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ROCHESTER, Minn. -- Bacteriophages, or phages, may play a significant role in treating complex bacterial infections in prosthetic joints, according to new Mayo Clinic research. The findings suggest phage therapy could provide a potential treatment for managing such infections, including those involving antibiotic-resistant microbes.

The research is published in the July issue of Clinical Infectious Diseases (CID).

"The treatment for chronic prosthetic joint infection has been surgery plus antibiotics, with surgery being the backbone of therapy. When these efforts fail, there can be significant suffering, loss of limb, even death," says author Gina Suh, M.D., Mayo Clinic infectious diseases specialist. "Phage therapy has the potential to be paradigm-shifting in how we treat infections in this era of increasing medical device use and antibiotic resistance."

Phages are naturally occurring viruses found throughout the earth that target and kill specific bacterial cells, including those that have grown resistant to multiple antibiotics. The microscopic organisms, numbering in the billions, destroy bacteria by injecting their DNA or RNA into the bacteria to replicate and burst the cells open.

Although phage therapy is new to Mayo Clinic, the bacterial predators were discovered more than a century ago, predating antibiotics. Today, much of the basic science of phages remains to be discovered.

Dr. Suh oversaw the first phage treatment at Mayo Clinic in June 2019, when a 62-year-old man was facing potential amputation after multiple failed courses of antibiotics and surgery. The intravenous use of phage therapy was approved by the U.S. Food and Drug Administration on a compassionate-use basis.

"We started phage therapy as kind of a last-ditch effort to save his limb, and the patient responded beautifully," Dr. Suh says. "He has remained asymptomatic after completing treatment and he experienced no adverse effects."

The patient's infection involved a biofilm that formed on his knee-joint replacement device -- a common complication among the millions of people worldwide who undergo life-enhancing joint replacements every year.

Study co-author Robin Patel, M.D., says biofilms are communities of bacteria held together in a slimelike substance and that growth in biofilms enables bacteria to evade the effects of many antibiotics.

"When bacteria grow as biofilms on surfaces, such as joint replacement devices, bacteria are difficult to eradicate because being in biofilm state makes them resistant to many of the antibiotics that would otherwise work against them," says Dr. Patel, director of Mayo Clinic's Infectious Diseases Research Laboratory.

Dr. Patel uses proteomic analysis to identify a patient's bacterium to begin the process of matching it with a phage.

"We then test a collection of phage against that particular patient's species of bacteria to determine which might work best," Dr. Patel says. "We're looking for the ability of phage to either kill or keep these bacteria from growing as a measure of activity."

She says as the world faces a growing public health threat from drug-resistant bacterial infections, and that it is possible that phage therapy could save lives, but more study is needed.

"There have been several patients who have been treated with phage with promising outcomes, but as a scientist, a single case like ours, or even a collection of single cases, is not enough to prove that a therapy is active," Dr. Patel says.

The next step in the study is to expand the clinical use of phage therapy on prosthetic-joint infections of the hip and knee. Mayo Clinic is launching a two-year clinical trial later this year to continue to evaluate phage therapy in the treatment of infectious diseases.

Durham, NC - A new platform reported on today in STEM CELLS Translational Medicine (SCTM) will enable long-term tracking of cardiomyocytes produced from induced pluripotent stem cells (iPSCs) after implantation into the heart. This non-invasive strategy, created by the use of modern gene editing to insert a gene called sodium/iodide symporter (NIS), features superior safety and allows long-term non-invasive cell tracking, plus offers the potential for a broad variety of applications in the preclinical and clinical development of cardiac and other cell therapies, its creators say.

The use of iPSCs, which can be generated directly from adult cells, to treat cardiac disease and other conditions is a much-debated topic in the medical world today. Some research shows they have promise in producing cardiomyocytes (the heart's muscle cells) to allow regeneration of tissue damaged by a heart attack; other studies contradict those results. Being able to follow cells long-term to determine where they go and what happens after implantation could go a long way in settling the issue.

However, current methods used to track iPSCs within the body (in vivo) have several limitations, particularly when it comes to immune-competent large animals (animals with immune systems able to respond adequately to stimulus by a toxin or foreign substance). Optical scanning of xenogeneic fluorescent proteins - a typical method for in vivo cell tracking in immune-deficient organisms -- is not applicable in these cases, for fear the foreign tracking proteins could trigger rejection via the body's immune system and an inability to non-invasively detect fluorescence in internal organs of larger animals. But the new tracking strategy reported on in SCTM promises to overcome these limitations.

The platform was developed by a multi-institutional team led by Cynthia Dunbar, M.D., and So Gun Hong, DVM, Ph.D., of the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.

"Better imaging techniques are crucial for improved cardiac therapies," Dr. Hong said. "In this study, we wanted to demonstrate a molecular imaging technique for non-invasive, long-term visualization of what happens after the NIS expressing heart cells are transplanted into cardiac muscle damaged by a heart attack. We also wanted to see if this technique would permit detection of teratomas -- which are tumors."

They chose the NIS gene as it is endogenous (normally produced within the body) and therefore does not trigger an immune response. Typically, it is produced only in a limited number of tissues, most notably the thyroid gland, where it functions to import iodide. Clinical thyroid scans take advantage of the NIS protein also being able to import radioactive and other tracer molecules that can be detected by standard clinical imaging methods such as PET scans.

Using CRISPR/Cas9 editing, Dr. Hong and coworkers incorporated a rhesus NIS gene into a "safe harbor" location in the genome of rhesus macaque iPSCs. These edited cells (NIS-RhiPSC-CMs) were then injected into the hind legs of one group of mice, to follow for teratomas, and into the hearts of another group of mice immediately following an induced heart attack. The transplanted NIS-RhiPSC-CMs in all animals were then monitored through PET and CT scans.

