Body

For some years, an active substance from the leaves of an ornamental plant has been regarded as a possible forerunner of a new group of potent drugs. So far, however, it has been very laborious to manufacture it in large quantities. That could now change: Researchers at the University of Bonn (Germany) have identified a bacterium that produces the substance and can also be easily cultivated in the laboratory. The results are published in the journal Nature Communications.

The coralberry currently once again adorns many living rooms: In winter it bears bright red fruits, which make it a popular ornamental plant at this time of year. For pharmacists, however, it is interesting for a different reason: It contains an active substance that has emerged in recent years as a beacon of hope against asthma and certain types of cancer.

Unfortunately, obtaining the substance with the cryptic name FR900359 (abbreviated: FR) in larger quantities is rather laborious. Cultivating the plants in greenhouses takes many weeks; moreover, the yield can vary enormously depending on the specimen. Incidentally, they do not produce the active ingredient themselves, but have bacteria in their leaves that do it for them. "However, these only grow in the coralberry and cannot be cultivated in the laboratory," explains Dr. Max Crüsemann of the Institute of Pharmaceutical Biology at the University of Bonn.

Complex assembly line

Manufacturing FR is a complex undertaking. The bacteria have a special assembly line for this purpose, in which a number of enzymes work hand in hand. The bacterial genetic makeup specifies how this assembly line must be set up. "We have now searched huge databases for other microorganisms that also have these genes for FR synthesis," Crüsemann explains. "In the process, we came across another bacterium. Unlike its coralberry relative, it does not grow in plants, but in soil and is easily propagated in culture media."

This finding should greatly facilitate the production of FR in the future. However, it also allows more detailed insights into how the active substance works. "We have known for several years that FR inhibits an important group of signaling molecules in cells, the Gq proteins," explains Cornelia Hermes of the Institute of Pharmaceutical Biology. "That makes FR extremely effective: To date, no other compound is known to inhibit Gq proteins with similar potency."

Hermes is pursuing her doctoral studies in the group of Max Crüsemann and Prof. Gabriele König and, together with her colleague Dr. René Richarz, was responsible for a large part of the study now published. One of the questions the researchers explored was, why FR is such a good inhibitor. The molecule consists of two parts, the actual core and a side chain that is attached to it like an arm. Both are produced separately and then linked together. "The side chain is essential for the function of FR," Crüsemann explains. "When it is absent or even slightly modified, the inhibitory effect on Gq proteins decreases significantly."

Central control station in the cell

The function of Gq proteins in the cell is similar to that of the emergency call center of a city: They are the place where various signals from outside the cell converge. This activates them and then in turn certain metabolic processes are switched on or off. Instead of inhibiting numerous signaling pathways, it is therefore sufficient to inhibit the Gq protein in order to achieve a therapeutic effect. This means that FR is extremely effective, but also, if it were administered to the whole body, very toxic. "The goal is therefore to administer FR only to cells with pathologically altered behavior," Crüsemann explains. Bacterial genes can be easily and specifically modified nowadays. "In this way, we can in principle generate FR variants with specific properties, such as those that are transported precisely to certain cells in the body and only do their work there," says the pharmaceutical biologist.

The history of the FR molecule is therefore likely to be extended by another chapter as a result of the study: The active substance was discovered more than 30 years ago by Japanese researchers. In 2015, its biological mode of action was described by the research groups led by Professors Gabriele M. König and Evi Kostenis at the Institute of Pharmaceutical Biology. This work now forms the basis for a research group of the German Research Foundation (DFG). Today, more and more research groups around the world are exploring the potential of the molecule. With the newly discovered bacterium, they now have a new tool at hand.

COVID-19 patients who also suffer from high blood pressure are more likely to fall severely ill with the disease, which also leaves them at greater risk of death. Scientists from the Berlin Institute of Health (BIH) and Charité - Universitätsmedizin Berlin, in collaboration with partners in Heidelberg and Leipzig, have now found that the immune cells of patients with hypertension are already pre-activated, and that this pre-activation is greatly enhanced under COVID-19.

This most likely explains the augmented response of the immune system and the more severe disease progression. However, certain hypertension-reducing drugs known as ACE inhibitors can have a beneficial effect. They not only lower blood pressure, but also counteract immune hyperactivation. The scientists have now published their findings in the journal Nature Biotechnology.

More than one billion people worldwide suffer from high blood pressure, or hypertension. Of the more than 75 million people around the world who have become infected with the SARS-CoV-2 virus worldwide so far, more than 16 million also have hypertension. These patients are more likely to become severely ill, which in turn results in an increased risk of death. It was previously unclear to what extent treatment with antihypertensive drugs could be continued during a SARS-CoV-2 infection - and whether they were more likely to benefit or harm the patients. This is because antihypertensives interfere with the exact same regulatory mechanism that the novel coronavirus SARS-CoV-2 uses to enter the host cell and trigger COVID-19.

Professor Ulf Landmesser is Medical Director of the CharitéCenter 11 for Cardiovascular Diseases, Director of the Medical Department of Cardiology and BIH Professor of Cardiology on the Charité's Campus Benjamin Franklin in Berlin. He recognized early on that patients with hypertension or cardiovascular diseases often experienced a particularly critical disease progression with COVID-19. "The virus uses the receptor ACE2 as an entry portal into the cells, and the formation of this receptor is potentially influenced by the administration of antihypertensive drugs," explains Landmesser. "We had therefore initially feared that patients receiving ACE inhibitors or angiotensin receptor blockers might have more ACE2 receptors on their cell surfaces and thus become more easily infected."

