Culture

A new paper published by McGill University researchers in JAMA Internal Medicine suggests that some clinical trials may promote the use of ineffective and costly treatments. That's the opposite of what clinical trials are aimed at, namely preventing ineffective and costly treatments from being taken up by physicians and patients.

The researchers focused their attention on the blockbuster pain drug pregabalin (Lyrica). One of the world's bestselling drugs, pregabalin is widely used for conditions that are not approved by Health Canada or the FDA ("off-label"). Relying on the published record of trials, they reconstructed the timeline of pregabalin drug development to understand what evidence was available to clinicians and clinical guideline creators when they were making treatment decisions and recommendations, and how testing was coordinated. Their underlying finding was that after pregabalin received its first approval, research was often better at creating the perception that pregabalin might work against other diseases than it was at proving it. For example, they found that despite nearly a decade passing since the publication of a small study suggesting that pregabalin might work to treat patients with low back pain, no large, rigorous follow-up trials have been published to date.

McGill Professor Jonathan Kimmelman, Director of the Biomedical Ethics Unit in the Faculty of Medicine, and the study's senior author, first came up with the idea for the study after watching the documentary film "The Merchants of Doubt." The film showed how the tobacco, chemical, and oil industries have manipulated science to sow doubt among regulators and the public about the relationship between their products and public health. Prof. Kimmelman wondered whether there might be an analogous process going on in medicine. Instead of sowing doubt, he thought pharmaceutical companies might want to create the perception that their drugs might be useful for conditions other than those for which they are approved. The researchers found something more complex at work, however, with many of the studies in their sample being publicly funded and others not reporting any industry funding at all. "We were surprised to find that the problems we document are partly driven by researchers who are receiving funding from federal research agencies and/or their own medical centers," notes Carole Federico, a PhD student under Prof. Kimmelman's supervision and the study's lead author.

"Drug development is like a relay race, where the first runner is trying to show a drug might possibly work, and the second runner is proving that a drug really does work," explains Prof. Kimmelman. "This relay race works really well before a drug is approved, because drug regulators like Health Canada and the FDA prevent companies from marketing their drug until they have run the whole race. Once a drug is already approved, however, the second runner in the relay race, the one whose job it is to prove that drug works in another disease, often drops the baton. Physicians are free to use the drug for conditions other than what it is approved for and there are no obligations for companies to prove a drug works in other diseases. That means that research testing already approved drugs for new diseases often encourages the use of treatments that may not be effective."

Federico is quick to add that, "there is nothing inherently wrong with off-label use of drugs. In fact, many drugs that are given off-label are supported by strong evidence. However, when drugs are prescribed off-label based on weak evidence, patients might be harmed because they are taking drugs that are ineffective for their condition. Likewise, healthcare systems are harmed if they are reimbursing for the costs of such ineffective treatments."

"We want to underscore that probably most, if not all researchers would argue that all of the individual trials in our sample were both reasonable and ethical," says Prof. Kimmelman. "Our point is not to condemn these individual trials. Instead, we are saying that--when you zoom out and look at what's happening at the level of the forest--the trees begin to look less healthy."

As physicians attempt to decrease antipsychotic use in seniors with dementia, they need to be aware that trazadone, frequently used as an alternative, is associated with a similar risk of falls and major fractures as atypical antipsychotics, according to new research in CMAJ (Canadian Medical Association Journal).

"As clinicians move to decrease antipsychotic use, we should not consider trazadone as a uniformly safer alternative to atypical antipsychotics, because trazadone use was associated with a comparable risk of falls and major osteoporotic fractures to atypical antipsychotics -- drugs associated with these adverse outcomes in our patient population," writes Dr. Jennifer Watt, St. Michael's Hospital, Toronto, Ontario, with coauthors.

The rate of dementia in Canada is 7%, but it approaches almost 25% in people older than age 85. In long-term care facilities, 62% of residents have dementia, and many exhibit aggressive behaviour. Although evidence is limited on efficacy, antipsychotics and trazadone, an antidepressant also used for sleep issues, are commonly prescribed for patients with dementia.

Using linked data from ICES, researchers looked at data on 6588 seniors newly dispensed trazadone and 2875 newly dispensed an atypical antipsychotic. They found that patients dispensed trazadone had a rate of falls and major fractures, including hip fractures, similar to that of the group receiving atypical antipsychotics. However, trazadone was associated with a lower risk of death in these patients.

"We hope this information can be used to inform conversations that patients and caregivers are having with clinicians about the benefits and risks of different treatment options," says Dr. Watt.

"Watt and colleagues also underscore the importance of prioritizing nonpharmacological approaches for the management of behavioural and psychological symptoms of dementia," writes Dr. Elia Abi-Jaoude, The Hospital for Sick Children (SickKids) and University Health Network, Toronto, Ontario, with coauthors in a related commentary http://www.cmaj.ca/lookup/doi/10.1503/cmaj.181486. "Nonpharmacological approaches comprise a variety of behavioural, environmental and caregiver-supportive interventions, and existing evidence suggests that these show greater effect than many psychotropic drug therapies."

"Comparative risk of harm associated with trazodone or atypical antipsychotic use in older adults with dementia: a retrospective cohort study" is published November 26, 2018.

Fred Hutchinson Cancer Research Center's latest findings on cancer immunotherapies, CRISPR for blood disorders, stem cell transplantation and insights on the immune system and cancer will be featured at the 60th annual meeting of the American Society of Hematology, which will be held Dec. 1-4 in San Diego. See highlights below.

ASH PRESS BRIEFING

This year's ASH press program will include a press briefing, "CAR T-Cell Therapies: New Research and Updates from Pivotal Trials," featuring Fred Hutch research on a combination therapy for chronic lymphocytic leukemia (more details below). The briefing will take place at 11:30 a.m. PST, Saturday, Dec 1, in Room 23 of the San Diego Convention Center. It is open to all media registered to attend the meeting. More details will be available in an ASH press release to be distributed at the briefing.