"The NIS-labeled heart cells looked and functioned similar to heart cells produced from iPSCs without the label. Following transplantation into the damaged heart tissue, the engrafted cells could be visualized until the study's conclusion at 10 weeks post-injection," Dr. Dunbar said. "This leads us to conclude that this new molecular imaging platform is primed for use in preclinical models and clinical trials and may bring us closer to the long-awaited era of gene therapy for heart disease and other diseases."

"This is an interesting study on the development of a new NIS-based platform using CRISPR/Cas9 gene editing to track the fate of cells after implantation to determine where they go and what happens to them," said Anthony Atala, M.D., Editor-in-Chief of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. "This approach offers wider applications in both the preclinical and clinical development of cardiac cell therapies."

In addition to funding from the NHLBI, this study was also funded by the National Cancer Institute, also part of the NIH.

The future has already arrived. (Partially) autonomous cars are already on our roads today with automated systems such as braking or lane departure warning systems. As a central vehicle component, the software of these systems must continuously and reliably meet high quality criteria. Franz Wotawa from the Institute of Software Technology at TU Graz and his team in close collaboration with the cyber-physical system testing team of AVL are dedicated to the great challenges of this future technology: the guarantee of safety through the automatic generation of extensive test scenarios for simulations and system-internal error compensation by means of an adaptive control method.

Ontologies instead of test kilometers

Test drives alone do not provide sufficient evidence for the accident safety of autonomous driving systems, explains Franz Wotawa: "Autonomous vehicles would have to be driven around 200 million kilometers to prove their reliability - especially for accident scenarios. That is 10,000 times more test kilometers than are required for conventional cars." However, critical test scenarios with danger to life and limb cannot be reproduced in real test drives. Autonomous driving systems must therefore be tested for their safety in simulations. "Although the tests so far cover many scenarios, the question always remains whether this is sufficient and whether all possible accident scenarios have been considered," says Wotawa. Mihai Nica from the AVL underlines this statement: "in order to test highly autonomous system, it is required to re-think how the automotive industry must validate and certify Advanced Driver Assistance Systes (ADAS) and Autonomous Driving (AD) systems. Therefore, AVL participates with TU Graz to develop a unique and highly efficient method and workflow based on simulation and test case generation for prove fulfillment of Safety Of The Intended Functionality (SOTIF), quality and system integrity requirements of the autonomous systems".

Together the project team is working on innovative methods with which far more test scenarios can be simulated than before. The researchers' approach is as follows: instead of driving millions of kilometers, they use ontologies to describe the environment of autonomous vehicles. Ontologies are knowledge bases for the exchange of relevant information within a machine system. For example, interfaces, behavior and relationships of individual system units can communicate with each other. In the case of autonomous driving systems, these would be "decision making", "traffic description" or "autopilot". The Graz researchers worked with basic detailed information about environments in driving scenarios and fed the knowledge bases with details about the construction of roads, intersections and the like, which AVL provided. From this, driving scenarios can be derived, by using AVL's world leading test case generation algorithm, that test the behavior of the automated driving systems in simulations.

Additional weaknesses uncovered

As part of the EU AutoDrive project, researchers have used two algorithms to convert these ontologies into input models for combinatorial testing that can subsequently be executed using simulation environments. "In initial experimental tests we have discovered serious weaknesses in automated driving functions. Without these automatically generated test scenarios, the vulnerabilities would not have been detected so quickly: nine out of 319 test cases investigated have led to accidents." For example, in one test scenario, a brake assistance system failed to detect two people coming from different directions at the same time and one of them was badly hit due to the initiated braking maneuver. "This means that with our method, you can find test scenarios that are difficult to test in reality and that you might not even be able to focus on," says Wotawa.

This work by Franz Wotawa et al was also presented in the journal "Information and Software Technology" at the beginning of 2020 and overlaps with the „Christian Doppler Laboratory for Methods for Quality Assurance of Cyber-Physical Systems". The CD lab is led by Franz Wotawa, and AVL is a corporate partner. Das Christian Doppler Labor (CD-Labor) wird von Franz Wotawa geleitet, die AVL ist Unternehmenspartnerin.

Adaptive compensation of internal errors

Autonomous systems and in particular autonomous driving systems must be able to correct themselves in the event of malfunctions or changed environmental conditions and reliably reach given target states at all times. "When we look at semi-automated systems already in use today, such as cruise control, it quickly becomes clear that in the case of errors, the driver can and will always intervene. With fully autonomous vehicles, this is no longer an option, so the system itself must be able to act accordingly," explains Franz Wotawa.

In a new publication for the Software Quality Journal, Franz Wotawa and his PhD student Martin Zimmermann present a control method that can adaptively compensate for internal errors in the software system. The presented method selects alternative actions in such a way that predetermined target states can be achieved, while providing a certain degree of redundancy. Action selection is based on weighting models that are adjusted over time and measure the success rate of specific actions already performed. In addition to the method, the researchers also present a Java implementation and its validation using two case studies motivated by the requirements of the autonomous driving range.

The project "AutoDrive" is funded under the EU Horizon2020 programme and will end in October 2020. The project is coordinated by Infineon Germany. In addition to TU Graz, the following Austrian organisations AVL List GmbH, Infineon Technologies Austria AG, TTTECH COMPUTERTECHNIK AG, TTTECH AUTO AG, the AIT Austrian Institute of Technology and the Virtual Vehicle Competence Center are also on board. More Information can be found on the project website.

This research is anchored in the Fields of Expertise "Mobility & Productions" and "Information, Communication and Computing", two of the five strategic research core areas of TU Graz.

Researchers at the Smithsonian Tropical Research Institute (STRI) in Panama have published dramatic maps showing the locations of lightning strikes across the tropics in Global Change Biology. Based on ground and satellite data, they estimate that more than 100 million lighting strikes on land each year will radically alter forests and other ecosystems in the region between the Tropic of Cancer and the Tropic of Capricorn.