Certain drugs that lower blood pressure could also help with COVID-19

To clarify this suspicion, the scientists analyzed individual cells from the respiratory systems of COVID-19 patients who were also taking medication for high blood pressure. Dr. Sören Lukassen, a scientist in Professor Christian Conrad's group at the BIH Digital Health Center, explains that they were subsequently able to give the all-clear: "We found that the drugs do not seem to cause more receptors to form on the cells. As a result, we do not believe that they make it easier for the virus to enter the cells in this way and thus cause the more severe course of COVID-19." On the contrary, cardiovascular patients taking ACE inhibitors actually displayed a lower risk of becoming severely ill with COVID-19. In fact, they displayed almost the same level of risk as COVID-19 patients without cardiovascular problems.

Severe course of COVID-19 linked to pre-activation of the immune system

The blood of hypertensive patients usually shows elevated levels of inflammation, which can be fatal in the case of a SARS-CoV-2 infection. "Elevated inflammation levels are always a warning signal that COVID-19 will be more severe, regardless of any cardiovascular issues," explains Landmesser. The scientists therefore employed single-cell sequencing methods to investigate the immune response of hypertensive patients with COVID-19.

"We analyzed a total of 114,761 cells from the nasopharynx of 32 COVID-19 patients and 16 non-infected controls, with both groups including cardiovascular patients as well as people without cardiovascular problems," reports Dr. Saskia Trump, research group leader in the lab of Irina Lehmann, who is BIH Professor for Environmental Epigenetics and Lung Research. "We found that the immune cells of the cardiovascular patients displayed strong pre-activation even before infection with the novel coronavirus," explains Lehmann. "After contact with the virus, these patients were more likely to develop an augmented immune response, which was associated with the severe disease progression of COVID-19. However, our results also showed that treatment with ACE inhibitors, though not with angiotensin receptor blockers, could prevent this augmented immune response following infection by the coronavirus. ACE inhibitors could thus reduce the risk of patients with hypertension from experiencing severe disease progression."

Delayed reduction in viral load

Furthermore, the scientists found that the anti-hypertensive drugs can also impact how quickly the immune system is able to reduce the viral load, i.e., the concentration of the virus in the body. "Here, we observed a clear difference between the different forms of treatment for high blood pressure," notes Roland Eils, Director of the BIH Digital Health Center. "In the patients treated with angiotensin II receptor blockers, the reduction in viral load was significantly delayed, which could also contribute to a more severe course of COVID-19. We did not observe this delay in the patients who were receiving ACE inhibitors to treat their hypertension."

Interdisciplinary collaboration speeds up research

More than 40 scientists have been working at a breakneck pace on this extensive study. "The ability to quickly provide answers to urgent questions during the ongoing pandemic requires interdisciplinary collaboration among many committed individuals," explains Eils. "COVID-19 is such a complex disease that we brought together experts from cardiology, immunology, virology, pulmonary medicine, intensive care and computer science for this study. Our goal was to provide a scientifically sound answer as quickly as possible to the question of whether simultaneous treatment with ACE inhibitors or angiotensin receptor blockers could have beneficial or even adverse effects during the COVID-19 pandemic."

No evidence of increased risk of infection

Thanks to the study, the teams from the BIH, Charité and collaborating institutions in Leipzig and Heidelberg can now reassure both patients and the physicians treating them: "Our study provides no evidence that treatment with anti-hypertensive drugs increases the risk of infection by the novel coronavirus," says Ulf Landmesser, summarizing the results. "However, treating hypertension with ACE inhibitors could be more beneficial for patients suffering from COVID-19 than treatment with angiotensin II receptor blockers - a hypothesis that is currently being further investigated in randomized trials."

Use of telehealth jumped sharply during the first months of the coronavirus pandemic shutdown, with the approach being used more often for behavioral health services than for medical care, according to a new RAND Corporation study.

Between mid-March and early May 2020, telehealth was used by more than 40% of patients with a chronic physical health condition and by more than 50% of those with a behavioral health condition, according to findings published in the Journal of General Internal Medicine.

Overall, almost half of the people who were undergoing treatment when the pandemic shutdown began reported using some form of telemedicine.

Researchers found that the use of telehealth for behavioral health conditions was lower among women and among people over the age of 60. Use of telehealth also was lower among Non-Hispanic Whites relative to Non-Hispanic Blacks, and was lower among those with less than a high school education relative to those with a college degree.

"While the increased use of telehealth was widespread, some groups of Americans reported using the services less often than others," said Dr. Shira H. Fischer, the study's lead author and a physician researcher at RAND, a nonprofit research organization. "If telehealth use is going to remain high, we need to ensure equity of access, particularly for behavioral health care where education, age and gender were all associated with levels of use."

In a finding with important implications for the future of telehealth, researchers also found that during the pandemic a large majority of telehealth users connected with their own doctor rather than a new or unfamiliar doctor.

Prior to the pandemic, patients frequently were reluctant to use telehealth because it often meant seeing a provider other than their own physician. According to researchers, sustaining the ability to see one's own doctor through telehealth may be critical to making telehealth a permanent part of routine health care.

Many reports have documented a spike in the use of telehealth services after the shutdown prompted by the coronavirus pandemic. The increase was made possible by emergency regulatory changes that were adopted to promote use of telehealth.

RAND researchers examined the increase in telehealth by surveying 2,052 adults who are a part of the RAND American Life Panel, a nationally representative internet panel. The questions about use of telehealth were part of a larger survey about life during the pandemic that was fielded between May 1 and May 6.

