Body

There is no cure for the more than 1.6 million people in the United States living with Crohn's disease (CD) and its symptoms, including abdominal pain, intestinal distress and severe weight-loss. CD is a form of inflammatory bowel disease (IBD) in which the body's own immune system attacks the gastrointestinal tract, and treatment is focused on controlling the symptoms of the disease in its acute phase and managing it in remission. But recently, researchers at Case Western Reserve University School of Medicine identified a pathway in the immune system activated in CD and which holds promise for investigating new treatments.

Fabio Cominelli, MD, professor of medicine at the School of Medicine and chief of gastroenterology at University Hospitals Cleveland Medical Center, led a three-year study, published recently in Cellular and Molecular Gastroenterology and Hepatology, focusing on the chronic inflammation that occurs in genetically susceptible individuals with CD.

Using mouse models of CD, Cominelli and his team investigated the interaction between a class of proteins called tumor necrosis factor and receptors on the surface, called Fn14. Their goal was to see how the tumor necrosis factor (or TWEAK, for Tumor Necrosis Factor-like Weak Inducer of Apoptosis) and its cell receptor, Fn14, may play a dual role of both protecting the intestine from acute and chronic inflammation characteristic in CD, and how it might also trigger it.

Scientists have been studying the TWEAK/Fn14 interaction for at least two decades to understand its role in inflammation. Cominelli and his team, however, are the first to describe this signaling complex in CD.

"During early inflammation, TWEAK/Fn14 activates to heal tissue damage," said Cominelli. "However, during later, chronic inflammation, increased and persistent levels of Fn14 may lead to pathologic inflammation and fibrosis."

Today's CD treatments, such as steroids and monoclonal antibodies, may work for a while, but often cease to be effective. They also may cause hypertension, infection and the risk of birth defects in pregnant women being treated for IBD. As CD patients endure a roller-coaster ride of flare-ups, repeated hospital stays, surgeries and treatments relieved by intervals of remission, the disease becomes dramatically life-changing and emotionally stressful.

To better understand the link between TWEAK/Fn14 and chronic inflammation, the team of researchers used mice bred to develop CD-like disease, and then genetically deleted the cell-surface receptor Fn14. The mice with genetically deleted Fn14 had less severe inflammation. Those with the Fn14 receptor had chronic intestinal inflammation and scarring.

To test whether their findings in mice could be meaningful to CD in humans, the research team then used molecular diagnostics to analyze resected intestinal tissues from patients with and without IBD. The results showed significant TWEAK/Fn14 overexpression in tissue from patients with CD. Cominelli believes that blocking Fn14 pharmacologically using novel drugs and antibodies may ameliorate the inflammation and fibrosis in CD.

The study has implications for cancer treatment as well. According to Cominelli, since chronic inflammation can lead to the initiation and growth of tumors in patients with IBD, those patients are exposed to a risk of developing colorectal cancer that is directly proportional to the extent and duration of their disease.

"This research establishes the rationale for investigating innovative therapies that can improve and save lives," Cominelli said.

Unlike many other cancers, most pancreatic tumors are rock hard. 

"That's one reason why pancreatic cancer is one of the most lethal types of cancer," says Kenneth Olive, PhD, associate professor of medicine and pathology & cell biology at Columbia University Vagelos College of Physicians and Surgeons and a pancreatic cancer researcher at the Herbert Irving Comprehensive Cancer Center.

"Pancreatic tumors recruit a thick layer of connective tissue called stroma that hardens the tumor and acts like a shield," says Olive, whose previous research first uncovered how the stroma makes it difficult for chemotherapy drugs to reach malignant cells. "As a result, most chemotherapy drugs can't build up to the levels needed to be effective."

To Olive, that suggests, paradoxically, a longer-lived--but less toxic--drug may work better. 

"For a pancreatic cancer drug to be effective, it needs to stick around long enough to seep past the stroma and accumulate in the tumor. But if it is going to persist for a long time in the blood, it can't be as toxic to the rest of the body," he says.