CAR T-cell combination therapy for chronic lymphocytic leukemia. Dr. Jordan Gauthier will describe how patients with relapsed, refractory chronic lymphocytic leukemia (CLL) treated with the drug ibrutinib before, during and after CAR T-cell therapy may experience fewer side effects and may be more likely to see their cancer go into remission compared with patients who received CAR T alone. Gauthier calls the results promising, though he cautions that at this point the study is small (fewer than 20 patients in each group). Ibrutinib is a small-molecule drug that keeps CLL cells from growing, and the CAR T-cell therapy targeted the CD19 protein on leukemia cells. Gauthier is a Fred Hutch senior research fellow and clinician working in the lab of Dr. Cameron Turtle. The study to be presented at ASH is an extension of the team's 2017 study published in the Journal of Clinical Oncology that showed how the CD19 CAR T-cell therapy led to durable molecular remissions in CLL patients who had failed other treatments.

CAR T-CELL THERAPY

With the success of CAR T-cell therapies for some blood cancers, Fred Hutch physician-scientists are taking a closer look at characteristics and outcomes of patients who have received the therapy with the aim of making the therapy work better for more people. Other CAR T-cell therapy work featured at this year's meeting includes taking a deep dive into how the cells behave and early findings on a new CAR T for multiple myeloma.

Factors impacting survival in adults treated with CD19 CAR T-cell therapy for acute lymphoblastic leukemia. Dr. Kevin Hay, a Fred Hutch research fellow and clinician working in the Turtle lab, will present data on characteristics of patients who have a lasting remission following CD19 CAR T-cell therapy for acute lymphoblastic leukemia. He found that disease-related factors, pre-CAR T-cell conditioning and hematopoietic cell transplantation performed after CAR T-cell therapy impacted survival. The findings from about 50 patients contribute to emerging evidence that CAR T-cell therapy can be used to get patients with difficult-to-treat disease into remission and that subsequent stem cell transplantation may enable them to survive longer without their disease returning.

When CAR T-cell therapy fails: Treatment strategies in lymphoma. CD19 CAR T-cell therapy has shown promise for patients with relapsed or refractory B-cell non-Hodgkin lymphomas, a population with historically poor outcomes and few treatment options. But up to 60 percent of patients do not achieve long-term remission after the therapy and there is no clear standard of what treatments to pursue when CAR T-cell therapy does not work. Dr. Victor Chow, a senior Hematology-Oncology fellow working with Dr. Ryan Lynch, an assistant professor and clinician at Hutch's clinical care partner, Seattle Cancer Care Alliance, and University of Washington, examined patient outcomes for a group of about 60 patients treated in the past five years whose disease progressed after CD19 CAR T-cell therapy. Chow will report on how the disease progressed following the failed therapy. While most of the patients who went on to receive additional treatment lived longer, their outcomes were still poor. The physicians hope these data will generate new ideas and inform future clinical trial strategies for this population without clear treatment options.

Profiling the anti-cancer behavior of CD19 CAR T cells. Little is known about the gene signatures of the engineered CAR T cells after they've been infused into patients. Dr. Alyssa Sheih, a postdoctoral researcher working in the Turtle lab, will speak about how she used TCR sequencing to track how the cells changed in patients who received the 1:1 ratio of millions of CD4 and CD8 CAR T cells. She compared the gene signatures of CAR T cells from the infused product and from blood samples from patients at different time points after receiving the therapy. Sheih discovered patterns of gene expression that corresponded with cells that expanded more than others after infusion. The researchers are using the proof-of-principle study to gain insight into strategies to improve CAR T-cell immunotherapy.

Early results from a new CAR T-cell therapy for multiple myeloma. CAR T cells targeted to a protein called BCMA on multiple myeloma cells is an emerging treatment strategy for this typically incurable blood cancer. Dr. Damian Green, a physician-scientist at Fred Hutch and Seattle Cancer Care Alliance will present early findings from a phase 1 first-in-human clinical trial which showed that all patients who had not responded to frontline therapies responded to the lowest dose of the experimental BCMA CAR T-cell therapy administered in a 1:1 ratio of engineered CD4 and CD8 cells. Green describes the findings as showing early promise; the therapy could be safe and effective and may represent a treatment option that improves the long-term prospects for patients with multiple myeloma.

GENE THERAPY

CRISPR-edited cells persist, effectively boost fetal hemoglobin in genetic blood disorders. Dr. Stefan Radtke, of Fred Hutch's Stem Cell and Gene Therapy Program led by Dr. Hans-Peter Kiem, will discuss CRISPR editing in a specialized subset of blood stem cells identified in 2017 by the Fred Hutch team as capable of repopulating the entire blood and immune system. The approach reduces by 90 percent the amount of reagents needed to carry out the gene modification (currently a bottleneck in the field) and has the potential to make gene therapy faster and safer. The ASH presentation, of work led by Dr. Olivier Humbert, a staff scientist in the Kiem Lab, is a first proof-of-principle that the edited cell subset persisted for at least a year in a large animal model and was able to increase fetal hemoglobin to counteract the defective hemoglobin produced in the genetic blood disorders sickle cell and beta thalassemia. Humbert and colleagues presented preliminary findings earlier this year.

STEM CELL TRANSPLANTATION

Bone marrow transplantation in older, frail adults with acute myeloid leukemia. Survival rates continue to improve for patients treated for AML, but treatment options for older and more frail patients have been limited, and these patients are often left out of clinical trials due to comorbidities. Dr. Mohamed Sorror, a Fred Hutch blood cancer physician and outcomes research scientist, is an expert in identifying patients in this demographic who would fare well - or not - in hematopoietic cell transplantation, which is considered the standard curative treatment for the disease. He will present on survival differences among some 700 patients enrolled on a multicenter trial.

ON THE HORIZON

Other notable experts and newsy topics being presented at ASH:

Regenerating immune function in the thymus. The thymus is a gland in the chest that acts like a boot camp for T cells, training them to identify and kill foreign invaders. The gland wears out with stress, infection and age, and finding ways to boost its productivity could help sustain human health. Dr. Jarrod Dudakov, a Fred Hutch immunologist, studies the signaling pathways of the thymus, and he and members of his lab will present the latest chapter in his quest to find master regulators that could be targets for helping the thymus to repair itself. In this video, Dudakov talks about how the thymus degenerates and the cells and molecules involved in repairing it, a mechanism he described earlier this year in Science Immunology.