When the pandemic began, nearly 40% of the Americans surveyed were being treated for a chronic physical health condition, while 15% were being treated for a behavioral health condition. Since the pandemic started, 16% had considered seeking care for a new or recurrent condition.

The study found that among patients who were receiving care when the pandemic began, 11% had used telehealth that included video conferencing from the middle of March to early May, a period of less than two months. In contrast, a survey conducted with the same panel in 2019 found that fewer than 4% had ever used video conferencing with a doctor.

Among people who used telehealth services, researchers found that the use of video telehealth was less common for physical health care (14% of patients) than for behavioral health care (30% of patients).

Lack of insurance was associated with lower telehealth use for new conditions, while use of telehealth was more common in the Northeast than other parts of the nation.

"There is a wide expectation that telehealth will continue after the pandemic ends. Lessons from the use of telehealth during this period should inform policy for the post-COVID-19 era," Fischer said.

In countries with a severe shortage of surgeons it is common for some operations to be carried out by medical staff with lower formal qualifications. Researchers at Karolinska Institutet, Sweden, have led an international study on the safety and efficacy of a common surgical procedure. The study, published in
JAMA Network Open, shows that inguinal hernia operations performed by associate clinicians at a hospital in Sierra Leone were just as safe and effective as those performed by doctors.

Many Sub-Saharan countries have a desperate shortage of surgeons, and to ensure that as many patients as possible can be treated, some operations are carried out by medical professionals who are not specialists in surgery. Such task sharing is supported by several bodies, including the World Health Organisation.

There are to date few clinical investigations into the safety and effectiveness of task sharing. Now researchers at Karolinska Institutet and, amongst other places, Kamakwie Wesleyan Hospital, Sierra Leone, have compared inguinal hernia operations performed by associate clinicians with those performed by non-specialist medical doctors. In Sierra Leone, medical doctors have no specific training in surgery but routinely perform surgical procedures as part of their regular work.

An estimated 220 million people around the world live with an inguinal hernia, which causes significant suffering and, 40,000 deaths each year. Twenty million inguinal hernia operations are performed every year, making it the most common general surgical procedure in the world, including in low-income countries like Sierra Leone. In Sierra Leone there are fewer than one surgeon per 100,000 population, and task sharing between MDs and associate clinicians is one way to provide general surgery to many people.

The study included 229 men operated on for inguinal hernia between 2017 and 2018 at a district hospital in rural Sierra Leone. The patients were randomly assigned to a doctor or an associate clinician for their surgery and were followed up after two weeks and one year.

The results suggest that task sharing with associate clinicians provides safe and effective surgery for non-life threatening inguinal hernias in countries where there is a shortage of surgeons.

"The study showed that associate clinicians were not inferior to registered doctors when it comes to recurrence, complications, groin pain or patient satisfaction," says the paper's last author Jenny Löfgren, assistant professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet. "There were even fewer cases of recurrence in the patients who had been operated on by associate clinicians compared to the group operated on by MDs. This was an extremely unexpected finding and task sharing appears to be an attractive option that can help the millions of people suffering from inguinal hernia."

The researchers' next step is to develop training programmes for doctors and associate clinicians in order to expand surgical services. Forthcoming studies will be conducted in Sierra Leone and Uganda.

Pregnant women who exercise more during the first trimester of pregnancy may have a lower risk of developing gestational diabetes, according to a new study led by Samantha Ehrlich, an assistant professor in the Department of Public Health at the University of Tennessee, Knoxville, and adjunct investigator with the Kaiser Permanente Division of Research. The analysis found that lower risk was associated with at least 38 minutes of moderate intensity exercise each day--a bit more than current recommendations of at least 30 minutes a day five days a week.

Gestational diabetes refers to diabetes diagnosed for the first time during pregnancy. It can pose serious health problems including pregnancy and delivery complications as well as increased future risk for diabetes in both mother and child.

Ehrlich said, "We know that exercise is safe and beneficial for healthy pregnant women. These results show that exercise is helpful in avoiding gestational diabetes, though you might need to do a little bit more than currently recommended to enjoy that benefit."

The observational study was based on women's self-reported levels of exercise during their first trimester of pregnancy. It found that exercising at least 38 minutes per day lowered the risk of gestational diabetes by 2.1 cases per 100 women and the risk of abnormal blood sugar by 4.8 cases per 100 women.

"We know that six to 10 women per 100 get gestational diabetes," Ehrlich said. "If being more active could reduce that by two women per 100, that's a clear benefit."

The study, published December 21 in the journal Diabetes Care, analyzes data collected for the Pregnancy Environment and Lifestyle Study (PETALS), a longitudinal study that included a physical activity questionnaire from 2,246 pregnant members of Kaiser Permanente Northern California. The women in the study were racially and ethnically diverse and of a wide range of pre-pregnancy weight classifications.

The authors suggest that the current recommendations may need to be rethought to improve women's chances of preventing gestational diabetes with exercise. The most recent guidelines from the American College of Obstetricians and Gynecologists were updated in 2020, and those from the US Department of Health and Human Services were updated in 2018.

Two studies in today's Nature Neuroscience, led by researchers at Boston Children's Hospital, Brigham and Women's Hospital (BWH), and Harvard Medical School (HMS), implicate mosaic mutations arising during embryonic development as a cause of autism spectrum disorder (ASD). The findings open new areas for exploring the genetics of ASD and could eventually inform diagnostic testing.