"Lightning influences the ability of forests to store biomass, and therefore carbon, because it tends to strike the largest trees," said Evan Gora, a post-doctoral fellow at STRI who recently finished his doctorate at the University of Louisville. "And lightning strikes may also be very important in savanna ecosystems."

Because lightning is so challenging to study, it has been overlooked as a change-agent in tropical forests where researchers focus their energy on more obvious disturbances like drought, fire, and high winds.

In a previous study, the first to examine the effects of lightning on a tropical forest landscape, the same team found that lightning probably kills half of the biggest trees in a Panamanian forest. Tropical ecologist Steve Yanoviak, study coauthor and professor at the University of Louisville who was studying ants in the tropical forest canopy--and often thought about the role of lightning while climbing trees, invited lightning researchers Jeffrey Burchfield and Phillip Bitzer from the University of Alabama at Huntsville to set up lightning detectors at STRI's Barro Colorado Island Research Station.

"We found that a lightning strike damages a total of 23.6 trees and kills 5.5 of these trees within a year, on average," Yanoviak said.

Now the team is asking how lightning affects tropical ecosystems everywhere. Gora led the effort to map lightning strike counts based on images from the Earth Networks Global Lightning Network (ENGLN) onto a map of tropical ecosystems created using land-cover categories from the International Geosphere-Biosphere Program and the Moderate Resolution Spectroradiometer (MODIS) Land Cover Climate Modeling Grid.

Based on satellite data about strike locations and on-the-ground effects around 92 lightning strikes, including many from the previous study, Gora and his colleagues estimated that lightning damages approximately 832 million tropical trees each year. Roughly a quarter of the trees probably die from their injuries.

Gora and colleagues then asked whether there was a connection between the number of lightning strikes and the type of ecosystem, its biomass and climate variables like rainfall and temperature. They found that lightning strikes were more frequent in forests, savannas and urban areas than in grasslands, shrublands and croplands.

Forests that experience more lightning strikes each year have fewer large trees per hectare, perhaps because the large individual trees in these forests stand out more, higher rates of woody biomass turnover (more tree biomass dies each year) and less total aboveground biomass.

But more burning questions remain. No one knows why some trees survive lightning strikes while others die, although it is likely that trees have evolved ways of coping with such a common threat.

And, as climate change accelerates, polluted, hot air over cities may also increase the number of lightning strikes there. What will the effects be on vegetation in urban areas?

"This is the best evidence to date that lightning is a major disturbance influencing tropical forest dynamics and structure," said STRI staff scientist and study co-author Helene Muller-Landau, "We suspect that our study vastly underestimates the total effect of lightning. Lightning strikes may play a major role in forest biomass/carbon cycling not only in tropical forests but also in other tropical ecosystems."

A team from IDIBELL and ICO, using a mouse orthotopic model, conducted a real-time personalized oncology study to test the best therapeutic option to treat a type of relapse sarcoma. Malignant Peripheral Nerve Sheath Tumor (MPNST) are very aggressive and do not usually have a good prognosis, especially if complete surgical excision cannot be achieved. To generate the orthotopic model, a small fresh fragment of the patient's tumor was implanted on the same day of surgery in the same mouse tissue. Once the tumor had grown in the mouse, several treatments were tested and the response was analyzed.

In the study, co-led by Dr. Conxi Lázaro and Dr. Alberto Villanueva, both of IDIBELL Oncobell program and researchers of the Catalan Institute of Oncology, the creation of the orthotopic model of MPNST allowed to realize, by Next Generation Sequencing techniques, genetic analyzes to determine the mutations that the patient presented.

Based on genetic analyzes, drug availability, and previously published results, in coordination with the team of oncologists that treated the pediatric patient from Hospital Sant Joan de Déu, ten drugs were tested in seven possible treatments in the mouse model. Based on the results obtained in the mouse, two treatment regimens were administered successively to the patient, who had previously developed lung metastasis. The patient did not show complete response to treatments, but along with a lung metastasectomy, he has been 46 months free of disease.

Juana Fernández Rodríguez, the first author of the work, indicates that although this mouse model has not exactly recapitulated what happens in humans, it is a pilot test to identify key aspects of personalized therapy. "The experience gained in this trial can help to better plan this type of murine model in real-time," says Fernández Rodríguez, "and help to fill the gap between the specific genetic alterations of each tumor and the treatments of patients, allowing to select the best therapeutic options."

This study was carried out in coordination with the Hospital de Sant Joan de Déu in Barcelona, the IGTP in Badalona, and was funded, among others, by the Fundación Proyecto Neurofibromatosis at the state level and of the CSR (Corporate Social Action) activity of the spin-off Xenopat SL.

Researchers from the Nanooptics Group at CIC nanoGUNE (San Sebastian) demonstrate that nanoscale infrared imaging - which is established as a surface-sensitive technique - can be employed for chemical nanoidentification of materials that are located up to 100 nm below the surface. The results further show that the infrared signatures of thin surface layers differ from that of subsurface layers of the same material, which can be exploited to distinguish the two cases. The findings, recently published in Nature Communications, push the technique one important step further to quantitative chemometrics at the nanoscale in three dimensions.

Optical spectroscopy with infrared light, such as Fourier transform infrared (FTIR) spectroscopy, allows for chemical identification of organic and inorganic materials. The smallest objects which can be distinguished with conventional FTIR microscopes have sizes on the micrometre-scale. Scientists at CIC nanoGUNE (San Sebastian), however, employed nano-FTIR to resolve objects, which can be as small as a few nanometres.