Testing a New Drug Combination

Olive's latest research, which was led by Jaime Eberle-Singh, PhD, while she was a graduate student at Columbia, may have identified a good candidate. The drug, an experimental compound called PTC596 that had shown antitumor activity in mouse and human pancreatic cancer cells, seemed to have the right qualities: PTC596 has a durable half-life (most cancer drugs have a half-life of a few minutes to hours) and can evade a pump that many cancer cells use to expel drugs. "This means that any amount of drug that makes it past the barrier can target the malignant cells," says Olive.

Based on those studies, Olive, Eberle-Singh, and their collaborators tested PTC596 in combination with gemcitabine (a first-line drug for pancreatic cancer) in genetically engineered mice with an aggressive form of pancreatic cancer that is generally resistant to chemotherapy.

The mice that were treated with the two-drug combination lived three times longer than those treated with only a single standard agent. "This result was exciting because it's exceedingly rare for any treatment to extend survival in this gold-standard mouse model," Olive says.

They also tested PTC596 in combination with gemcitabine and another drug commonly used to treat pancreatic cancer, nab-paclitaxel, using human pancreatic tumors grown in mice. This combination further enhanced efficacy, making the tumors shrink outright. 

"Based on the drug's safety profile and our own findings, there's a good rationale for testing PTC596 in combination with standard therapy in patients with pancreatic cancer," says Olive.

Microtubule Breakdown

Olive's team also discovered that PTC596 blocks the formation of microtubules--a network of proteins involved in cell division and transport of nutrients within the cell. He demonstrated that PTC596 may act synergistically with nab-paclitaxel, another microtubule-binding agent. 

"Combining different microtubule inhibitors has the potential to play an important role in the future of oncology, as there are many agents that each impact microtubules in different ways that could produce synergy," Olive says. 

WASHINGTON, D.C., August 6, 2019 -- Invisible to the human eye, molecular interactions between gases and liquids underpin much of our lives, including the absorption of oxygen molecules into our lungs, many industrial processes and the conversion of organic compounds within our atmosphere. But difficulties in measuring gas-liquid collisions have so far prevented the fundamental exploration of these processes.

Kenneth McKendrick and Matthew Costen, both at Heriot-Watt University, in Edinburgh, U.K., hope their new technique of enabling the visualization of gas molecules bouncing off a liquid surface will help climate scientists improve their predictive atmospheric models. The technique is described in The Journal of Chemical Physics, from AIP Publishing.

"The molecule of interest in our study, the hydroxyl radical, is an unstable fragment of a molecule that affects the whole of the understanding of atmospheric chemistry and things that genuinely affect climate," said McKendrick. "Some of these important OH reactions take place at the surface of liquid droplets, but we can't see surface interactions directly, so we measure the characteristics of the scattered molecules from real-time movies to infer what happened during their encounter with the liquid."

Laser sheets are the key to the technique, inducing a short-lived fluorescent signal from each molecule as it passes through 10 nanosecond pulses. Laser-induced fluorescence isn't new in itself, but this was the first time laser sheets have been applied to scattering from a surface in a vacuum with no other molecules present to interfere with the scattering from the molecular beam. This enabled the McKendrick team to capture individual frames of molecular movement, from molecular beam to liquid surface and scattering, which were compiled into movies.

Unlike previous methods of capturing gas-liquid interactions, all the characteristics needed to understand the interaction -- speed, scatter angle, rotation, etc. -- are captured within the simple movies that McKendrick describes as "intuitive." By observing the molecular film strips, McKendrick's team noted molecules scattered at a broad range of angles, similar to a ball bouncing off in all directions when thrown onto an uneven surface. This simple observation directly proved the surface of liquids is not flat.

"When you get down to the molecular level, the surface of these liquids is very rough, so much so that you can barely tell the difference between the distribution of molecules when directed down vertically onto the surface or when at an angle of 45 degrees. This finding is important for understanding the chances of different molecular processes happening at the liquid surface," said McKendrick.