Mosaic mutations affect only a portion of a person's cells. Rather than being inherited, they arise as a "mistake" introduced when a stem cell divides. A mutation in a stem cell will only be passed to the cells that descend from it, producing the mosaic pattern. When mosaic mutations occur during embryonic development, they can appear in the brain and affect the function of neurons. The earlier in development a mutation happens, the more cells will carry it.

Characterizing mosaic mutations in the brain

The two studies were part of the Brain Somatic Mosaicism Network, funded by the National Institute of Mental Health. The first study used deep, ultra-high-resolution whole-genome sequencing to quantify and characterize mosaic mutations in the frontal cortex of people with and without ASD. It was led by Rachel Rodin, MD, PhD and Christopher Walsh, MD, PhD, of Boston Children's, and Yanmei Dou, PhD and Peter Park, PhD, of HMS.

When the researchers examined samples of brain tissue from 59 deceased people with ASD and 15 controls -- the largest cohort of brain samples ever studied -- they found that most of the brains had mosaic "point" mutations (alterations in a single "letter" of genetic code). They calculated that embryos acquire several such mutations with each cell division, and estimate that about half of us carry potentially harmful mosaic mutations in at least 2 percent of our brain cells.

In the brains of people with ASD, however, mosaic mutations were more likely to affect parts of the genome that have a pivotal role in brain function. Specifically, they tended to land in "enhancers," portions of DNA that do not code for genes but regulate whether a gene is turned on or off.

"In the brains of people with autism, mutations accumulate at the same rate as normal, but they are more likely to fall into an enhancer region," says Rodin, first author on the paper. "We think this is because gene enhancers and promoters tend to be in DNA that's unwound and more exposed, which probably makes them more susceptible to mutations during cell division."

"Mutations in enhancers are a hidden kind of mutation that you don't see in typical diagnostic exome sequencing, and it may help explain ASD in some people," notes Walsh, chief of genetics and genomics at Boston Children's and co-senior author on the paper with Park, who led the study's computational analyses. "We also need to better understand the effects of these mutations on neurons."

Mosaic deletions and duplications

The second study is the first large-scale investigation of copy number variants (CNVs) in people with ASD that occur in a mosaic pattern. As opposed to point mutations in a single gene, CNVs are deletions or duplications of whole segments of a chromosome, which may contain multiple genes.

A team led by Maxwell Sherman, MS of BWH, Po-Ru Loh, PhD of BWH, Park, and Walsh studied blood samples from about 12,000 people with autism and 5,500 unaffected siblings provided by the Simons Simplex Collection and the Simons Powering Autism Research for Knowledge (SPARK) datasets. They used blood as a proxy for brain tissue and applied novel computational techniques to sensitively detect mosaic mutations that likely arose during embryonic development.

"People have been interested in CNVs in autism for a long time, and would occasionally notice that some of them were mosaic, but no one had really looked at them in a large-scale study," says Loh, co-senior author on the paper with Walsh and Park.

From these large samples, the team identified a total of 46 mosaic CNVs in the autism group and 19 in siblings. The CNVs affected 2.8 to 73.8 percent of blood cells sampled from each subject.

Size matters

Notably, the people with ASD were especially likely to have very large CNVs, with some involving 25 percent or more of a chromosome. The CNVs spanned a median of 7.8 million bases in the ASD group, versus 0.59 million bases in controls.

"This is one of the more interesting and surprising aspects of our study," says Sherman, the paper's first author and a PhD student at MIT. "The kids with ASD had very large CNVs that often hit dozens of genes, and likely included genes important for development. If the CNVs were in all their cells, rather than in a mosaic pattern, they would likely be lethal."

The study also suggested that the larger the CNVs, the greater the severity of autism as assessed with a standard clinical measure. Another surprise was that smaller CNVs already known to be associated with ASD when found in all cells, such as deletions or duplications of 16p11.2 or 22q11.2, were not associated with autism when they occurred in a mosaic pattern.

"This suggests that in order to get autism, you have to mess up a large number of cells in the brain in a pretty substantial way," says Walsh. "We're fairly sure that these large CNVs change the behavior of the neurons that carry them."

"We don't really know what cell fraction is important, or what particular chromosomes are most susceptible," notes Loh. "These events are still very rare, even in people with autism.
As larger cohorts are assembled, we hope to get some finer-grained insights."

The findings of these studies could eventually be incorporated into diagnostic testing in children with autism. Testing could incorporate the non-coding portions of the genome, such as gene enhancers and promoters, and include higher-resolution chromosomal analysis to identify large mosaic CNVs. For now, the findings add to the ever-evolving autism puzzle, deepening the mystery of why so many different genetic mechanisms can lead to the same presentation of autism.

Tales of post-apocalyptic landscapes in which few survivors emerge into a new and much different world have long been popular tales woven by screenwriters and authors. While many enjoy these stories, thinking of them as nothing but a guilty pleasure, they may not realize that immersing themselves in fiction has prepared them for the reality of 2020, according to a team of researchers.

John Johnson, professor emeritus of psychology at Penn State, recently conducted research with several colleagues revealing that an individual's enjoyment of horror films could have better prepared them for the COVID-19 pandemic as opposed to others who do not enjoy frightening entertainment. Their findings are documented in Personality and Individual Differences.

"My latest research collaboration was unique in that my colleagues wanted to identify factors beyond personality that contributed to people's psychological preparedness and resilience in the face of the pandemic," Johnson explained. "After factoring out personality influences, which were actually quite strong, we found that the more movies about zombies, alien invasions and apocalyptic pandemics people had seen prior to COVID-19, the better they dealt with the actual, current pandemic. These kinds of movies apparently serve as mental rehearsal for actual events.