In nano-FTIR (which is based on near-field optical microscopy), infrared light is scattered at a sharp metallized tip of a scanning-probe microscope. The tip is scanned across the surface of a sample of interest and the spectra of scattered light are recorded using Fourier transform detection principles. Recording of the tip-scattered light yields the sample's infrared spectral properties and thus the chemical composition of an area located directly below the tip apex. Because the tip is scanned across the sample surface, nano-FTIR is typically considered to be a surface-characterization technique.

Importantly though, the infrared light that is nano-focussed by the tip does not only probe a nanometric area below the tip, but in fact probes a nanometric volume below the tip. Now the researchers at CIC nanoGUNE showed that spectral signatures of materials located below the sample surface can be detected and chemically identified up to a depth of 100 nm. Furthermore, the researchers showed that nano-FTIR signals from thin surface layers differ from that of subsurface layers of the same material, which can be exploited for determination of the materials distribution within the sample. Remarkably, surface layers and subsurface layers can be distinguished directly from experimental data without involving time-consuming modelling. The findings have recently been published in Nature Communications.

The inflammatory molecule interleukin-17A (IL-17A) triggers immune cells that in turn reduce IL-17A's pro-inflammatory activity, according to a study by National Eye Institute (NEI) researchers. In models of autoimmune diseases of the eye and brain, blocking IL-17A increased the presence of other inflammatory molecules produced by Th17 cells, immune cells that produce IL-17A and are involved in neuroinflammation. The finding could explain why IL-17-targeted treatments for conditions like the eye disease autoimmune uveitis and multiple sclerosis (MS) have failed. A report on the findings was published in Immunity. NEI is part of the National Institutes of Health.

In autoimmune uveitis, immune cells become abnormally activated and begin to destroy healthy cells, including light-sensing photoreceptors and neurons. A key immune cell involved in this response is the Th17 lymphocyte, which produces several pro-inflammatory molecules known as cytokines. A hallmark of Th17 cells is the ability to produce IL-17A, which attracts immune cells called neutrophils that can damage tissue. Nevertheless, multiple clinical trials of drugs that block IL-17A have failed to help people with autoimmune uveitis or MS.

"IL-17 is the prototypical inflammatory immune molecule blamed for autoimmunity in the neuro-retina and the brain, but there's been some controversy about the role it plays," said Rachel Caspi, Ph.D., chief of the Laboratory of Immunology at NEI and senior author of the study. "In our model of autoimmune uveitis, we noticed that without IL-17, the amount of tissue damage unexpectedly stayed the same and we had higher levels of other inflammatory molecules."

Caspi and colleagues used mouse models to investigate how IL-17A functions in the course of disease. The researchers were able to selectively remove IL-17A from Th17 cells and examine the cells' behavior in models of both uveitis and MS. Curiously, they found that these cells produce more IL-17F, GM-CSF, and possibly other inflammatory molecules. The researchers concluded that these additional inflammatory cytokines compensate for the loss of IL-17A in driving inflammation.

"How could this work? we asked ourselves," said Caspi. "Scientists are like little kids, when they get an answer to one question, there is immediately the next level of 'why?' So we started looking at the deeper mechanisms that make the whole thing tick."

Usually, the IL-17A signal is picked up by other cells - including retinal tissue cells and neutrophils - that carry the IL-17 receptor. This receptor is a cell-surface protein cells that fits with IL-17A like a lock and key. But in this case, the researchers found copies of the IL-17 receptor on the surface of the Th17 cells that made the IL-17A in the first place.

"The process of cells binding a signal they have themselves produced - called autocrine signaling - has been known to happen in other cell types on occasion. But it hasn't been seen in Th17 cells before," said Caspi.

Caspi and colleagues found that when IL-17A binds to its receptor on Th17 cells, this triggers a signaling cascade that turns up the cells' production of an anti-inflammatory molecule, interleukin-24 (IL-24), which was not previously known to be produced by Th17 cells. IL-24 in turn suppresses the rest of the Th17 cells' inflammatory program, turning down the production of cytokines like IL-17F, GM-CSF and possibly IL-22. Thus, without IL-17A, this autocrine loop does not happen, causing the Th17 cells to overproduce the other inflammatory cytokines and thereby increase inflammation.

IL-17A has been associated with several types of uveitis, a disease that causes up to 15% of cases of blindness in the U.S. Uveitis is generally treated with steroids, which can have serious side-effects.

"There are some diseases, like psoriasis, where anti-IL-17A therapy has been spectacularly successful. We expected that this would also apply to uveitis, but it turned out not the be the case," said Caspi. "This study might explain why clinical trials targeting IL-17A to treat uveitis were not successful, and suggests that a combination approach involving both IL-17A and IL-24 may be more effective in treating autoimmune disorders of the nervous system."

WASHINGTON--Plant-based diets rich in whole carbohydrates can improve insulin sensitivity and other health markers in individuals with type 1 diabetes, according to two case studies published by researchers from the Physicians Committee for Responsible Medicine in the Journal of Diabetes & Metabolism.

Both case studies followed individuals with type 1 diabetes who adopted plant-based diets rich in whole carbohydrates--including fruits, vegetables, whole grains, and legumes. The patients' health care teams tracked their blood sugar control, heart disease risk factors, and other health measurements before and after the diet change.

One case study followed a female patient who was diagnosed with type 1 diabetes in 2018. At the time, her A1c was 8.7%. She initially adopted a low-carbohydrate (less than 30 grams of carbohydrate per day), high-fat diet that was high in meat and dairy. Her blood sugar stabilized, but she required more insulin per gram of carbohydrate consumed. Her total cholesterol also increased from 175 to 221 mg/dL. In January 2019, she switched to a plant-based diet, eliminating dairy products, eggs, and meat. The patient was able to decrease her insulin dosage, maintain her A1c level at 5.4%, and drop her cholesterol level to 158 mg/dL.