As they improve their technique, McKendrick's team hopes to collect more refined information from atmospheric relevant liquids. But McKendrick points out the technique is not limited to the field of atmospheric science and is likely to soon be applied to understanding the gas-solid interactions that occur in processes such as the catalytic conversion of gases in car engines.

Scientists at Trinity College Dublin have announced a major breakthrough with important implications for sufferers of a common eye disease - dry Age-Related Macular Degeneration (AMD) - which can cause total blindness in sufferers, and for which there are currently no approved therapies.

The scientists discovered that a key component of the cells lining the retinal blood vessels, namely claudin-5, may be central to the development of the common blinding eye disease, AMD. In pre-clinical models, it was discovered that "leaky blood vessels" pre-disposed the eye to developing features of AMD.

"We were initially surprised that these blood vessels of the inner retina contributed to an AMD-like pathology, however it now appears that their dysfunction may represent one of the earliest initiating factors of the disease," said Dr Natalie Hudson, Post-doctoral researcher at Trinity, and first author of the study.

Age-Related Macular Degeneration (AMD)

AMD is the most common form of central retinal blindness in the aging population. The disease involves a loss of central visual acuity, such that everyday tasks such as reading, watching TV, driving, or using computers become difficult and in some cases impossible.

There are two forms of AMD: 'dry' and 'wet'. While therapies are available for the management of wet AMD, there are no treatments, therapies or cures yet approved for dry AMD, which accounts for the majority of cases in Ireland and worldwide.

Patients living with dry AMD are presently recommended to pursue lifestyle changes, such as stopping smoking, and improving diet and exercise regimes. Novel forms of therapy are desperately needed in an ever-aging society, with life expectancy currently far exceeding the rate of development of drugs for aging associated conditions.

Dr Matthew Campbell, Assistant Professor in Genetics at Trinity, said: "Identifying the early molecular events that cause dry AMD will allow us to develop a targeted approach to therapy. In this case, we believe that regulating the integrity of the retina's blood vessels may, over time, help to prevent the development of dry AMD."

Dr Mark Cahill, consultant Ophthalmologist at the Royal Victoria Eye and Ear Hospital (RVEEH), added. "Our findings have highlighted the power of basic and clinical research working towards identifying novel targets for AMD therapy, which will ultimately benefit patients in the future."

Scientists working on a new tuberculosis (TB) vaccine have achieved a major step forward by showing that a promising TB antigen and a novel vaccine adjuvant can be protected from heat damage with a technique developed at the University of Bath.

Their method prevents these crucial vaccine components from spoiling outside of a fridge - meaning a thermally stable vaccine that can be reliably delivered to remote areas around the world is more likely.

There is an urgent need not only for a new TB vaccine, but also for methods to keep vaccines stable outside of the refrigeration 'cold chain' - as up to 50% of vaccine doses are discarded before use due to exposure to suboptimal temperatures. Thermostable vaccines have therefore been named a priority research area in the World Health

Organisation's Global Vaccine Action Plan 2011-2020.

Ensilication, a method developed at the University of Bath, "shrink-wraps" vaccine proteins in position using layers of silica that build up into a cage around the molecules - so they don't unravel when exposed to temperatures that would usually break them down. The proteins are held in place until ready to be removed from the silica cage and delivered.

The research team from the Departments of Biology & Biochemistry and Chemistry first demonstrated that the TB antigen ag85b and a vaccine fused with the adjuvant protein Sbi are sensitive to breaking down outside of refrigerated temperatures. They then showed that these vaccine components were protected from heat damage when ensilicated and kept on a shelf at room temperature for long periods of time without loss of structure and function.

This is first time that ensilication has been used to improve the thermal stability of proteins in a vaccine setting, after proof-of-principle work using model proteins.

The results are a big step forward not only in developing a thermally-stable TB vaccines, but in showing that ensilication could be used for many different kinds of vaccines.

The study is published in Scientific Reports.