To me, this implicates an even more important message about stories in general -- whether in books, movies or plays. Stories are not just entertainment, but preparation for life."

Johnson said that in what might be considered retirement, his emeritus status has allowed him to continue to be engaged in the research projects of his choosing, while also helping other researchers along the way.

"Now that I am retired, I have all the time in the world and the freedom to choose any kind of research project that I find truly interesting," said Johnson. "Many of my most recent projects began at the invitation of other researchers who hoped that I could lend my expertise to these projects. Most of these researchers are just beginning their careers, so in a way, I am teaching and mentoring them as well as helping them conduct their research."

Johnson's impact on personality research continues to be felt even in retirement, as young researchers and longtime colleagues still reach out to draw on his expertise.

"This study was conceived by a graduate student in human development and biology at the University of Chicago, Coltan Scrivner," Johnson said. "I had recently reviewed a terrific paper he wrote on morbid curiosity, so I knew who he was. Coltan conducts research on the psychology of horror, and therefore contacted two Danish researchers who were experts on horror, Mathias Clausen and Jens Kjeldgaard-Christiansen, to see if they would collaborate with him. I had previously conducted and published research with Mathias and Jens on what attracts people to horror and villains, so they invited me to the project. We all had input; mine was primarily on how to measure personality, preparedness and resilience, and how to conduct the statistics. Coltan collected the data online, and we quickly wrote up the results and submitted to a journal that was looking for studies on COVID-19. It has been an absolute joy to work with the Danish research team and their colleagues."

The researchers designed a survey they pilot-tested. They administered the final survey to 310 persons via a website. Thirteen items in the survey assessed positive and negative resilience. A set of six questions covered preparedness for the pandemic.

Participants then indicated the extent to which they were fans of horror, zombie, psychological thriller, supernatural, apocalyptic/post-apocalyptic, science fiction, alien-invasion, crime, comedy, and romance genres in movies and television. Next, participants were asked about the past and present experience with and interest in films that were explicitly about pandemics. Other questions appeared in the survey for other projects and as controls.

The results of their collaborated effort may be enough to make many feel justified in staying up late to watch horror films, in spite of what their mothers told them.

"What we found was that people who watched certain kinds of movies before the pandemic seemed to be helped by them during the pandemic," Johnson said.

Though, for those ready to fire up Netflix and get their horror fix now, they may be late to the party in preparing for the COVID pandemic. But, as Johnson explained, it is never too late to make ready for the next hurdle in life.

"I'm not sure that watching such movies now would be helpful for our current situation," he said. "However, my understanding of pandemics and other life-challenging events is that similar future challenges are absolutely inevitable. The past is often forgotten too easily. Who remembered the Spanish flu epidemic until scientists brought up that piece of history during COVID-19? This reinforces my belief that consuming stories from books, films and maybe even video games is not just an idle pastime, but a way for us to imagine simulated realities that help prepare us for future challenges."

Idle pastimes are not something easily understood by an individual with Johnson's passion, and his continued efforts beyond his teaching days highlight that.

"I think that a lot of people assume that when professors retire with emeritus rank, they spend all of their time traveling, pursuing hobbies, or just relaxing at home," said Johnson. "Although I have certainly done those things since I retired, I have also continued to conduct research and publish articles, often collaborating with younger researchers who need my expertise in personality measurement."

An analysis of a large nationally representative longitudinal study by University of California San Diego Herbert Wertheim School of Public Health and Human Longevity Science report that starting tobacco products, including e-cigarettes, before the age of 18 is a major risk factor for people becoming daily cigarette smokers.

Reporting in the January 11, 2021 online edition of Pediatrics, researchers found that in 2014 people age 12 to 24 who used e-cigarettes were three times as likely to become daily cigarette smokers in the future. Among those who reported using a tobacco product, daily use increased with age through age 28. Daily cigarette smoking nearly doubled between 18 to 21 year olds (12 percent) and 25 to 28 year olds (21 percent).

"This is the first paper that actually looks at progression to dependent cigarette smoking among young adults. In these data, e-cigarettes are a gateway for those who become daily cigarette smokers," said the study's first author, John P. Pierce, PhD, Professor Emeritus at Herbert Wertheim School of Public Health and Human Longevity Science and UC San Diego Moores Cancer Center. "The start product has changed from cigarettes to e-cigarettes, but the end product has stayed the same. When users become dependent on nicotine, they are converting to cigarette smoking."

Researchers used data from the Population Assessment of Tobacco and Health (PATH) Study, a longitudinal study of tobacco use and its effect on the health of people in the United States. The PATH Study, undertaken by the National Institute on Drug Abuse (NIDA) and the FDA Center for Tobacco Products under contract to Westat, enrolled a nationally representative sample of 12 to 24 year olds between in 2013 and 2014 and re-interviewed them annually for four years to explore progression to daily use among experimenters of 12 tobacco products.

In the first year, 45 percent of study participants reported using at least one tobacco product in their lifetime. By the fourth year, as participants aged, 62 percent reported some tobacco experimentation. Among those who have ever experimented with tobacco, 73 percent had tried cigarettes and 72 percent had tried e-cigarettes. Further, more than half tried hookahs and cigarillos. Traditional cigars, filtered cigars, smokeless products, pipes and snus were each tried by more than10 percent of study participants.

The analyses revealed that, by year four, 12 percent of participants were using tobacco products daily -- half of whom became daily users after the first year. Seventy percent of daily users smoked cigarettes and most of them (63 percent) used cigarettes exclusively. Of those who smoked cigarettes and used another tobacco product, half vaped e-cigarettes on a non-daily basis.