"This study challenges the misconception that carbs are the enemy when it comes to diabetes," says study author Hana Kahleova, MD, PhD, director of clinical research at the Physicians Committee. "The patient in this case study experienced the opposite: Adding more healthful carbohydrates to her diet stabilized her glycemic control, reduced her insulin needs, and boosted her overall health."

The other individual--a 42-year-old man who had been diagnosed with type 1 diabetes at age 25--eliminated animal products from his diet and switched to a whole food, plant-based diet. He increased his consumption of carbohydrates from 150 grams to 400-450 grams per day. After adopting a carbohydrate-rich plant-based diet, he lost weight, required less insulin, and reduced his A1c--a measure of blood sugar levels over a 3-month period--from 6.2% to a range between 5.5-5.8%.

The authors note that a previous small study supported the case studies' results, finding that a high-carbohydrate, high-fiber diet improved glycemic control in 10 people with type 1 diabetes. As a next step, the authors suggest that randomized clinical trials are needed to verify the case studies' findings, assess their generalizability, and quantify the effectiveness of plant-based diets in the management of type 1 diabetes.

Previous studies have found that low-fat, plant-based diets can be beneficial for those with type 2 diabetes. Research has also shown that those eating a plant-based diet have approximately half the risk of developing type 2 diabetes, compared with non-vegetarians.

"Decades of research has proven that a plant-based diet can be beneficial for those with type 2 diabetes. Now, these groundbreaking case studies are offering hope that the same may be true for those with type 1 diabetes," adds Dr. Kahleova.

July 23, 2020 - Although rates of surgery for Crohn's disease have decreased over the years, many patients still require surgical treatment - due to inadequate responses to medical therapy, severe attacks of acute colitis, and many other situations. Reflecting the latest research evidence and clinical practice, an updated set of recommendations for surgery in patients with Crohn's disease have been published in Diseases of the Colon & Rectum (DC&R), the official journal of the American Society of Colon and Rectal Surgeons (ASCRS). The journal is published by Wolters Kluwer.

Developed by the ASCRS Clinical Practice Guidelines Committee, the revised recommendations were posted today on the DC&R website and will appear in the journal's August issue. Amy L. Lightner, MD, of the Cleveland Clinic was lead author on behalf of the Committee. She comments, "We hope these guidelines will offer guidance in navigating the increasingly complex and multi-disciplinary management of Crohn's disease."

Surgery for Crohn's Disease: Indications and Considerations Before, During and After Surgery

"Crohn's disease is an idiopathic, incurable chronic inflammatory disease of the GI tract, which affects over one million people in the United States and continues to increase in incidence for unknown reasons," according to the guideline statement. With effective medical therapies, the need for surgical treatment of Crohn's disease, including emergency surgery, has decreased over the years.

Yet nearly half of patients still require surgery within five years after being diagnosed with Crohn's disease, and remain at high long-term risk of repeat surgery. The prior ASCRS Crohn's disease practice guidelines were published in 2015. The 2020 updated clinical practice guidelines reflect the research that has been published over the interval, including grades specific for each recommendation about how the new evidence may impact clinicians' practice. The 2020 guidelines consist of 28 recommendations, organized into five categories:

Operative Indications. Several recommendations address the varied indications for surgery in patients with Crohn's disease. Although most patients respond to anti-inflammatory therapies, including steroids and monoclonal antibodies, some develop "medically refractory" disease, requiring surgery due to inadequate response, complications, or other inability to tolerate medical treatment.

Other indications for surgery include severe colitis (inflammation of the colon) with "impending or actual" perforation; strictures (narrowing of the bowel) that cannot be treated with medications or endoscopy; "penetrating" disease such as perforations, abscesses, or fistulas; and hemorrhage (bleeding). The revised guidelines also include an expanded discussion of surgical treatment for patients with dysplasia (precancerous lesions) or cancer of the colon and rectum - a long-term complication of Crohn's disease.

Site-Specific Operations. The guidelines include an extensive discussion and recommendations for surgery at different sites along the gastrointestinal tract. In each situation, the Committee includes recommendations for the extent of surgery and the need for an ostomy. This section also includes recommendations for emergency surgery in patients with severe, acute Crohn's colitis.

Preoperative, Intraoperative, and Postoperative Considerations. The revised guidelines include three updated sections focusing on considerations before, during, and after surgery for patients with Crohn's disease. In the preoperative period, treatment with steroids should be discontinued if possible, due to the risk of infection. Other recommendations address the need for preoperative nutritional support and the importance of smoking cessation.

Intraoperative recommendations call for the use of minimally invasive surgical approaches, when possible. Key considerations of surgical technique are discussed, including new evidence on surgical advances. Postoperative considerations address the role of medical therapy to treat residual disease activity or maintain Crohn's disease in remission after surgery.

The Committee emphasizes that the management of patients with Crohn's disease involves different medical disciplines working in conjunction together; as such, the guidelines "represent only a portion of the treatment necessary for the optimal care of these patients." Dr. Lightner adds: "Given the ever-evolving management options for patients with Crohn's Disease, this guideline provides an up-to-date summary of current management."

Even by the standards of quantum physicists, strange metals are just plain odd. The materials are related to high-temperature superconductors and have surprising connections to the properties of black holes. Electrons in strange metals dissipate energy as fast as they're allowed to under the laws of quantum mechanics, and the electrical resistivity of a strange metal, unlike that of ordinary metals, is proportional to the temperature.

Generating a theoretical understanding of strange metals is one of the biggest challenges in condensed matter physics. Now, using cutting-edge computational techniques, researchers from the Flatiron Institute in New York City and Cornell University have solved the first robust theoretical model of strange metals. The work reveals that strange metals are a new state of matter, the researchers report July 22 in the Proceedings of the National Academy of Sciences.

"The fact that we call them strange metals should tell you how well we understand them," says study co-author Olivier Parcollet, a senior research scientist at the Flatiron Institute's Center for Computational Quantum Physics (CCQ). "Strange metals share remarkable properties with black holes, opening exciting new directions for theoretical physics."