The role of the microbiome in recovering from stem cell transplantation. The population of gut microbes changes when patients go through blood stem cell transplants as a result of antibiotics and other agents they receive as part of the life-saving treatment. Fred Hutch researchers are investigating how the microbiome interacts with immune cells in hopes of better understanding and treating graft vs. host disease, a common side effect of transplantation that occurs when the newly transplanted immune system attacks healthy tissue. Dr. Alyssa Sheih, postdoctoral fellow working in the Turtle Lab, will present a poster on how a common type of T cell called MAIT cells is linked to the populations of different microbes in stool samples of patients before, during and after stem cell transplantation. She says that the regrowth of MAIT cells -- which can comprise up to 10 percent of T cells -- accompanies the presence of gut bacteria species that are linked to not developing GVHD. The project is part of the Fred Hutch Microbiome Research Initiative, which is led by infectious disease expert Dr. David Fredricks.

Cord blood transplantation for cancer and other blood disorders. Transplantation of blood stem cells from umbilical cord blood can treat blood disorders in patients who have not been able to find a suitable match among other donor sources, which is particularly difficult for patients of mixed ethnicity. Dr. Filippo Milano is associate director of Fred Hutch's Cord Blood Program, and he cares for patients at Seattle Cancer Care Alliance. He will be available at the ASH meeting to discuss cord blood transplantation for cancer and other blood disorders. He was lead author of a 2016 New England Journal of Medicine study which found that high-risk leukemia patients who received cord blood transplants had a lower risk of relapse. He will lead a newly funded clinical trial for HIV-positive patients with leukemia, which has the potential to treat both cancer and HIV by using donor cells that are resistant to the virus.

Long-term outcomes for patients receiving stem cell transplantation. Dr. Stephanie Lee, vice president of ASH, is a physician-scientist at Fred Hutch who cares for stem cell transplant patients at Seattle Cancer Care Alliance. She will become president of ASH in 2020. Lee is an expert in chronic graft vs. host disease and long-term survivorship following transplantation.

A new national survey by the American Dairy Association Mideast finds 94 percent of Americans admit to throwing food away at home. In fact, the average family wastes nearly a third of the food they buy, with the average American tossing 250 pounds of food each year.

"Imagine coming home with four bags of groceries and throwing one straight into the trash. That's really what is happening in most households," said Karen Bakies, RDN, LD, FAND, a registered dietitian and vice president of nutrition affairs for the American Dairy Association Mideast in Columbus, Ohio. "Whether people are over purchasing groceries or getting tired of their leftovers, too much food is being thrown away in America."

The survey found the top reason for throwing away food at home is that it's past its expiration date, while 60 percent have tossed food because they didn't think it was safe to eat. However, a few simple changes can help your family use more and waste less. Bakies offers the following tips to help ease the burden of food waste on the environment and on your wallet:

Organize Your Fridge - Try to follow the "first in, first out" rule, by rotating older food to the front of your refrigerator so it's not forgotten. Where you store certain foods can also make a big difference in how long they stay fresh. Cheese and yogurt should be tightly sealed on the top shelf, while produce is best stored in humidity-controlled drawers. And even though your refrigerator door seems to be made to hold your gallon of milk, storing it there will cause it to get warm each time the door is opened. Instead, put milk in the back of the bottom shelf where it will stay cold.

Get Creative - Find new ways to use those extra ingredients to create new family favorites. If you bought a pint of whipping cream and a recipe only called for a cup, the extra is great folded into scrambled eggs or mashed potatoes the next day. Think your produce looks like it's past its prime? It could still be added to soups, stir fry or casseroles. You can also throw any extra fruit and yogurt you have into the blender for a healthy smoothie.

Move Perishables to the Freezer - Whether there's leftovers from a prepared meal or you have some extra fruits and veggies, if you can't use it right away, freeze it. This can be especially helpful for dairy foods. Milk, cheese and butter can be frozen for weeks and taken out of the freezer when you need them. You can also portion out tablespoons of herbs and sauces and freeze them in ice cube trays. Just pop one out to use in any recipe.

"A family of four could save up to $2,000 by wasting less food, but it's not just great for your family, it's also great for your community. Just half of that money is enough to provide over 8,000 meals to those in need." said Bakies. "And if you do find yourself with extra groceries, donate them to a local food pantry rather than letting them go to waste."

It can be tough to remember how and where to store every, single food item, so Bakies also recommends using the USDA's FoodKeeper app. It's an easy way to get tips and information on how to store and cook over 400 foods and can even send alerts when food in your refrigerator is approaching the end of its recommended storage.

Patients in the UK who have survived critical illnesses requiring care in an intensive care unit (ICU) frequently report symptoms of anxiety, PTSD and/or depression, according to a study published in open access journal Critical Care. Those reporting symptoms of depression after critical illness appear to be at a greater risk of death.

Researchers at the University of Oxford investigated psychological disorders in a cohort of 4,943 of former ICU patients. They found that 46% of patients reported symptoms of anxiety, 40% reported symptoms of depression and 22% reported symptoms of PTSD, while 18% of patients in the study reported symptoms of all three psychological conditions.

Dr Peter Watkinson, the corresponding author said: "Psychological problems after being treated for a critical illness in the ICU are very common and often complex when they occur. When symptoms of one psychological disorder are present, there is a 65% chance they will co-occur with symptoms of another psychological disorder."

To investigate possible links between treatment in an ICU and symptoms of psychological disorders, the authors asked a total of 4,943 patients who received treatment in one of 26 ICUs in the UK between 2006 and 2013, to complete a questionnaire on their symptoms of anxiety, depression and PTSD three months after discharge from ICU and again 12 months after discharge.

The authors found that patients who reported symptoms of depression were 47% more likely to die from any cause (all-cause mortality) during the first two years after discharge from the ICU than those who did not report these symptoms.