Among the 17 percent of daily users who were vaping every day, almost half were also non-daily cigarette smokers. Further follow-up will determine whether these young daily tobacco users continue to use both products or whether they settle on a single product, said Pierce.

"What we're seeing is that the proportion who are daily e-cigarette users did not increase with age. Whereas with cigarettes the number of users jumps up rapidly with age," said Pierce. "This rapid increase with age only occurred with cigarettes, not with any other tobacco products."

Less than 1 percent of study participants who experimented with just one tobacco product progressed to daily cigarette smoking. People who had tried five or more products increased their risk of becoming daily cigarette smokers by 15 percentage points.

"Trying e-cigarettes and multiple other tobacco products before the age of 18 is also strongly associated with becoming daily cigarette smoking," said senior author Karen Messer, PhD, professor at UC San Diego Herbert Wertheim School of Public Health and Human Longevity Science and director of biostatics at UC San Diego Moores Cancer Center.

"We know that e-cigarette use among high school seniors, most under the age of 18, increased from 38 percent in 2016 to 45 percent in 2019. These results suggest that recent rapid growth in adolescent e-cigarette use will lead to increased daily cigarette smoking among young adults in the United States, reversing decades of decline in cigarette smoking."

Researchers have taken an important step forward in developing a controlled human infection model to test leishmaniasis vaccines.

The University of York-led study identified and characterised a new strain of Leishmania parasite that will form the basis of a new controlled human infection model for the disease which is transmitted by the bite of sand flies. The team then produced the parasite to the standards required for use in human clinical studies.

The use of controlled human infection models has already proved invaluable in accelerating vaccine development for cholera, malaria, typhoid, influenza and other important infectious diseases. Such models are also being developed as part of the fight against COVID-19.

Around one billion people globally are estimated to be at risk of being infected with leishmaniasis in more than 98 countries.

Professor Paul Kaye from the Hull York Medical School who led the study said: "This is an important milestone for leishmaniasis vaccine development, bringing us a step closer to having the tools needed to evaluate potentially life-saving or life-changing vaccines in a timely and cost-effective manner.

"Reducing the financial burden associated with large scale clinical trials is of particular significance, given the limited funding available to develop vaccines for neglected diseases such as leishmaniasis."

The next phase of the research project will seek to recruit healthy volunteers to participate in a clinical trial to see how the body responds to the parasite and to determine how many participants are needed in future vaccine trials to determine vaccine efficacy.

Leishmaniasis is characterised by slow-to-heal skin ulcers that may spread to other areas of the body or mucosal surfaces causing lifelong stigma, or to the internal organs resulting in the potentially fatal visceral leishmaniasis. Current drug treatments are inadequate and there are currently no vaccines for human leishmaniasis. There are a reported 1,500,000 new cases and 20,000-30,000 deaths annually.

Marijuana use increases throughout the calendar year, with use up 13 percent on average at the end of each year (2015-2019) compared to the beginning, according to a new study published in the journal Drug and Alcohol Dependence.

"We found that marijuana use is consistently higher among those surveyed later in the year, peaking during late fall or early winter before dropping at the beginning of the following year. We think this may be due, in part, to a 'Dry January' in which some people stop drinking alcohol or even stop using marijuana as part of a New Year's resolution," said Joseph Palamar, PhD, MPH, an associate professor of population health at NYU Grossman School of Medicine, an affiliated researcher with the Center for Drug Use and HIV/HCV Research (CDUHR) at NYU School of Global Public Health, and the study's lead author. "We're now in the time of year when people are the least likely to use marijuana."

Prior research shows that alcohol and drug use vary by time of year, with drug use often increasing during summer months, possibly due, in part, to social events. These seasonal variations can inform interventions--for instance, studies show that programs to reduce heavy drinking among college students should begin during the summer.

To better understand seasonal trends in marijuana use, Palamar and his colleagues analyzed data from 282,768 adolescents and adults who responded to the National Survey on Drug Use and Health from 2015 to 2019. The survey asked participants about their past-month use of marijuana and other substances, and the researchers estimated their use within each calendar quarter: January through March, April through June, July through September, and October through December.

Each year, as the calendar year progressed, marijuana use grew, increasing in summer and fall months before dropping as each new year began. While 8.9 percent reported using marijuana in January through March, 10.1 percent reported using in October through December, a 13-percent relative increase.

These seasonal trends occurred independently of annual growth in marijuana use and were seen across nearly all groups surveyed, regardless of sex, race/ethnicity, and education level. Teens were one exception; their marijuana use grew in the summer but declined in the fall months back to winter and spring levels.

Recreational use may be driving the growth throughout the year, as similar small increases occurred among those living in states with and without legal medical marijuana, and among those without a prescription for medical marijuana. Seasonal marijuana use also increased among those who reported using other substances, including alcohol, nicotine, and especially LSD.

The researchers note that the consistent dip in marijuana use during winter months could be a result of a variety of factors: a lower supply this time of year from cannabis harvests, colder weather keeping people inside who usually smoke outdoors, or people quitting marijuana as a New Year's resolution.

"Ultimately, we hope that these findings can be utilized by researchers and clinicians alike," said study coauthor Austin Le, DDS, a research associate at NYU Langone Health and orthodontic resident at NYU College of Dentistry. "Researchers studying marijuana use should consider seasonal variation, as surveys administered at the end of the year may yield different results than at the beginning of the year. And for those who wish to reduce marijuana use, it appears the best time for such targeting may be later in the year--when use is highest."