In addition to Parcollet, the research team consisted of Cornell doctoral student Peter Cha, CCQ associate data scientist Nils Wentzell, CCQ director Antoine Georges, and Cornell physics professor Eun-Ah Kim.

In the quantum mechanical world, electrical resistance is a byproduct of electrons bumping into things. As electrons flow through a metal, they bounce off other electrons or impurities in the metal. The more time there is between these collisions, the lower the material's electrical resistance.

For typical metals, electrical resistance increases with temperature, following a complex equation. But in unusual cases, such as when a high-temperature superconductor is heated just above the point where it stops superconducting, the equation becomes much more straightforward. In a strange metal, electrical conductivity is linked directly to temperature and to two fundamental constants of the universe: Planck's constant and Boltzmann's constant. Consequently, strange metals are also known as Planckian metals.

Models of strange metals have existed for decades, but accurately solving such models proved out of reach with existing methods. Quantum entanglements between electrons mean that physicists can't treat the electrons individually, and the sheer number of particles in a material makes the calculations even more daunting.

Cha and his colleagues employed two different methods to crack the problem. First, they used a quantum embedding method based on ideas developed by Georges in the early '90s. With this method, instead of performing detailed computations across the whole quantum system, physicists perform detailed calculations on only a few atoms and treat the rest of the system more simply. They then used a quantum Monte Carlo algorithm (named for the Mediterranean casino), which uses random sampling to compute the answer to a problem. The researchers solved the model of strange metals down to absolute zero (minus 273.15 degrees Celsius), the unreachable lower limit for temperatures in the universe.

The resulting theoretical model reveals the existence of strange metals as a new state of matter bordering two previously known phases of matter: Mott insulating spin glasses and Fermi liquids. "We found there is a whole region in the phase space that is exhibiting a Planckian behavior that belongs to neither of the two phases that we're transitioning between," Kim says. "This quantum spin liquid state is not so locked down, but it's also not completely free. It is a sluggish, soupy, slushy state. It is metallic but reluctantly metallic, and it's pushing the degree of chaos to the limit of quantum mechanics."

The new work could help physicists better understand the physics of higher-temperature superconductors. Perhaps surprisingly, the work has links to astrophysics. Like strange metals, black holes exhibit properties that depend only on temperature and the Planck and Boltzmann constants, such as the amount of time a black hole 'rings' after merging with another black hole. "The fact that you find this same scaling across all these different systems, from Planckian metals to black holes, is fascinating," Parcollet says.

EAST LANSING, Mich. - How accurate was William Shakespeare when he said, "'Tis better to have loved and lost than never to have loved at all"? Researchers from Michigan State University conducted one of the first studies of its kind to quantify the happiness of married, formerly married and single people at the end of their lives to find out just how much love and marriage played into overall well-being.

The study -- published in the Journal of Positive Psychology -- examined the relationship histories of 7,532 people followed from ages 18 to 60 to determine who reported to be happiest at the end of their lives.

"People often think that they need to be married to be happy, so we asked the questions, 'Do people need to be in a relationship to be happy? Does living single your whole life translate to unhappiness? What about if you were married at some point but it didn't work out?,'" said William Chopik, MSU assistant professor of psychology and co-author of the paper. "Turns out, staking your happiness on being married isn't a sure bet."

Chopik and Mariah Purol, MSU psychology master's student and co-author, found that participants fell into one of three groups: 79% were consistently married, spending the majority of their lives in one marriage; 8% were consistently single, or, people who spent most of their lives unmarried; and 13% had varied histories, or, a history of moving in and out of relationships, divorce, remarrying or becoming widowed. The researchers then asked participants to rate overall happiness when they were older adults and compared it with the group into which they fell.

"We were surprised to find that lifelong singles and those who had varied relationship histories didn't differ in how happy they were," said Purol. "This suggests that those who have 'loved and lost' are just as happy towards the end of life than those who 'never loved at all.'"

While married people showed a slight uptick in happiness, Purol said the margin was not substantial -- nor what many may expect. If the consistently married group answered a 4 out of 5 on how happy they were, consistently single people answered a 3.82 and those with varied history answered a 3.7.

"When it comes to happiness, whether someone is in a relationship or not is rarely the whole story," Chopik said. "People can certainly be in unhappy relationships, and single people derive enjoyment from all sorts of other parts of their lives, like their friendships, hobbies and work. In retrospect, if the goal is to find happiness, it seems a little silly that people put so much stock in being partnered."

If someone longs for a lifelong partner to start a family and build a happy life together, Chopik and Purol's research suggests that if that individual isn't completely happy to begin with, getting married won't likely dramatically change it all.

"It seems like it may be less about the marriage and more about the mindset," Purol said. "If you can find happiness and fulfillment as a single person, you'll likely hold onto that happiness -- whether there's a ring on your finger or not."

An international research project coordinated by the Vienna University of Technology (TU Wien), with participation from researchers of the University of Barcelona, shows for the first time that flood pattern over the last decades in Europe have changed compared to past centuries. The study, published in the journal Nature, concludes we are in one of the most flood-rich periods in Europe from the last five hundred years.

The study shows that, within the last half of the millennium, the last three decades are among the most important periods regarding frequency and magnitude of floods in Europe. Also, during these three decades, distribution of the floods have changed, as well as the temperature of the air and flood seasonality, with a higher percentage of floods in summer. Regarding the temperature of the air, from 1500 to 1900, floods used to take place with higher frequency during cold climate phases, while after 1990, floods increased within the context of global warming.