Dr Peter Watkinson said: "Our findings suggest that depression following care of a critical illness in the ICU may be a marker of declining health and clinicians should consider this when following up with former ICU patients."

The authors caution that the generalizability of the results outside of the UK may be limited as the data was only collected from UK based patients. Furthermore, the observational nature of the study and its reliance of self-reported data mean that it does not allow for conclusions about cause and effect between ICU care and symptoms of psychological disorders.

Strains of the bacterium Enterobacter, similar to newly found opportunistic infectious organisms seen in a few hospital settings, have been identified on the International Space Station (ISS). The strains found in space were not pathogenic to humans, but researchers believe they should be studied for potential health implications for future missions, according to a study published in the open access journal BMC Microbiology.

Researchers at the Jet Propulsion Laboratory, California Institute of Technology, USA investigated five strains of Enterobacter that were isolated from the space toilet and the exercise platform on the ISS in March 2015 as part of a wider effort to characterize the bacterial communities that live on surfaces inside the space station. To identify the species of Enterobacter collected on the ISS and to show in detail the genetic make-up of the individual strains, the researchers compared the ISS strains to all publicly available genomes of 1,291 Enterobacter strains collected on Earth.

Dr Kasthuri Venkateswaran, Senior Research Scientist at the Jet Propulsion Laboratory Biotechnology and Planetary Protection Group and the corresponding author of the study said: "To show which species of the bacteria were present on the ISS, we used various methods to characterize their genomes in detail. We revealed that genomes of the five ISS Enterobacter strains were genetically most similar to three strains newly found on Earth. These three strains belonged to one species of the bacteria, called Enterobacter bugandensis, which had been found to cause disease in neonates and a compromised patient, who were admitted to three different hospitals (in east Africa, Washington state and Colorado)."

Comparing the genomes of the five ISS strains to the three clinical Earth strains allowed the authors to get a better understanding of whether the ISS strains showed characteristics of antimicrobial resistance, if they had gene profiles similar to those found in known multi-drug resistant bacteria, and to identify genes related to their ability to cause disease (pathogenic potential).

Dr. Nitin Singh, first author of the publication said: "Given the multi-drug resistance results for these ISS E. bugandensis genomes and the increased chance of pathogenicity we have identified, these species potentially pose important health considerations for future missions. However, it is important to understand that the strains found on the ISS were not virulent, which means they are not an active threat to human health, but something to be monitored."

The authors found that the ISS isolates had similar antimicrobial resistance patterns to the three clinical strains found on Earth and that they included 112 genes involved in virulence, disease and defense. While the ISS E. bugandensis strains were not pathogenic to humans, the authors predicted via computer analyses, a 79% probability that they may potentially cause disease. However, analyses in living organisms should be carried out to confirm this.

Dr Venkateswaran said: "Whether or not an opportunistic pathogen like E. bugandensis causes disease and how much of a threat it is, depends on a variety of factors, including environmental ones. Further in vivo studies are needed to discern the impact that conditions on the ISS, such as microgravity, other space, and spacecraft-related factors, may have on pathogenicity and virulence."

A new global field size data set collected as part of a crowdsourcing citizen science project by IIASA researchers has shown that the proportion of smallholder farms may be much larger than previously thought, contributing much more to global food production.

Smallholder farms are classified as being made up of fields less than around 2 ha in size. Evidence is increasing that such farms make a substantial contribution to world food production, but until now, the data on the number and distribution of smallholder farms has been lacking. Previous estimates have suggested that smallholder farms make up between 12 and 24% of the global total. However, the new research led by IIASA researcher Myroslava Lesiv shows that smallholder farms in fact make up 40% of the global agricultural area.

The study is the first to estimate field sizes at the global, continental, and national level, and covers the entire world, rather than just 55 countries as in earlier studies. The data are much more detailed and denser than anything previously collected. The crowdsourcing method used is a unique approach to quantifying and mapping field size.

The crowdsourcing campaign began in June 2017 using the Geo-Wiki app. It lasted for four weeks and was focused on collecting field size data. The Geo-Wiki app takes high resolution satellite imagery from Google Maps and Microsoft Bing and allows users to visually assess those images, for example for land cover or human impact. In this case, users were asked to assess images of agricultural land.

A field was defined as any enclosed agricultural area, including arable and pasture land, which could be separated by roads, permanent paths or vegetation, and users could choose one of five field size categories - very large (greater than 100 ha), large (16-100 ha), medium (2.56-16 ha), small (0.64-2.56 ha), and very small (less than 0.64 ha).

The user was asked to define which field sizes were present, and if there was more than one field size, which was the dominant size, using either an estimation grid, or with an area measuring tool. Each image was checked by three users and all users were trained in using the app through the use of a video and slides before they began. Users also had to complete ten training images before contributing to the official survey, with feedback given on each. Random 'control' images that had been expertly assessed were randomly shown to users, and if these were incorrectly classified, the user received text feedback. The researchers added this quality control feature to improve the quality of the results. Prizes were offered as an incentive to participate.

A previous Geo-Wiki study in 2011 collected 13,000 unique samples, but this latest survey collected 130,000 samples. The researchers used the 390,000 classifications (from three 'visits' to each site) to create a map and calculate agricultural area proportions at the global, continental, and national levels.

Dominant field sizes across the world vary. African countries such as Ethiopia, Mali, Nigeria, and Tanzania along with China, India, and Indonesia, tend to have very small fields. European nations tend to have medium-sized fields. Australia, Brazil, Kazakhstan, and the US tend to have very large fields. In some areas, including northern China, central India and Turkey, the field size is very mixed.

The crowdsourced data set is openly available for use in future research, for example integrated assessment modeling, comparative studies of agricultural dynamics across different contexts, or for training and validation of remote sensing field size delineation. Such information could also contribute to achieving the UN Sustainable Development Goal 2 (SDG2) - End hunger, achieve food security and improved nutrition and promote sustainable agriculture, according to the researchers. If policymakers have an accurate overview of the global distribution of field sizes, this will provide a better background for decision making related to food systems and agriculture. Field size is a good indicator of agricultural intensity.