In addition to Palamar and Le, Benjamin Han of the University of California, San Diego's Department of Medicine, Division of Geriatrics co-authored the study. The research was supported by the National Institute on Drug Abuse, part of the National Institutes of Health (grants R01DA044207 and K23DA043651).

About CDUHR
The mission of the Center for Drug Use and HIV/HCV Research (CDUHR) is to end the HIV and HCV epidemics in drug using populations and their communities by conducting transdisciplinary research and disseminating its findings to inform programmatic, policy, and grass roots initiatives at the local, state, national, and global levels. CDUHR is a Core Center of Excellence funded by the National Institute on Drug Abuse (Grant #P30 DA011041). It is the first center for the socio-behavioral study of substance use and HIV in the United States and is located at the NYU School of Global Public Health. For more information, visit http://www.cduhr.org.

About NYU Langone Health
NYU Langone Health is a world-class, patient-centered, integrated academic medical center, known for its excellence in clinical care, research, and education. Included in the 260+ locations throughout the New York area are six inpatient locations: Tisch Hospital, its flagship acute-care facility in Manhattan; Rusk Rehabilitation, ranked as one of the top 10 rehabilitation programs in the country; NYU Langone Orthopedic Hospital, a dedicated inpatient orthopedic hospital in Manhattan with all musculoskeletal specialties ranked top 10 in the country; Hassenfeld Children's Hospital at NYU Langone, a comprehensive pediatric hospital, also in Manhattan, supporting a full array of children's health services; NYU Langone Hospital--Brooklyn, a full-service teaching hospital and level 1 trauma center located in Sunset Park, Brooklyn; and NYU Langone Hospital--Long Island, a full-service teaching hospital and level 1 trauma center located in Nassau County on Long Island. Also part of NYU Langone Health is the Laura and Isaac Perlmutter Cancer Center, a National Cancer Institute-designated comprehensive cancer center; NYU Grossman School of Medicine, which since 1841 has trained thousands of physicians and scientists who have helped to shape the course of medical history; and NYU Long Island School of Medicine. For more information, go to nyulangone.org, and interact with us on Facebook, Twitter, YouTube, and Instagram.

About NYU School of Global Public Health
At the NYU School of Global Public Health (NYU GPH), we are preparing the next generation of public health pioneers with the critical thinking skills, acumen, and entrepreneurial approaches necessary to reinvent the public health paradigm. Devoted to employing a nontraditional, interdisciplinary model, NYU GPH aims to improve health worldwide through a unique blend of global public health studies, research, and practice. The School is located in the heart of New York City and extends to NYU's global network on six continents. Innovation is at the core of our ambitious approach, thinking and teaching. For more, visit: http://publichealth.nyu.edu/

# # #

BOSTON - Patients with tuberous sclerosis complex, a genetic disorder characterized by the growth of noncancerous tumors in multiple organs of the body, have limited treatment options. A team led by investigators at Massachusetts General Hospital (MGH) has now shown that gene therapy can effectively treat mice that express one of the mutated genes that cause the disease. The research is published in Science Advances.

The gene, called TSC2, codes for tuberin, a protein that acts to inhibit cell growth and proliferation. When mutations occur in TSC2, resulting in a lack of tuberin in cells, the cells enlarge and multiply, leading to the formation of tumors.

To restore the function of TSC2 and tuberin in a mouse model of tuberous sclerosis complex, researchers developed a form of gene therapy using an adeno-associated virus vector carrying the DNA that codes for a condensed form of tuberin (which fits within the vector's carrying capacity) and functions like the normal full-length tuberin protein. Mice with tuberous sclerosis complex had a shortened life span of about 58 days on average, and they showed signs of brain abnormalities consistent with those that are often seen in patients with the disease. When the mice were injected intravenously with the gene therapy treatment, however, their average survival was extended to 462 days, and their brains showed reduced signs of damage.

"Current treatments for tuberous sclerosis complex include surgery and/or lifelong treatment with drugs that cause immune suppression and potentially compromise early brain development. Therefore, there is a clear need to identify other therapeutic approaches for this disease," says co-lead author Shilpa Prabhakar, an investigator in the MGH departments of Neurology and Radiology. "Adeno-associated virus vectors have been used widely in clinical trials for many hereditary diseases with little to no toxicity, long-term action in nondividing cells, and improvement in symptoms," adds Prabhakar. She notes that benefits can be seen after a single injection, and some forms of the viral vector can efficiently enter the brain and peripheral organs after intravenous injection.

The U.S. Food and Drug Administration has approved a limited number of gene therapy products for use in humans, and the results from this study suggest that clinical trials are warranted to test the strategy's potential in patients with tuberous sclerosis complex.

(St. Louis) - A new study by investigators at the Shriners Hospital for Children -- St. Louis suggests the damaging effects of obesity are not due to body weight but rather come from something much smaller - biochemical signals released by fat cells.

The study focuses on the link between overweight or obesity and the development of osteoarthritis, a painful disease of the joints. The investigation was led by Dr. Farshid Guilak, director of the St. Louis Shriners Hospital Research Center.

"We've shown here that it's not overloading of the joints that is responsible for osteoarthritis, but, more likely, a factor given off by fat cells that makes cartilage susceptible to degeneration," said Guilak, who also serves as the Mildred B. Simon Professor of Orthopaedic Surgery at Washington University, a partner of the St. Louis Shriners Hospital.