The data analysis identified nine periods of floods that were more abundant and the associated regions. Among the most notable periods are 1560-1580 (western and central Europe), 1760-1800 (most part of Europe), 1840-1870 (western and southern Europe), and 1990-2016 (western and central Europe). According to the analysis, the current phase is the third most severe regarding floods. However, this data is at the expense of the duration of the current phase of abundant floods, to be concluded. Now, floods cause annual damages accounting for more than 100,000 million euros, and the general tendency of abundant floods is increasing.

Historical data from half a millennium

The international study, coordinated by Günter Blöschl, director of the Institute of Hydraulic Engineering and Water Resources Management in TU Wien, counts on the participation of thirty-four research groups from all over Europe, among which are also researchers of the National Museum of Natural Sciences (CSIC Madrid) and the University of Almería (UAL).
In the study, researchers analysed thousands of historical documents with direct and contemporary information on flood episodes in Europe from 1500 to 2016. Research teams of the University of Barcelona, CSIC and the University of Almería provided historical data from Spain and a part of the series in Switzerland. Both countries have detailed records in the European context.

Mariano Barriendos, researcher at the Department of History and Archaeology of the UB, together with Andrea Kiss (TU Wien), note that "the special challenge of this study was to compare sources and texts that were very different from others from other centuries and cultural regions". They put those texts in their historical context with deep attention to details and a cross-check between episodes of different kinds of documents, places and basins. For instance, the case of data in the Spanish Mediterranean watershed, this check included 4,500 flood cases.

Differences in current river floods

"In our previous studies, especially those focused on alpine basins with glacial presence, we knew there was a high number of flood periods in the past that coincided with cold climate abnormalities", notes Professor Lothar Schulte, coordinator of the Consolidated Research Group on Paleoecology, Natural Risks and Environmental Management (PaleoRisk) at the Department of Geography of the UB. The comparison with air temperature reconstructions in all Europe could verify that the most notable historical flood periods were colder than intermediate phases.

These results seem to contradict the observation which states that in some areas, such as northern-eastern Europe, the recent warm weather is aligned with severe floods. "Our study shows for the first time that underlying mechanisms have changed: while in the past, floods took place more frequently in colder conditions, the opposite is what happens now", notes Professor Maria del Carme Lasat, coordinator of the Consolidated Research Group on Meteorology at the Department of Applied Physics of the UB. "The hydrological conditions of the present are very different from those in the past", adds Fernando Sánchez Rodrigo, physicist at the University of Almería. "The co-variability of temperatures and rainfall, and their modifications, as well as the intensification or weakness due to atmospheric dynamics, can be key aspects to understand those processes", continues the expert.

The seasonality of floods within the year has changed as well. Previously, the 41% of floods in central Europe took place in summer, compared to the nowadays' 55%. These shifts are related to changes in rainfall, evaporation and snowmelt, and are an important indicator to distinguish between the role of climate change and other control factors such as deforestation and river management.

These results have been obtained thanks to a new databased compiled by the authors of the study, which includes the exact dating of almost all flood episodes recorded in documentary and bibliographical sources. Gerardo Benito, research professor of Earth Sciences of the CSIC, notes that this database is a direct evidence of the level of floods during periods of climate crisis, with a high potential for risk studies. The new study is the first to assess historical periods of floods for a whole continent with such detail during the last five hundred years.

Better data, better forecasts

Due to the change in flood generating mechanisms, Günter Blöschl advocates the use of tools to assess the risk of floods that capture the physical processes involved, and management strategies that can incorporate recent changes in the risk analysis. The team of authors highlights that the management of floods should adapt to these new realities because, regardless of the necessary efforts to mitigate climate change, the effects of this phenomenon will take place during the coming decades.

AURORA, Colo. (July 23, 2020) - Peer mentorship is a critical and more accessible option for professional and personal growth than traditional mentor-mentee relationships, according to a new paper from the University of Colorado Anschutz Medical Campus.

The paper, published in the Journal of Investigative Medicine, finds that peer mentorship, especially in academic medicine, is more inclusive and accessible than traditional hierarchical relationships. Furthermore, the flexibility afforded by participating in peer mentorship groups transcends typical academic settings through online blogs and social media groups, which have become critical in the era of COVID19.

By examining the strengths and weaknesses of various mentorship models, including trainee programs, formal mentorship, grant-based training, ad-hoc relationships and social media groups, researchers have found that peer mentorship is better suited to foster success, including among underrepresented groups. This point is underscored by the success of the authors' own peer mentoring group on the Anschutz campus.

"We started our group because we felt that, as women in academic medicine, we really needed to support each other," says Melanie Cree-Green, lead author and associate professor of pediatrics-endocrinology at the University of Colorado School of Medicine. "Our group of eight women formed three years ago and meets every three weeks. In that time, we have had five promotions, major grant funding - and other positive career milestones that happened thanks in part to our support for one another," says Jill Kaar, co-author and associate professor of pediatrics-endocrinology at the University of Colorado School of Medicine.

Success of these groups is contingent on the establishment of guidelines and rules to ensure members are all on the same page and discord is avoided. "There are ground rules: consistency in meeting, everything stays in confidence, accountability," says Kaar.

The importance of flexible peer-mentoring models has possibly never been more evident than during the Covid-19 pandemic. "The peer mentorship during the pandemic has been amazing," says Cree-Green. "A physician Facebook group that I belong to with a few thousand others in the U.S. has been 2-5 weeks ahead of what's in the news re COVID-related topics - sharing instructions on how to print ventilator splitters, heparin dosing, ventilator settings. Those groups just started booming, and they absolutely made a huge difference to patient care."

The paper provides a framework on how to establish guidelines, encouraging those in medical academia to seek support from other people to form a foundation for their careers. "Peer mentorship is a very different kind of mentoring than we're traditionally taught," says Cree-Green. "It can be very effective to communicate with and understand your peers, and we want to encourage people to form their own mentor groups, especially as things are changing so rapidly. It's not a new concept, but it's an underutilized one."