"We have filled the gaps in available information on global field size distribution by covering countries where no statistical surveys were carried out and no mapping was done with the help of remote sensing. Therefore, the field size data set we developed provides full and accurate information on the distribution of field sizes to support policy decision making related to food security issues," says Lesiv.

During the Triassic period (252-201 million years ago) mammal-like reptiles called therapsids co-existed with ancestors to dinosaurs, crocodiles, mammals, pterosaurs, turtles, frogs, and lizards. One group of therapsids are the dicynodonts. Researchers at Uppsala University in Sweden, together with colleagues in Poland, have discovered fossils from a new genus of gigantic dicynodont. The new species Lisowicia bojani is described in the journal Science.

The earth is about 4.5 billion years old and has gone through many geological periods and dramatic change. During the Triassic period, about 252-201 million years ago, all land on Earth came together and formed the massive continent called Pangea. During this time, the first dinosaurs came into being as well as ancestors to crocodiles, mammals, pterosaurs, turtles, frogs, and lizards. Recently, scientists have become interested in another type of animal, therapsids. Therapsids were "mammal-like" reptiles and are ancestors to the mammals, including humans, found today. One group of therapsids is called dicynodonts. All species of dicynodonts were herbivores (plant eaters) and their sizes ranged from small burrowers to large browsers. Most of them were also toothless. They survived the Permian mass extinction and became the dominant terrestrial herbivores in the Middle and Late Triassic. They were thought to have died out before the dinosaurs became the dominant form of tetrapod on land.

For the first time, researchers in the research programme Evolution and Development at Uppsala University in collaboration with researchers at the Polish Academy of Sciences (Warsaw), have discovered fossils from a new species of dicynodont in the Polish village of Lisowice. The species was named Lisowicia bojani after the village and a German comparative anatomist named Ludwig Heinrich Bojanus who worked in Vilnius and is known for making several important anatomical discoveries. The findings show that the Lisowicia was about the size of a modern-day elephant, about 4.5 metres long, 2.6 metres high and weighed approximately 9 tons, which is 40 percent larger than any previously identified dicynodont. Analysis of the limb bones showed that they had a fast growth, much like a mammal or a dinosaur. It lived during the Late Triassic, about 210-205 million years ago, about 10 million years later than previous findings of dicynodonts.

"The discovery of Lisowicia changes our ideas about the latest history of dicynodonts, mammal Triassic relatives. It also raises far more questions about what really make them and dinosaurs so large," says Dr Tomasz Sulej, Polish Academy of Sciences.

"Dicynodonts were amazingly successful animals in the Middle and Late Triassic. Lisowicia is the youngest dicynodont and the largest non-dinosaurian terrestrial tetrapod from the Triassic. It's natural to want to know how dicynodonts became so large. Lisowicia is hugely exciting because it blows holes in many of our classic ideas of Triassic 'mammal-like reptiles'," says Dr Grzegorz Niedzwiedzki, Uppsala University.

The first findings of fossils from Lisowice in Poland were made in 2005 by Robert Borz?cki and Piotr Menducki. Since then, more than 1,000 bones and bone fragments have been collected from the area, including fossils from Lisowicia. The area is thought to have been a river deposit during the Late Triassic period.

The discovery of Lisowicia provides the first evidence that mammal-like elephant sized dicynodonts were present at the same time as the more well-known long-necked sauropodomorph dinosaurs, contrary to previous belief. Sauropodomorphs include species like the Diplodocus or Brachiosaurus. It fills a gap in the fossil record of dicynodonts and it shows that some anatomical features of limbs thought to characterize large mammals or dinosaurs evolved also in the non-mammalian synapsid. Finally, these findings from Poland are the first substantial finds of dicynodonts from the Late Triassic in Europe.

"The discovery of such an important new species is a once in a lifetime discovery," says Dr Tomasz Sulej.

In the wake of recent high-profile successes catching criminals using publicly-accessible genomic data, results that build momentum for this approach, James Hazel and colleagues argue for the establishment of a universal forensic DNA database for law enforcement purposes. It could be more productive, less discriminatory and more private, they explain in a Policy Forum. Recently, publicly available genomic databases belonging to direct-to-consumer genomic companies, like GEDmatch, have been used to identify alleged killers by linking their crime scene DNA to the genetic information volunteered by their family members. Outside of publicly open databases, privately held genomic data can still be obtained, too; a subpoena is all that is generally required. According to Hazel et al., law enforcement requests for private data are likely to increase as this method of forensic investigation becomes more widely used. While DNA is a powerful crime-solving tool, there is a great deal of uncertainty concerning the extent to which law enforcement agencies should be able to obtain and use public and private genomic data assemblages. According to the authors, the development of a 'universal forensic database' could alleviate some of the challenges and controversy. The authors suggest that such a database would overcome the biases inherent in today's forensic databases, which are largely derived from samples from individuals arrested or convicted of crimes, which generally represent young, non-white populations; consumer genetic databases, by contrast, are predominantly made up of samples from Caucasian individuals. Additionally, the authors suggest that the database could contain only a small subset of an individual's genetic markers and reveal far less sensitive medical information. Despite the advantages, Hazel et al. note that the creation of such a large database would likely be expensive and require a great deal of legislative oversight and restrictions for law enforcement agencies. However, the societal and economic benefits of a productive, less discriminatory and more private system would offset the costs.

CORVALLIS, Ore. - Corals and the microbes they host evolved together, new research by Oregon State University shows.

The findings, published today in Nature Communications, add fresh insight to the fight to save the Earth's embattled coral reefs, the planet's largest and most significant structures of biological origin.

Funded by the National Science Foundation, the study involved hundreds of samples of scleractinian corals - also known as stony corals - which since their first appearance 425 million years ago have branched into more than 1,500 species.

Many of those are major builders of coral reefs, which are found in less than 1 percent of the ocean but are home to nearly one-quarter of all known marine species. Reefs also help regulate the sea's carbon dioxide levels and are a crucial hunting ground that scientists use in the search for new medicines.

