and his colleague, Richard Johnson, MD, also a professor at the CU School of Medicine, wanted to understand why vasopressin, which maintains the body's water levels, was elevated in those with obesity and diabetes.

They fed mice sugar water, specifically fructose, and found that it stimulated the brain to make vasopressin. The vasopressin in turn stored the water as fat causing dehydration which triggered obesity. Treating the mice with non-sugary water reduced the obesity.

According to Lanaspa, this is the first time scientists have shown how vasopressin acts on dietary sugar to cause obesity and diabetes.

"We found that it does this by working through a particular vasopressin receptor known as V1b," he said. "This receptor has been known for a while but no one has really understood its function. We found that mice lacking V1b were completely protected from the effects of sugar. We also show that the administration of water can suppress vasopressin and both prevent and treat obesity."

The researchers also discovered that dehydration can stimulate the formation of fat.

"This explains why vasopressin is so high in desert mammals as they do not have easy access to water," Johnson said. "So vasopressin conserves water by storing it as fat."

This data fits with observations showing that obese people often have signs of dehydration. It also explains why high salt diets may also cause obesity and diabetes.

The researchers found that water therapy effectively protected against metabolic syndrome - a collection of conditions including high blood pressure, high blood sugar and high triglyceride levels that increase the risk of heart disease, stroke and type 2 diabetes.

"The best way to block vasopressin is to drink water," Lanaspa said. "This is hopeful because it means we may have a cheap, easy way of improving our lives and treating metabolic syndrome."

Johnson summed up the findings this way.

"Sugar drives metabolic syndrome in part by the activation of vasopressin. Vasopressin drives fat production likely as a mechanism for storing metabolic water," he said. "The potential roles of hydration and salt reduction in the treatment of obesity and metabolic syndrome should be considered."

In the search for new ways to treat the incurable eye disease glaucoma, researchers at Karolinska Institutet and St. Erik Eye Hospital in Sweden have discovered more clues as to its pathogenesis. A new study shows how metabolic disturbance of the neurons coincide with raised pressure in the eye. In animal and cell models, rapamycin and pyruvate treatments were shown to have a protective effect. The study is published in the journal PNAS.

Glaucoma is an incurable disease that leads to partial or total loss of vision in 80 million people worldwide, 100,000 - 200,000 of whom in Sweden. The three major risk factors are age, high intraocular pressure, and genetic predisposition. The only treatment strategies currently available target the pressure in the eye using eye drops or surgery; despite this, the risk of blindness in one eye is still high.

A new study now reveals a connection between metabolic disturbance in the retinal ganglion cells (nerve cells in the retina whose axons make up the optic nerve) and high intraocular pressure. In animal models, the researchers have found a blocking of the cells' ability to convert glucose into other essential molecules, one of which is pyruvate.

"We demonstrate how glaucoma is associated with metabolic disturbance in these cells," says Pete Williams, research group leader at the Department of Clinical Neuroscience, Karolinska Institutet and head of St. Erik Eye Hospital's new glaucoma laboratory. "More specifically, we show that there is a correlation between high intraocular pressure and low levels of pyruvate. When we gave a pyruvate supplement it had a protective effect in both animal and cell models."

He continues: "We need to explore this connection more closely and see if it applies to humans too. We want to focus on cheap and readily available substances and dietary supplements able to complement current treatment methods for glaucoma."

The researchers also studied the relationship between the regulation of mTOR, an important protein in cellular metabolism, and glaucoma. Their results demonstrate how the mTOR-inhibitor rapamycin, which is approved for other diseases, was also able to protect the retinal ganglion cells.

The study was conducted on rodent models of glaucoma and cell and tissue models and involved, amongst other techniques, RNA sequencing and metabolomics to identify changes in the retinal ganglion cells.

The research group at Karolinska Institutet and St. Erik Eye Hospital have been researching glaucoma for many years, and have previously found a correlation between low levels of the molecule NAD and old age and elevated intraocular pressure. A clinical study published this summer showed that following administration of nicotinamide (the amide of vitamin B3), one quarter of the study participants reported improved vision.

A clinical study is now underway at Columbia University Medical Center that combines pyruvate with nicotinamide.

"Meanwhile, we're continuing the basic research on metabolism in the retinal ganglion cells and trying to find biomarkers for the disease," adds Dr Williams. "This will give us more tools for treating these patients in the future."

Scientists have shown for the first time that cerebral malaria causes death in adults by triggering oxygen-deprivation in the brain, in new research published in Clinical Infectious Diseases.