Lead author Professor Jean van den Elsen, said: "A new TB vaccine is really urgently needed to supplement or replace the existing BCG vaccine and reduce the number of TB cases and deaths - particularly as drug-resistant TB infections remain high."

First author Ayla Wahid, added: "To make the vaccine as effective as possible it needs to be thermally-stable, or in other words not spoil outside of a fridge, which is why we're really encouraged by these results. Cold-chain storage leads to a lot of wastage and expense which could be avoided by ensilication."

Dr Asel Sartbaeva, who invented ensilication, added: "Our results reveal the potential of ensilication in storing and transporting life-saving vaccines at ambient temperatures globally - in particular to remote areas of developing countries where disease rates are often highest.

"With up to 50% of vaccines being thrown away, and refrigeration raising vaccine costs by up to 80%, this is a major global health challenge that we need to overcome. By demonstrating for the first time that ensilication works to protect vaccine-relevant proteins from breaking down outside a fridge we're a big step closer to achieving this goal."

Nonsteroidal anti-inflammatory drugs (NSAIDs) can help to control the pain and inflammation in individuals with osteoarthritis (OA), but a new Arthritis & Rheumatology study suggests that NSAIDs contribute to cardiovascular side effects in these patients.

The study matched 7,743 OA patients with 23,229 non-OA controls. The risk of developing cardiovascular disease among people with OA was 23% higher compared with people without OA. Among secondary outcomes assessed in the study, the risk of congestive heart failure was 42% higher among people with OA compared with people without OA, followed by a 17% greater risk of ischemic heart disease and a 14% greater risk of stroke.

Investigators found that approximately 41% of the increased risk of cardiovascular disease among people with OA was mediated through their NSAID use. NSAIDs also played a substantial role in developing the study's secondary outcomes.

"To the best of our knowledge, this is the first longitudinal study to evaluate the mediating role of NSAID use in the relationship between osteoarthritis and cardiovascular disease in a large population based sample," said senior study author Aslam Anis, PhD, FCAHS, of the School of Population and Public Health at the University of British Columbia. "Our results indicate that osteoarthritis is an independent risk factor for cardiovascular disease and suggest a substantial proportion of the increased risk is due to the use of NSAIDs. This is highly relevant because NSAIDs are some of the most commonly used drugs to manage pain in patients with osteoarthritis. It's important for people with OA to talk to their care providers and discuss the risks and benefits of NSAIDs."

An analysis of published studies found that Nordic walking--a low impact aerobic activity consisting in walking with poles--can benefit patients with breast cancer by having a positive impact on swelling, physical fitness, disability, and quality of life.

The European Journal of Cancer Care analysis, which included nine relevant studies, revealed no adverse effects associated with the exercise.

"Current evidence...stems from a small number of investigations with limited methodological quality. Therefore, further well?designed studies are still needed to explore the potential benefits of Nordic walking on this population," the authors wrote.

In an analysis of information on 10,463 UK patients diagnosed with colorectal cancer from 2006 to 2013, patients under the age of 50 years were more likely to initially experience non-specific symptoms before being referred to cancer specialists.

In the Colorectal Disease analysis, young patients were more likely to present with abdominal pain and via an emergency. They also experienced a longer interval between referral to diagnosis by 12.5 days compared with those aged 60 to 69 years.

"Primary care physicians should be made aware of these differences if there is to be a reduction in missed opportunities to prevent emergency diagnoses," the authors wrote.

Major surgery is associated with a small long-term decline in cognitive functioning - equivalent, on average, to less than five months of natural brain ageing, finds a study in The BMJ today.

But the odds of substantial cognitive decline also increase after surgery - approximately doubling - although the likelihood of this is much lower than after admission to hospital for a medical condition, the findings show.

Cognitive decline is the gradual loss of brain functioning that occurs with ageing. It often starts decades before the conventional definition of old age and accelerates with ageing and the presence of an increasing number of underlying health conditions.

Certain health issues, such as stroke, can lead to a large "step change" in cognitive decline, and there have been concerns that surgery might also do this, with some patients refusing beneficial surgical procedures as a result, say the researchers.