"Many corals have gone extinct during industrialization and many others are threatened with extinction," said study co-author and OSU microbiologist Rebecca Vega Thurber, who is featured in the 2018 Oregon State University-produced documentary "Saving Atlantis." "If we see patterns of evolution between microbiomes and corals, that gives us an idea of which microbes to target - to learn what they do, how they help corals resist climate change, and how they help to buffer against nutrient pollution. We can look in more depth at the microbes and understand how they help or hurt their hosts."

Modern corals are home to a complex composition of dinoflagellates, fungi, bacteria and archaea that together make up the coral microbiome. Shifts in microbiome composition are connected to changes in coral health.

"Likely the ancestral corals also harbored complex microbial communities but there's a lot we don't know about how these coral-microbe symbioses evolved or the key factors influencing microbial communities in modern corals," Vega Thurber said. "Certain species of corals have distinct microbiomes, to the point where that occurred at some point in their evolutionary history. Not 400 million years ago, but there are specific groups of microbes that do show very strong evidence of evolving with their hosts more recently."

Vega Thurber and Ryan McMinds, a Ph.D. student in her lab and co-first author of the paper, were part of an international collaboration that also included Penn State University's Monica Medina and former Oregon State post-doctoral scholar Jesse Zaneveld, now an assistant professor at the University of Washington-Bothell.

The massive, computationally challenging research project involved taking 600 coral samples from 21 reefs off the coasts of Australia, spanning 17 degrees of latitude.

"On a lot of different scales, the more similar the coral hosts, the more similar the microbial communities are - both the whole community and particular microbes," McMinds said. "We collected samples from as many kinds of corals as was possible. For every sample set, we looked at the corals' tissue, skeleton and mucus to see what microbes were there."

To do that, the researchers sequenced the 16S rRNA gene. The gene is present in every living organism, McMinds explains, but is slightly different. He likened it to a "molecular bar code" of each organism it belongs to.

From there, the scientists could look for patterns between different corals' microbial communities and determine whether co-evolution of the corals and their microbiomes had taken place.

"We found strong support for coral-microbe 'phylosymbiosis,' in which coral microbiome composition and richness is reflected in coral host's evolutionary history," Vega Thurber said. "When speciation for modern reef-building coral families began between roughly 25 million and 65 years ago, that was accompanied by large changes in microbiome richness. And changes continued to accumulate during more recent speciation events."

Coral diversity is too great for assessing the various factors that maintain the microbiome of every single coral species, but these findings provide general rules for microbiome assembly "that inform estimates of the effects of microorganisms in understudied portions of the coral tree."

"Now we have a framework for analyzing scleractinian coral microbes that can reveal how the corals' evolutionary history, host traits and local environment interact to shape microbiomes," Vega Thurber said. "In the coral world, there's been a longstanding hypothesis that microbes and coral co-evolved, but there hadn't been a sufficient data set to test that before now."

It was something of a surprise to researchers to find that the microbial communities of the corals' calcium carbonate skeletons showed greater microbiome richness compared to the tissue and mucus microbiomes. Also, the skeletal microbiomes displayed the strongest signal of long-term phylosymbiosis - a pattern in which the diversification of a related group of host organisms correlates with changes in dissimilarities among their microbiomes.

"We originally thought corals would show signs of phylosymbiosis throughout their entire phylogenetic history, and the results support that for the skeleton and tissue but not the mucus," McMinds said. "Despite variability in the chemical composition of mucus between species and significant host-specificity in the mucus microbiome, host specificity was limited to relatively recent divergences."

He also noted the research found potential significance in "a few groups of microbes no one had thought were important to look at."

"There are thousands of different species of microbes and not that many that researchers have thought were interesting, and we identified a couple of other microbial targets that might be influencing coral health," McMinds said. "We don't know for sure if they are important, but evidence suggests they're changing along with their hosts, so it's probably something important they're doing. They're not a standard symbiont but it seems they're something worth looking at more closely."

In a 15-year study of thousands of children, including those with dyslexia and autism spectrum disorders, researchers discovered that a so-called core language skill, as identified here, was stable from infancy to adolescence. These findings affirm that when a child's language skills are lagging, early intervention is best. As an infant, grasping a language is one indicator of cognitive and social development. Children exhibit individual differences in competency, however; for example, individuals who are the same age can differ noticeably in terms of their language comprehension. It is important to know whether these differences shrink, grow, or remain stable over time, so that interventions can be timed optimally for children who struggle relative to their peers. Differences in language development can be seen in atypically developing children including preterm, dyslexic, autistic and hearing-impaired, compared to typically developing infants. But, little is known about how biological risk affects language stability in atypically developing children. Based on caregiver reports and direct assessments of children from the Avon Longitudinal Study of Parents and Children, Marc H. Bornstein and colleagues analyzed, in two groups, the stability of what they dubbed a core language skill over a 15-year period (starting when children were six months of age and lasting until they were 15). The first group consisted of 935 typically developing children. The second comprised a total of 5,167 children, 4,111 typical and 1,056 atypically developing children. Both groups exhibited clear evidence for individual variation in a core language skill at all ages. But, even when accounting for nonverbal intelligence, sociability, maternal age and education, an individual's core language skill abilities relative to their peers proved consistent from infancy to adolescence in all groups, except for babies between six months and one year old. The strong stability from very early in development suggests that lagging language skills should be addressed as early as possible (and long before school entry), say the authors.

MINNEAPOLIS - Eating leafy greens, dark orange and red vegetables and berry fruits, and drinking orange juice may be associated with a lower risk of memory loss over time in men, according to a study published in the November 21, 2018, online issue of Neurology®, the medical journal of the American Academy of Neurology.

"One of the most important factors in this study is that we were able to research and track such a large group of men over a 20-year period of time, allowing for very telling results," said study author Changzheng Yuan, ScD, of Harvard T.H. Chan School of Public Health in Boston. "Our studies provide further evidence dietary choices can be important to maintain your brain health."