ORLANDO, July 23, 2020 - For frogs dying of the invasive chytridiomycosis disease, the leading cause of amphibian deaths worldwide, the genes responsible for protecting them may actually be leading to their demise, according to a new study published today in the journal Molecular Ecology by University of Central Florida and the Smithsonian Conservation Biology Institute (SCBI) researchers.

The lowland leopard frog, found in river drainages in Arizona, is one of a few amphibian species in which some individuals survive infection by Batrachochytrium dendrobatidis chytrid fungus (Bd) while other individuals do not--even when they live in the same local population.

In a study of lowland leopard frogs infected with Bd, the fungus that causes the disease chytridiomycosis or chytrid, researchers found that frogs that died from the disease had higher expression of major histocompatibility complex and other immune system genes than frogs that survived it.

Those genes help organisms fight off infections and foreign substances.

"This result was totally counterintuitive and the opposite of the pattern we expected to recover," said Anna Savage, the study's lead author, an associate professor in UCF's Department of Biology and former postdoctoral fellow at SCBI's Center for Conservation Genomics (CCG).

"My previous research on these immune genes showed that some variants were associated with higher survival to Batrachochytrium dendrobatidis, so I hypothesized that those genes were enabling the frogs to have a stronger immune response that would kill the fungus," she said.

"Instead, it seems like those stronger responses are linked to susceptibility, and the genes associating with survival are linked to reduced immune function."

Savage said acquired immune responses can be very potent, require a lot of energy from the body and can sometimes produce toxic byproducts that harm the host and the pathogen.

"Immune responses are much more complex than just an on-off switch," she said. "A big part of the immune system is regulating the type, timing and dosage of a particular response, and if any of those components get dysregulated, it can have extremely negative consequences."

She said, for instance, Batrachochytrium dendrobatidis suppresses the host immune system by killing B and T lymphocytes. "Because those are the same cells that proliferate during acquired immune responses, producing lots of those cells might just be wasting energy on something that chytrid can easily destroy," she said.

Amphibian populations are in decline around the world, with two-thirds of the world's 8,000 species considered to be threatened and nearly 200 species that have already gone extinct in the last two decades.

In the U.S., amphibian populations overall are declining at a rate of nearly 4 percent a year, with some areas, such as the Rocky Mountains and the West Coast, facing a higher rate of decline, according to the U.S. Geological Survey.

Although the researchers studied immune gene expression in lowland leopard frogs with chytridiomycosis, the findings may be useful for studying the disease in other frog species due to genetic similarities they share, Savage said.

Lowland leopard frogs were chosen for the study because their responses to chytridiomycosis vary from one individual to the next, unlike many other frog species that are completely susceptible to the disease or are completely resistant or tolerant.

This allowed the researchers to rule out genetic variation between species and pinpoint specific differences in lowland leopard frogs' immune genes that predicted different responses to infection.

The frogs were collected in Arizona and shipped overnight to the Smithsonian's National Zoo in Washington, D.C., where the infection experiments were conducted.

Subsequent analyses of gene expression occurred at the Smithsonian Conservation Biology Institute's Center for Conservation Genomics. Statistical analyses of the data were performed at UCF.

Robert Fleischer, senior scientist and head of the SCBI's CCG, co-authored the study and was Savage's main advisor for the research when she was a postdoctoral fellow at the Smithsonian.

Fleischer said the results help in understanding why some frogs survive the disease and others do not.

"If we can solve this mystery, and we have taken a big step in that direction with this study, our hope and plan is to use this information to develop resources and strategies to mitigate the disease in the more susceptible species, and to counter the worldwide tide of extinction and endangerment caused by chytrid," he said.

The researcher said the findings also show that acquired immune responses, such as those generated by vaccination, may not always be useful in combating invasive diseases of conservation concern.

A new technology that can allow for better light control without requiring large, difficult-to-integrate materials and structures has been developed by Penn State researchers. The new photonic integrated chip could allow for many advances in the optical field and industry, ranging from improvements in virtual-reality glasses to optical remote sensing, according to the researchers.

Led by Xingjie Ni, assistant professor of electrical engineering, the research was recently published in Science Advances. Penn State electrical engineering doctoral candidates Xuexue Guo, Yimin Ding, Xi Chen and Yao Duan were co-authors on the paper.

Traditionally, scientists have had two options when it comes to controlling light for use in various optical devices. The first is a photonic integrated circuit (PIC) that can be incorporated onto small chips but has limited ability to control free-space light -- light propagating in air, outer space or a vacuum, as opposed to being guided in fibers or other waveguides. The second is a newly emergent metasurface -- an artificially engineered thin layer that allows for light manipulation at subwavelength scale but cannot be integrated on a chip.

Ni and his fellow researchers solved this problem by incorporating the best qualities of the two previous options into a new, hybrid photonic architecture that has metasurfaces integrated onto a PIC chip while maintaining high light controllability.

"This incorporation of the PICs and metasurfaces makes it possible to drive the metasurfaces using guided waves inside the PICs," Ni said. "It enables routing light among different metasurfaces, performing multiple complex functions on a single chip."

This new development could have applications in optical communications, optical remote sensing -- LiDAR -- free-space optical interconnects for data centers and virtual reality and augmented reality displays. ?

"The developed technology will pave exciting ways for building multifunctional PIC devices with flexible access to free space as well as guided, wave-driven metasurfaces with full on-chip integration capability," Ni said.

According to Ni, the most intriguing aspects of his research are the implications for future developments and the success of combining the best traits of existing technology.

"I think the most exciting part of the research is that we married two powerful technologies with complementary capabilities -- integrated photonics and metasurfaces," he said. "Our hybrid system has the advantages from both the metasurfaces and the PICs. In addition, our design is highly flexible and modular. A library of the building blocks can be established for reusing and creating consistent functional components across various devices or systems."