Few previous studies have looked at the potential impact of major surgery on cognitive decline and most of them have relied on a single preoperative assessment of cognitive functioning rather than tracking cognitive decline over time.

To address this, the researchers accessed data on 7,532 British civil servants enrolled in the Whitehall II Study, which has been looking at the impact of social, behavioural, and biological factors on long term health.

All the patients were aged between 35 and 55 in 1985 and received up to five cognitive assessments over a 19-year period (1997 to 2016).

Any hospital admissions requiring at least a two-night stay were identified in hospital episode statistics. Overall, 8,982 "major" events were identified: 4,525 operations; 4,306 medical admissions; and 151 strokes.

Among the 7532 participants, 4954 weren't admitted to hospital for major surgery, but 1250 were: 613 for a medical condition and 715 for both reasons.

After accounting for age-related cognitive decline, the authors calculated that major surgery was associated with a small additional cognitive decline of less than five months (0.35 years), on average.

Admissions for medical conditions and stroke were associated with a far greater additional cognitive decline of 1.4 and 13 years, respectively.

Hospital admission for major surgery or a medical condition also increased the odds of substantial cognitive decline by 2.3 and 6.2, respectively.

Substantial cognitive decline occurred in 5.5% of patients who spent time in hospital for a surgical procedure and 12.7% of those treated in hospital for a medical condition, compared with 2.5% of people who had no major hospital admissions.

This is an observational study, so no firm conclusions can be drawn about cause and effect, and hospital admissions likely act as a surrogate measure for ill health, the researchers point out. What's more, no information on the type of anaesthesia used was available, so its potential role in any long-term cognitive change couldn't be assessed.

Nevertheless, the researchers conclude: "Overall our data suggest that major surgery is associated with a small long term mean change in the age-related cognitive trajectory, with the odds of substantial decline doubling."

While they emphasise that the impact of surgery on cognition is lower than for medical admissions, this needs to be explained to patients, they say. "This information should be conveyed to patients and be weighed against the potential health and quality of life benefits of surgery during informed consent."

Researchers in a linked editorial say, "This study is reassuring in that the authors found no large declines in cognition after surgery." But as cognition deteriorates towards the end of life and contact with health services increases during this time, further exploration into mortality is key, they add.

"Importantly, we need to know which risk factors are modifiable and which are not. If some of [the] findings (particularly those linked to non-surgical admissions) are closely related to dying it might be challenging to disentangle the preventable from the inevitable."

They conclude: "Although the Whitehall study cannot reflect the UK's population, estimates obtained from this cohort reinforce the need for action to shift population risk profiles for cognitive decline [...] across the life course."

DUARTE, Calif. -- City of Hope researchers have identified a potential combination targeted therapy for a deadly type of leukemia found in some infants, a population too young to receive full-blown chemotherapy.

Called "mixed lineage leukemia (MLL)-rearranged B cell acute lymphoblastic leukemia (B-ALL)," this blood cancer subtype comes with bleak health outcomes (overall survival rate is less than 50%), disease recurrence and development of resistance to existing therapies.

"Our proof-of-concept animal experiments revealed a promising combination targeted therapy that may one day provide lifesaving treatment to babies, young children, teenagers and adults who do not have many options currently," said Markus Müschen, M.D., Ph.D., chair of the Department of Systems Biology at City of Hope and corresponding author of the new study. "The next step is to test our theory in clinical trials."

Published in the journal Genes & Development on Aug. 8, the study highlighted the transcription factor BCL6 (a protein that promotes tumor formation and drug resistance) as a new target for the treatment of MLL-rearranged B-ALL.

About 10% of B-ALL involve abnormal separation and then relocation of chromosome parts in the MLL gene on chromosome 11.

"Treatment options for infants with leukemia are limited, and patients with MLL-rearranged leukemia are in a group with particularly poor outcomes," Müschen said. "The vast majority of infants and newborns with leukemia actually carry an MLL-rearrangement, so we are very pleased that this combination treatment concept may eventually help this group of patients."