The study looked at 27,842 men with an average age of 51 who were all health professionals. Participants filled out questionnaires about how many servings of fruits, vegetables and other foods they had each day at the beginning of the study and then every four years for 20 years. A serving of fruit is considered one cup of fruit or ½ cup of fruit juice. A serving of vegetables is considered one cup of raw vegetables or two cups of leafy greens.

Participants also took subjective tests of their thinking and memory skills at least four years before the end of the study, when they were an average age of 73. The test is designed to detect changes that people can notice in how well they are remembering things before those changes would be detected by objective cognitive tests. Changes in memory reported by the participants would be considered precursors to mild cognitive impairment. The six questions include "Do you have more trouble than usual remembering a short list of items, such as a shopping list?" and "Do you have more trouble than usual following a group conversation or a plot in a TV program due to your memory?"

A total of 55 percent of the participants had good thinking and memory skills, 38 percent had moderate skills, and 7 percent had poor thinking and memory skills.

The participants were divided into five groups based on their fruit and vegetable consumption. For vegetables, the highest group ate about six servings per day, compared to about two servings for the lowest group. For fruits, the top group ate about three servings per day, compared to half a serving for the bottom group.

The men who consumed the most vegetables were 34 percent less likely to develop poor thinking skills than the men who consumed the least amount of vegetables. A total of 6.6 percent of men in the top group developed poor cognitive function, compared to 7.9 percent of men in the bottom group.

The men who drank orange juice every day were 47 percent less likely to develop poor thinking skills than the men who drank less than one serving per month. This association was mainly observed for regular consumption of orange juice among the oldest men. A total of 6.9 percent of men who drank orange juice every day developed poor cognitive function, compared to 8.4 percent of men who drank orange juice less than once a month. This difference in risk was adjusted for age but not adjusted for other factors related to reported changes in memory.

The men who ate the most fruit each day were less likely to develop poor thinking skills, but that association was weakened after researchers adjusted for other dietary factors that could affect the results, such as consumption of vegetables, fruit juice, refined grains, legumes and dairy products.

The researchers also found that people who ate larger amounts of fruits and vegetables 20 years earlier were less likely to develop thinking and memory problems, whether or not they kept eating larger amounts of fruits and vegetables about six years before the memory test.

The study does not show that eating fruits and vegetables and drinking orange juice reduces memory loss; it only shows a relationship between them.

A limitation of the study was that participants' memory and thinking skills were not tested at the beginning of the study to see how they changed over the course of the study. However, because all participants completed professional training, they can be assumed to have started with relatively high cognitive function in early adult life. In addition, the study participants were all male health professionals such as dentists, optometrists, and veterinarians. Thus, the results may not apply to women and other groups of men.

Smoking during pregnancy increases the chance that your baby will become obese. New research published in Experimental Physiology examined potential reasons for this phenomenon, using tissue which is normally discarded following birth.

Smoking and obesity are two of the biggest public concerns facing populations around the world. Despite wide-scale public health campaigns, in the UK 7.4 million (15.1%) of adults still smoked in 2017 [1]. Furthermore, 26% of adults and up to 20% of children are obese, with the overall cost of obesity to wider society estimated at £27 billion [2]. The rates of childhood obesity have been and are continuing to increase, meaning environmental factors beyond diet, exercise, and genetics must be contributing. As such, an understanding of some of the mechanisms behind smoking related health conditions could help act as a springboard for the development of effective treatments.

It has been long understood that babies born to mothers who smoke cigarettes during pregnancy are at increased risk of premature birth and low birth weight. However, more recent research has shown that a mother smoking whilst pregnant can result in a baby becoming obese. Lead author Leryn Reynolds, Ph.D. and colleagues set out to uncover what mechanisms might contribute to this.

Chemerin is a protein produced by fat cells, and has been found to be present in higher levels in the blood of obese people. The research team used the discarded foreskins of recently circumcised newborn males as a surrogate tissue to study chemerin levels in neonates exposed to cigarette smoke during pregnancy. This skin was used as it is safe and simple to collect, and the research team had previously demonstrated it to have similar properties to other tissues (like fat) which would have been too invasive to collect from babies.

The results showed that chemerin was more prevalent in the skin of infants whose mothers smoked during pregnancy. More detailed analysis suggested that this increased expression corresponded with reduced DNA methylation, which is one mechanism which regulates the expression of chemerin. This protein is associated with obesity, and therefore increased expression could increase the likelihood of a baby becoming obese. These results thus suggest that smoking in pregnancy could be leading to changes in the regulation of genes which play an important role in fat cell development and obesity.

One limitation of this study is that the results cannot be generalised to females, given changes were only measured in male neonates. Going forward, the authors plan to measure chemerin levels in isolated cells from the umbilical cord of both baby boys and girls, which is similarly easy to obtain. The researchers also hope to conduct experiments on smoke exposure during pregnancy in mice, as it is easier to control for other factors which might affect obesity. Further various tissues can also be measured to assess gene expression in order to better understand how in utero smoke exposure impacts the whole body.

Senior and corresponding author on the research paper, Kevin Pearson, Ph.D., explained the rationale behind his group's study, and their aims going forward: "Our long-term plan is to study the impact of exercise during pregnancy and its ability to improve health outcomes in offspring. However, as we began to transition our work from laboratory animals to humans, it quickly became apparent that a fairly high percentage of the pregnant population delivering at our hospital continued to smoke cigarettes throughout pregnancy. Thus, we set out to investigate the mechanisms of why babies born to smokers are at risk for later diseases. In the future, we would love to work on ways to improve smoking cessation programs or ways that we can increase exercise levels in smokers as a way to combat the negative outcomes in offspring, but we are really just starting to scratch the surface in this area."

Children with stomach viruses increasingly are given probiotics to ease symptoms of vomiting and diarrhea. But a major U.S. study led by Washington University School of Medicine in St. Louis shows that a commonly used probiotic is not effective in improving symptoms in young patients with gastroenteritis.

The findings are published Nov. 22 in The New England Journal of Medicine.

While rarely fatal in the United States, gastroenteritis -- frequently yet erroneously called "stomach flu" -- accounts for 1.7 million pediatric emergency room visits and more than 70,000 hospitalizations each year.