Already available treatments, such as hypothermia, may slow brain oxygen-deprivation in cerebral malaria patients. The researchers say these neuronal survival-enhancing approaches could soon be trialled in adults with cerebral malaria, alongside existing anti-malarial treatments, to hopefully improve survival.

In 2019, there were an estimated 229 million cases of malaria worldwide. The estimated number of malaria deaths stood at 409,000 in 2019. Cerebral malaria is a severe, life-threatening complication of Plasmodium falciparum infection, the most widespread and lethal of the five malaria parasites that can infect humans through the bite of Anopheles mosquitoes. Up to 20% of people with cerebral malaria die despite anti-malarial treatment, and neurocognitive after-effects are common in survivors.

The research team, based at the London School of Hygiene and Tropical Medicine (LSHTM), Ispat General Hospital, Heidelberg University, and the Center for the Study of Complex Malaria in India, used cutting-edge MRI scanning techniques to monitor the brains of cerebral malaria patients. The Center for the Study of Complex Malaria in India is one of the International Centers of Excellence for Malaria Research funded by the U.S. National Institutes of Health.

By comparing the changes in the brains of survivors with those who died from the disease across different age-groups, they revealed that death in adults was frequently associated with severe oxygen-deprivation, or hypoxia.

For children, however, the study confirmed previous research findings in Africa that severe brain swelling, leading to respiratory arrest, was the most common cause of death in this age group.

Co-lead of the study and Associate Professor in Malaria Pathogenesis at LSHTM, Dr Sam Wassmer, said: "The effects of malaria on the brain - the body's most inaccessible organ - have puzzled scientists for the last century. But now the emergence of neuroimaging facilities in malaria-endemic areas is revolutionising our understanding, allowing us to see what's going on inside patients' brains."

65 patients with cerebral malaria and 26 control patients with 'uncomplicated' malaria, who were being treated at Ispat General Hospital in Rourkela, India, participated in the study. They received a type of MRI scan that allows precise measurement of changes in the volume of the brain, an indicator of swelling, and the diffusion of water molecules in the tissue, an indicator of oxygen deprivation.

The team found that brain swelling tends to decrease with the age of the patient, and that, unlike in children, there was no correlation between brain swelling and death in adult patients from the same cohort.

Instead, fatal adult cases were found to have severe oxygen deprivation affecting all brain structures, compared to only localised oxygen-deprivation in survivors. This was corroborated by significantly elevated levels of specific molecules in the blood, which also indicate oxygen-deprivation. These could be used to allow the identification of patients at risk of developing fatal disease upon admission and inform their clinical management.

Dr Wassmer said: "For years, scientists have relied on autopsies to understand the pathology of cerebral malaria, but these don't allow you to compare between survivors and fatalities. By using neuroimaging techniques to see a snapshot of the living brain, we were able to identify the specific cause of death in adults.

Dr Sanjib Mohanty, study co-lead from the Centre for the Study of Complex Malaria, India, said: "The results suggest the tantalising prospect of targeted treatments for cerebral malaria, and we are now planning clinical trials to test whether adjunctive therapies for oxygen-deprivation are effective for adults. If successful, this could be a significant step toward reducing the death toll of one of the world's most deadly diseases."

JUPITER, Fla. --Dec. 14, 2020--Imagine trying to throw a bullseye when the dartboard lies buried within a crumpled box. That's the challenge faced by scientists working to make new medicines for some "undruggable" diseases, including a type of metastatic breast cancer.

Scientists refer to diseases as "undruggable" when their targets lie on a protein molecule that folds inward, or in a way that shields the active site from would-be treatments.

Addressing this problem of "undruggable" proteins, a team of Scripps Research scientists has invented a tool that bypasses the awkward proteins completely, and instead modifies elements involved in their construction and regulation. This new tool, called Chem-CLIP-Fragment Mapping, focuses on RNA, molecules that read genes and help build proteins, among other duties.

RNAs have not been viewed as drug targets until recently, due to challenges that include a short-lived existence, changeable shape, and limited array of building blocks. The new RNA drug-discovery tool, described in Monday's issue of the Proceedings of the National Academy of Sciences, addresses these and other challenges to enable both the rapid discovery and optimization of RNA-targeting compounds, says Chemist Matthew Disney, PhD, of Scripps Research, Florida.

"It allows us to tackle very hard molecular recognition problems to enable us to make lead medicines across multiple indications," Disney says. "This opens great potential to redefine what's truly 'undruggable.'"