The science that led to the discovery

Müschen and his colleagues analyzed gene expression data from a clinical trial that involved 207 pediatric patients who were at high-risk for B-ALL. They noticed higher-than-normal amounts of BCL6 proteins at disease diagnosis, quicker cancer recurrence and reduced overall survival.

Pulling the data of 49 patients from that pediatric clinical trial, City of Hope researchers noticed BCL6 messenger RNA levels were significantly higher in patients whose cancer relapsed. They observed that patients lacking MLL gene rearrangements had low BCL6 protein levels. Some 85% of them were alive and relapse-free four years after diagnosis. In contrast, only 37% of patients with MLL-rearranged B-ALL experienced relapse-free survival four years after diagnosis. This group tended to have high levels of the BCL6 protein.

The untangling of this data prompted Müschen and his colleagues to conduct experiments involving patient samples and mouse models. They found that most mice with MLL-rearranged B-ALL have abnormal BCL6 protein levels and that BCL6 was rarely found in other kinds of B-ALL.

When the MLL gene was introduced to mouse models, the result was a 10- to 25-fold increase in BCL6 protein levels. In fact, the researchers observed that the BCL6 protein and MLL gene have a symbiotic relationship where each helps the other exist and multiply.

Through other experiments, the researchers discovered that BCL6 blocks the function of a protein commonly known as BIM (BCL2L11), which is responsible for killing tumors and preventing cancer progression. They found that the peptide RI-BPI and the small molecule FX1 could unblock this pathway so that BIM could function normally and kill tumors. Further testing showed that RI-BPI and FX1 work synergistically with ABT-199, a small molecule targeted therapy that has been approved by the U.S. Food and Drug Administration to treat chronic lymphocytic leukemia and small lymphocytic lymphoma.

"Our experiments showed that turning off BCL6 in combination with using ABT-199 could be a simple and nontoxic way to overcome drug resistance," Müschen said. "We've proven the method works in mouse models. Now we're passing this knowledge on to scientists worldwide so that our proposed combination targeted therapy can be tested in clinical trials."

The American College of Physicians (ACP) and the nation's leading physician and public health organizations called for policies to reduce firearms-related injuries and deaths in the U.S. in a new call-to-action, "Firearm-Related Injury and Death in the United States: A Call to Action from the Nation's Leading Physician and Public Health Professional Organizations," published today in the Annals of Internal Medicine.

"We are living in a world where gun violence is becoming increasingly common, and as physicians, we have a responsibility to address this public health crisis and to keep our patients safe and healthy," said Robert McLean, MD, FACP, president, ACP.

ACP, together with the American Academy of Family Physicians, American Academy of Pediatrics, American College of Surgeons, American Medical Association, American Psychiatric Association, and the American Public Health Association, delineate the following in a new policy paper:

Comprehensive criminal background checks for all firearm purchases, including sales by gun dealers, sales at gun shows, private sales and transfers between individuals with limited exceptions should be required.

Research into the causes and consequences of firearm violence and unintentional injuries and deaths to help identify, test, and implement strategies to reduce these unnecessary injuries and deaths is urgently needed.

Currently, federal laws prohibiting domestic abusers from accessing firearms apply only to spouses and not dating partners-- this loophole in the background check system must be closed. Offenders who have been found guilty of a crime of violence against a family member or intimate partner, including dating partners, cohabitants, stalkers, and those who victimize a family member other than a partner or child should be reported to the National Instant Criminal Background Check System and be prohibited from purchasing or possessing firearms.

Storing firearms safely and securely is essential to reducing the risk of unintentional or intentional injuries or deaths from firearms, particularly in homes with children, adolescents, people with dementia, people with substance use disorders, and the small subset of people with serious mental illnesses that are associated with greater risk of harming themselves and others.