While historically regarded as an unavoidable part of aging, osteoarthritis is now appearing more commonly in children. This is due in part to widespread increases in childhood obesity, coupled with injuries that commonly occur in adolescents, such as knee ligament tears. Little scientific research had been done in the past on the connection between obesity and osteoarthritis because, Guilak said, it was simply dismissed as byproduct of overloading the joints with increased body weight. But the new study by investigators at the St. Louis Shriners Hospital and the Washington University School of Medicine shows that weight gain alone isn't the cause.

INSIDE THE RESEARCH

The researchers used a unique type of mouse that has no fat cells anywhere in their bodies. Even when they were fed an unhealthy, extremely high-fat diet, these mice did not develop osteoarthritis in any of their joints. The researchers were surprised to find that even with a knee injury that normally causes rapid degeneration of the cartilage, fat-free mice were protected from getting osteoarthritis.

Then, the researchers implanted a tiny piece of fat under the skin of these mice, so small it had no effect on their body weight. The mice became susceptible to osteoarthritis, even though there was no weight gain. This showed researchers that fat outside the knee joint plays a critical role in cartilage health.

The study was published in the journal Proceedings of the National Academy of Sciences. It was designed and executed by the lead author Dr. Kelsey Collins, a postdoctoral fellow in Guilak's laboratory.

"This study demonstrates that factors outside of the knee joint can affect cartilage health, which opens the door for a wide range of new osteoarthritis treatment targets we can investigate," Collins said. "Once we identify the factors given off by fat cells that are responsible for these effects on the joint, we hope to develop new drugs to target them."

In the meantime, Guilak, who also co-directs the Washington University Center for Regenerative Medicine and is a professor of biomedical engineering and of developmental biology, said that a healthy diet and weight loss are the first lines of prevention for osteoarthritis.

"Something like this could take years to develop, but we're excited about its prospects for reducing joint damage, as well as many of the other unhealthy effects of obesity," Collins said.

What The Study Did: This study adapted a well-established tool for measuring inequity from economics--the Lorenz curve--to measure racial inequities in COVID-19 testing.

Author: Aaloke Mody, M.D., of the Washington University School of Medicine 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/jamanetworkopen.2020.32696)

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.

New Curtin University research has found a dramatic increase in people's trust in government in Australia and New Zealand as a result of the COVID pandemic.

Published in the Australian Journal of Public Administration, the team surveyed people in Australia and New Zealand in July 2020 and found confidence in public health scientists to also be high and for this trust to be manifested in higher usage of government COVID phone apps.

Lead researcher Professor Shaun Goldfinch, ANZSOG WA Government Chair in Public Administration and Policy based at the John Curtin Institute of Public Policy at Curtin said the management of the pandemic by authorities led to a dramatic increase in trust in government.

"Using an online panel, we surveyed a representative sample of 500 people each in Australia and New Zealand, several months into the COVID pandemic and found a high level of confidence, with around 80 per cent of respondents agreeing government was generally trustworthy," Professor Goldfinch said.

"Around three quarters of those surveyed agreed management of the pandemic had increased their trust in government and more than 85 per cent of respondents had confidence that public health scientists worked in the public interest.

"We also found this trust and confidence strongly predicted COVID phone app use, largely through convincing people that the app was beneficial."

Professor Goldfinch said confidence in government had increased in Australia and New Zealand from a similar study in 2009, with 80 per cent and 83 per cent, respectively, agreeing government is generally trustworthy, compared to 49 per cent and 53 per cent in the earlier study.

"This rise is due in part to positive perceptions of the management of the pandemic, with around three quarters of respondents agreeing the way the crisis was handled had increased their trust in government," Professor Goldfinch said.

"Because the research was conducted during a global pandemic, the findings may not signal a long?term change in trust in government, which may return to previous levels when, and if, the crisis passes.

"Regardless, trust in government could be viewed as a 'reservoir' that can be drawn upon when needed so that citizens are willing to take what might be unusual and unprecedented actions when their trust is high, including the use of government apps. As such, trust remains key to effective government, particularly during crises."

The SARS-CoV-2 virus was introduced to the United Kingdom well over 1,000 times in early 2020, according to researchers who analyzed more than 50,000 viral sequences from the first wave of the COVID-19 pandemic in the UK. The virus lineages introduced before the UK's national lockdown in March tended to be larger and more geographically dispersed. Infectious disease epidemics are composed of chains of transmission, yet little is known about how co-circulating transmission lineages vary in size, spatial distribution and persistence. Understanding these features could help target interventions, track variants with different impacts on their human hosts, and more. The UK's COVID-19 epidemic during early 2020 was one of the world's largest. It was also well represented by virus genomic sampling, in large part because of efforts by the national COVID-19 Genomics UK (COG-UK) consortium. Through its consortium, the UK shares large volumes of virus genetic data publicly on a weekly basis. Here, researchers led by Louis du Plessis used data from this consortium and from other sources to reconstruct where and when COVID-19 was introduced to the UK during its first wave (March - June 2019). They also used information on epidemiological factors and travel data. Before the March 23 lockdown, more than 1,000 identifiable UK transmission lineages - including all eight of the largest, longest-enduring lineages - were established and co-circulating in the UK, according to their results. Even as the largest and most widespread lineages persisted into the summer, the UK national lockdown coincided with limited importation and reduced regional lineage diversity, say du Plessis and colleagues. Their results suggest that earlier travel and quarantine interventions could have helped to reduce the acceleration and intensity of the UK's first wave of cases. They also show that highest number of transmission chains were introduced to the UK from Spain (33%), France (29%), and then Italy (12%) - with China accounting for only 0.4% of imports. The results of the study show it's possible to use genomic tracking to trace individual virus transmission lineages accurately through time and space - an approach that could be adopted at regional, national, and international scales for future pandemics.