Disney and first author Blessy Suresh, a graduate student in his lab, demonstrate the tool's power by identifying a medicinal compound that acts on an important breast cancer target. Their article, "A general fragment-based approach to identify and optimize bioactive ligands targeting RNA," was written in collaboration with Scripps Research Chemist Christopher Parker, PhD.

The system adapts a recent advance in protein-targeting drug-discovery which uses weakly binding, drug-like chemical fragments to reveal promising templates. Here, the fragments are "functionalized," or appended with tags and light-sensitive modules, allowing them to be seen and identified, a protein-targeting strategy originally developed by Parker as a postdoctoral fellow in the lab of Scripps Research biochemist Benjamin Cravatt, PhD. Key to the system's use with RNA are technologies and databases built in Disney lab over a decade.

"This is what Scripps Research is, we develop tools," says Parker, now an assistant professor at Scripps Research, Florida. "Our collaborative environment allows us to do this."

The Chem-CLIP-Frag-Map system accelerates the drug-discovery effort because it reveals multiple opportunities to bind, and hence modify, the RNA targets, Disney explains. This helps scientists engineer and optimize potential medicines to bind more tightly, be more specific, and less apt to have off-target side-effects, right from the beginning, saving time.

"These two things bind cooperatively, and so the whole is better than the parts," Disney says.

For their proof-of-concept study, the Scripps Research team used the Chem-CLIP-Frag-Map tool to find compounds for microRNA-21, a key RNA involved in triple-negative breast cancer, an aggressive type of breast cancer that lacks precision-targeted treatments.

"The system helped us optimize the fragments to design bioactive complexes with higher selectivity and potency as compared to starting fragments," Suresh says. "We were able to screen 460 fragment-based probes in just a couple of hours. This screening method can be easily scaled up to a much more high-throughput format."

The Chem-CLIP-Frag-Map tool uses a light-sensitive module called a diazirine group that covalently crosslinks to RNA with exposure to UV light.

"This is a chemical that has a weak magnet-like attraction to other nearby molecules. So when it's placed near disease-associated proteins, or now RNAs, it can thus bind to them, revealing the shape a medicine would need to take to bind to that disease-associated protein or RNA," Disney explains.

Most people diagnosed with breast cancer respond to a precision medicine, such as those that act on the hormones estrogen or progesterone, or those that target a protein called HER2. People whose cancer doesn't fit either of those categories are dubbed "triple negative." Triple-negative breast cancer affects 10 to 15 percent of all people diagnosed with breast cancer. Triple-negative breast cancers tend to be more aggressive, and have a worse prognosis, as some key proteins have been deemed undruggable.

The new drug-discovery tool shows that undruggability need not end the search for precision treatments, Disney says.

"For every protein encoded in human DNA, there are 75 or 80 types of RNA encoded, so this new tool offers great hope for virtually all diseases now deemed 'undruggable,' including triple-negative breast cancer," Disney says.

Since the beginning of the COVID-19 pandemic, there have been reports in the professional literature on possible hearing loss caused by the disease. A new study from Tel Aviv University (TAU), in collaboration with the Galilee Medical Center, finds no evidence of damage to the auditory system as a result of COVID-19 infection.

The study was led by Professor Karen Avraham of TAU's Sackler Faculty of Medicine. The results were published online in the journal Otology & Neurotology on December 8, 2020.

"Since the beginning of the pandemic, it has been clear that COVID-19 has some long-term effects, such as the loss of the sense of smell and taste," Professor Avraham explains. "The possibility of hearing loss, however, has been debated among medical practitioners, with some reporting this symptom in recovered patients.

"The question is whether such hearing loss is caused by damage to the auditory system, or whether it is a temporary symptom caused by fluids clogging the middle ear, as often happens with a common cold."

The researchers began to investigate this question during the first wave of the pandemic, when the numbers of patients in Israel were still relatively small. Participants included eight asymptomatic individuals who had tested positive for COVID-19 and eight healthy volunteers who served as a control group, none of whom reported any previous hearing loss. The study provided for the first time quantitative measures for hearing quality following exposure to the virus.

"Our study explored whether COVID-19 can cause permanent neural or sensory damage to the hearing system. We found no evidence for such damage," says co-author Dr. Amiel Dror of the Galilee Medical Center and the Azrieli Faculty of Medicine at Bar-Ilan University. "We measured electrical data from the brainstem to test the entire route of soundwaves through the ear until electric waves are ultimately received in the brain. We also examined the activity of the inner ear hair cells that intensify and tune the sound. We found no difference between the COVID-19-positive subjects and the control group."