The great majority of those with a mental illness or substance use disorder are not violent; however, screening, access and treatment for mental health disorders play a critical role in reducing self-harm and interpersonal violence. The organizations represented in this paper support improved access to mental health care and caution against broadly including all individuals with a mental health or substance use disorder in a category of individuals prohibited from purchasing firearms.

Extreme risk protection order (ERPO) laws, which allow families and law enforcement to petition a judge to temporarily remove firearms from individuals at imminent risk of using them to harm themselves or others, should be enacted in a manner consistent with due process.

Physicians can and must be able to advise their patients on issues that affect their health, including counseling at-risk patients about mitigating the risks associated with firearms in the home and firearm safety.

The magnitude and frequency of mass attacks are unacceptable to our organizations. A common-sense approach to reducing casualties in mass shooting situations must effectively address high-capacity magazines and firearms with features designed to increase their rapid and extended killing capacity.

For more than two decades, ACP has advocated for the urgent need for impactful legislation that would reduce firearms-related injuries and deaths, and our policy paper sparked the "This Is Our Lane" movement of physicians speaking out on gun violence prevention. Additionally, in light of last weekend's shootings in El Paso, Texas and Dayton, Ohio, ACP released a statement expressing our frustration and sadness.

"We need to protect our patients, their families, and our communities across the country from needless injuries and deaths, it's time for the U.S. to put firearms violence prevention at the forefront of the health care conversation," said Dr. McLean. "We are committed to working with all stakeholders, and continuing to speak out, to address this public health threat."

What The Study Did: This randomized clinical trial compared a technology-enhanced community health nursing intervention that included text message medication reminders with standard care for female adolescents and young adults with pelvic inflammatory disease.

Authors: Maria Trent, M.D., M.P.H., of the Johns Hopkins University School of Medicine in Baltimore, is the corresponding author.

(doi:10.1001/jamanetworkopen.2019.8652)

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

Distinct markers in the blood of people with coeliac disease have been detected within a few hours of gluten being consumed.

The findings address a longstanding mystery about what drives the adverse reaction to gluten in coeliac disease and could lead to a world-first blood test for diagnosing the disease.

A potential blood-based test would be a vast improvement on the current approach which requires people to consume gluten for a number of weeks, and even months, for the testing to be accurate.

The research, published today in Science Advances, involved an international collaboration of the world's leading coeliac disease experts.

The peer-reviewed study included the Walter and Eliza Hall Institute of Medical Research in Australia, University of Oslo in Norway, and in the U.S., Massachusetts General Hospital and University of Chicago. The study was led by Boston-based biotechnology company ImmusanT Inc.

Associate Professor Jason Tye-Din, head of coeliac research at the Institute and a gastroenterologist at The Royal Melbourne Hospital said work was now underway to explore the development of a simple blood test for coeliac disease.

"For the many people following a gluten-free diet without a formal diagnosis of coeliac disease, all that might be required is a blood test before, and four hours after, a small meal of gluten.

"This would be a dramatic improvement on the current approach, which requires people to actively consume gluten for at least several weeks before undergoing an invasive procedure to sample the small intestine," Associate Professor Tye-Din said.

Coeliac disease affects approximately 1.4 per cent of people globally, many of whom remain undiagnosed. Symptoms of the disease are caused by a damaging immune response to gluten. After consuming gluten, patients can experience reactions such as nausea, vomiting, abdominal pain and diarrhoea.

Dr Bob Anderson, a joint senior author of the paper and the Chief Scientific Officer of ImmusanT Inc., said the new findings could address an important medical need.

"For the first time we have described the inflammatory reaction that patients with coeliac disease experience in the immediate hours after they are exposed to gluten.

"The unpleasant symptoms associated with the disease are linked to an increase in inflammatory molecules in the bloodstream, such as interleukin-2 (IL-2), produced by T cells of the immune system. This response is similar to what happens when an infection is present, however for people with coeliac disease, gluten is the trigger.

"This information underpins a potential new approach to diagnosis that addresses the emerging medical need to identify patients without coeliac disease who may be better served by other treatments for their chronic symptoms," Dr Anderson said.