The study, involving nearly 1,000 children ages 3 months to 4 years, provides evidence against the popular and costly use of probiotics -- live microorganisms believed to restore the balance of intestinal bacteria and boost the immune system.

"Probiotics have become an increasingly popular way to treat children experiencing acute gastroenteritis," said the study's lead author, David Schnadower, MD, who conducted the research as a Washington University professor of pediatrics and a physician at St. Louis Children's Hospital. "Some smaller studies have indicated that probiotics may help, however, such studies had a number of limitations. We sought to provide independent and conclusive evidence for or against probiotic use in infants and toddlers with acute gastroenteritis."

The researchers evaluated a common probiotic known as Lactobacillus rhamnosus GG, or LGG, which is sold over the counter as Culturelle. Certain versions of the probiotic are intended for babies and children.

A similar study in Canada, also published in the same issue of The New England Journal of Medicine and co-authored by Schnadower, evaluated effectiveness of a different probiotic -- Lacidofil -- in children with gastroenteritis. The findings of that study, led by the University of Calgary Cumming School of Medicine in Alberta, mirrored those in the U.S. study.

"The results of the U.S. and Canadian studies were not ambiguous," added the U.S. study's co-author, Phillip I. Tarr, MD, Washington University's Melvin E. Carnahan Professor of Pediatrics and director of the Pediatric Division of Gastroenterology, Hepatology and Nutrition. "Probiotics had no effect on the children. Parents are better off saving their money and using it to buy more fresh fruits and vegetables for their children."

There are no treatments for pediatric acute gastroenteritis other than giving children fluids to prevent dehydration and, sometimes, medication to relieve nausea. The lack of options has prompted some physicians and parents to give ill children probiotics.

Probiotics generally are considered safe. However, the Food and Drug Administration (FDA) does not regulate dietary supplements such as probiotics as stringently as it does prescription and over-the-counter drugs. "Also, manufacturers of probiotics generally can claim that these microorganisms have positive health benefits without rigorous evidence to support their use," Schnadower said.

Consumers worldwide spend billions of dollars each year on probiotic enriched foods, as well as over-the-counter supplements in pill and powder form. The researchers cited statistics showing that the global market for probiotics is predicted to expand in the United States from $37 billion in 2015 to $64 billion in 2023.

"Because of the popularity of probiotics, it was important to make sure their use is worth the cost," said Schnadower, who is now the senior academic director of the Division of Emergency Medicine at Cincinnati Children's Hospital Medical Center. "In this instance, probiotics added no measurable benefit, and, therefore, they are not worth the added cost."

The U.S. study involved 971 children treated between July 2014 and June 2017 in the emergency departments at St. Louis Children's and nine other geographically diverse U.S. academic medical centers. Participants were eligible if they had come to the emergency room with symptoms of gastroenteritis: watery stools, vomiting, diarrhea or other signs of acute intestinal infection. They also had to have not have taken probiotics in the preceding two weeks.

Half of the children in the study were randomly assigned to receive the probiotic LGG twice daily for five days, while the others took a similarly looking and tasting placebo. Otherwise, the children received standard clinical care.

Neither the researchers nor the parents knew which children had received the probiotics.

Regardless of whether the children took a placebo or probiotic, their symptoms and recovery were nearly identical. The data showed that diarrhea in both groups of kids lasted about two days and the kids missed an average of two days of day care.

"We tested many different scenarios -- infants compared with toddlers, whether the patient had taken antibiotics, whether the gastroenteritis was caused by virus or bacteria, and how long the diarrhea had been going on before the treatment was given. We also had the probiotic independently tested for purity and strength. Every time, we reached the same conclusion," Schnadower said. "LGG did not help."

Probiotics are a multibillion-dollar industry with marketing claims of being an effective treatment for a multitude of ailments, including diarrhea. However, findings from a new study from the University of Calgary show the popular product has no effect on gastroenteritis, commonly yet erroneously called the stomach flu, in children.

"We studied the effects of giving probiotics to hundreds of children whose parents brought them into emergency departments across the country suffering from vomiting and diarrhea," says Dr. Stephen Freedman, MD, pediatric emergency medicine physician with Alberta Health Services, holder of the Alberta Children's Hospital Foundation Professorship in Child Health & Wellness and member of Cumming School of Medicine's Alberta Children's Hospital Research Institute. "We found no evidence that probiotics had any effect on reducing symptoms, or helping with recovery."

Freedman led a six-site Canadian study that included almost 900 children. He was also the co-principal investigator on a 10-site, concurrently conducted study in the United States, led by Dr. David Schnadower, MD that recruited almost 1,000 children. Findings from both studies will be published in the New England Journal of Medicine Thursday, November 22.

"There were smaller trials that had shown promising results. We wanted to replicate these findings on a large scale to see whether the age of the patient, the type of infection, and the use of antibiotics or length of time a child had the illness would affect the response to probiotics," says Schnadower, MD, who conducted the research as a professor of pediatrics at Washington University School of Medicine in St. Louis and is now a professor at University of Cincinnati College of Medicine. "The findings in both studies were consistently negative regardless of how the data were analyzed."

Researchers tested two commercially available brands of probiotics. Recruitment for the Canadian double-blind randomized study began in 2013. Children ranged in age from three to 48 months. Half of the children received probiotics while the other half received a placebo.

"These findings, taken together, are very powerful. The findings show that children treated with probiotics have the exact same outcomes across a large range of symptoms, as those given placebo -- the probiotics had no effect," says Freedman, who is also a member of the O'Brien Institute for Public Health at the Cumming School of Medicine. "The results deliver a clear message that we need to question the role and benefits of probiotics for other health applications using large, patient oriented, rigorous clinical trials."

Probiotics are generally considered safe to use. They are classified as food ingredients in Canada and can be sold as natural health products. As such, they do not require the same rigorous scientific testing that medications require, such as multiple clinical trials, in order to make beneficial claims. "Until now, most studies into the effects of probiotics have been small and industry funded," says Freedman. "In order to better serve families we need independent research to either prove or disprove the claims marketers are making on health care products."