"It's true that at this initial stage the study examined asymptomatic patients," Professor Avraham continues. "But objective scientific research takes a long time, and we started recruiting our volunteers in April, at the peak of the first wave pf the pandemic in Israel. There are so many speculations about this virus and the damage inflicted by it, and we have shown that at least in the auditory system no damage was detected."

"It's very important to base our knowledge of the virus upon objective studies and refrain from hasty conclusions," says Dr. Dror. "The social media have attributed numerous illnesses and symptoms to the coronavirus, but often the information is unfounded and leads to unwarranted stress, as well as needless pressure on the health system."

Co-author Dr. Eyal Sela of the Galilee Medical Center and the Azrieli Faculty of Medicine at Bar-Ilan University concludes, "This study proposes that the COVID virus does not cause extensive neurological damage but is rather spotty, mostly affecting the sense of smell. Moreover, the hearing impairment among some patients is mostly transient and secondary to fluid buildup in the middle ear, as for the common cold, and therefore likely passes once the acute disease is over."

The researchers are currently conducting a much more comprehensive study with hundreds of patients, including persons who had been severely ill and even ventilated.

Due to the COVID 19 pandemic and the associated intensive search for therapeutics and vaccines, the chemical substance class of nucleosides is experiencing an enormous increase in interest. Natural and synthetic nucleosides have an antiviral effect and can act as building blocks of ribonucleic acids (RNA). When incorporated into RNA, novel interactions within the macromolecule result with positive consequences for stability and biological effectiveness.

In medicinal chemistry, the molecular family of carbon (C)-nucleosides is particularly in demand. These differ from the naturally more frequently occurring nitrogen (N)-nucleosides - the classical building blocks of RNA - in the way the sugar is linked to the so-called nucleic base. Instead of a carbon-nitrogen bond, C-nucleosides have a carbon-carbon bond. This is biochemically much more stable and gives active ingredients a longer biological half-life. For the first time, two researchers from Graz University of Technology and the acib competence centre (Austrian Centre of Industrial Biotechnology) have now succeeded in biocatalytically producing C-nucleosides with the help of enzymes. The concrete results have been published in Nature Communications.

Yes to the enzyme "YeiN"

Bernd Nidetzky, Head of the Institute of Biotechnology and Bioprocess Engineering at TU Graz and at the same time Scientific Director of the Austrian Centre of Industrial Biotechnology (acib), and Martin Pfeiffer from acib discovered and characterized in a study the enzyme "YeiN", which can link the two nucleoside building blocks ribose-5-phosphates and uracil by means of a specific carbon bond. They are the first researchers worldwide to demonstrate an enzyme that is a suitable biocatalyst for the production of C-nucleosides.

Efficient and eco-friendly production

With the help of the catalytic power of "YeiN", the Graz-based company was able to produce several derivatives of the important C-nucleoid pseudouridine. They were also able to show that one of these derivatives can be incorporated into RNA and thus enable the modification of RNA. This is particularly relevant for the production of RNA-based therapeutic products, as the incorporation of pseudouridine into the RNA increases stability and half-life and thus improves the effectiveness of therapeutic RNA, such as a vaccine.

"In our study we show that pseudouridine can be produced biocatalytically. Compared to a purely chemical synthesis, this is a much more efficient way, since fewer reaction steps and no toxic chemicals are required. The biocatalytic production of C-nucleosides is therefore a very strong, elegant alternative to classical chemical synthesis and even superior to it in terms of efficiency," says Bernd Nidetzky. Based on the findings published in Nature Communications, research can now be conducted to expand the substrate spectrum of "YeiN". The goal? The biocatalytic synthesis of further relevant C-nucleosides.

RNA vaccines

The first comprehensive vaccinations against COVID-19 with RNA vaccines have been running for a few days. These completely novel vaccines contain genetic information of the pathogen and induce cells to produce a viral protein, which is then presented to the immune system. The subsequent immune reaction protects the body from an actual virus infection. If one is already infected with the virus, antiviral drugs can prevent the virus from multiplying.

The C-nucleoside based drug Remdesivir has these necessary antiviral properties and is effective against a number of RNA viruses, including corona and ebola viruses. The active ingredient has received conditional approval in the EU for the treatment of COVID-19 patients. The biocatalytic production of C-nucleosides could provide further impetus for this new hope as well as RNA vaccines based on C-nucleosides.