Researchers at ImmusanT first discovered the immune markers while assessing blood samples during the Phase 1 trial of a potential coeliac therapy called Nexvax2. Gastrointestinal symptoms in patients injected with the gluten peptides, particularly nausea and vomiting, correlated with higher levels of IL-2 in their blood.

Subsequent testing showed the consumption of gluten produced the same IL-2 response in people with coeliac disease.

CEO of Coeliac Australia, Ms Michelle Laforest, said the finding would be welcome news for the coeliac community in Australia.

"The potential for a one-off gluten challenge and blood test could make a significant difference to many thousands of Australians who report sensitivity to gluten but have been unable to tolerate the current testing approach.

"It is clear this research has the potential to revolutionise the current testing regime for coeliac disease globally," Ms Laforest said.

Bottom Line: A nationwide population-based study in Taiwan suggests attention-deficit/hyperactivity disorder (ADHD) may be associated with a higher risk of death from injury causes, including suicide, unintentional injury and homicide. Although the risk of suicide-related death was higher in patients with ADHD than in those without, the absolute risk of death was low and suicide deaths were rare, with natural-cause deaths and unintentional injury deaths accounting for a higher number of deaths than suicide in the group of patients with ADHD. This observational study used registry data and included nearly 276,000 patients (ranging in age from 4 to 44) first diagnosed with ADHD between 2000 and 2012 and nearly 2 million individuals without ADHD for comparison. There was no increased risk of natural-cause death between the two groups. More research is needed to understand the causes of injury deaths in patients with ADHD and identify ways to mitigate them. Limitations of the study include the findings may not generalizable to others, including people with ADHD who aren't diagnosed and those in other international settings. The study also couldn't analyze the effects of ADHD medications and other potential mitigating factors, such as family history and psychosocial stress.

Authors: Charles Tzu-Chi Lee, Ph.D., National Taiwan Normal University, Taipei, and coauthors

(doi:10.1001/jamanetworkopen.2019.8714)

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

Leesburg, VA, August 7, 2019--According to an ahead-of-print "Focus On" article published in the November issue of the American Journal of Roentgenology (AJR), collaborative research has not only standardized the definition of a complete imaging history, but also engineered systems to include supportive prompts in the order entry interface with a single keystroke--sustainably improving the quality of imaging histories, themselves.

A Kaiser Permanente multidisciplinary team--physicians, both primary care and medical imaging providers, as well as information technology and practice improvement professionals--first defined the various components of a complete imaging history, a process that underwent several improvement cycles where consensus audits were regularly performed.

The final apparatus of the collaborative team's complete imaging history definition included the following responses:

what happened;

when it happened;

where the patient was experiencing pain;

and the ordering provider's concern.

These four prompts were then inserted into the electronic physician order entry process, and performance was monitored for an additional 18 months.

From March 13, 2017 to December 16, 2018, 10,236 total orders were placed by ordering providers in the study clinic. Of the orders audited in the baseline period, 16.0% (64/397) contained all four history components, which increased to 52.0% (2200/4234; absolute increase of 36.0%, relative increase of 225.0%; p

Moreover, the mean number of characters ordering providers entered into the imaging histories they submitted increased from 45.4 characters per order during the baseline period to 75.4 (66.1% increase, p

"Before this intervention, ordering providers in the institution were provided a single free-text box to enter whatever history information they felt to be relevant," wrote Daniel S. Bor from Kaiser Permanente's Department of Medical Imaging. "Our medical imaging team identified that frequently these unguided histories were incomplete, inconsistent, and of variable quality."

"Anecdotally," Bor continued, "radiologists have attributed the ability to make difficult diagnoses, such as subtle stress fractures, to having access to more complete imaging histories from ordering providers. We have also noticed that increased clinical information results in radiologists feeling less of a need to recommend additional downstream or repeat imaging."

Bor noted, too, that the project team remains optimistic that the emergence of artificial intelligence could facilitate an automated method to improve imaging histories and support high-quality radiologist interpretations.