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BOSTON - Using cutting-edge imaging technology, researchers at Massachusetts General Hospital (MGH) have shown that the brains of young men with autism spectrum disorder (ASD) have low levels of a protein that appears to play a role in inflammation and metabolism. This surprising discovery, which published online today in the journal Molecular Psychiatry provides an important new insight into the possible origins of ASD, which affects one in 59 children.

ASD is a developmental disorder that emerges in early childhood and is characterized by difficulty communicating and interacting with others. While the cause is unknown, growing evidence has linked ASD to inflammation of brain tissue, or neuroinflammation. One sign of neuroinflammation is elevated levels of a substance called translocator protein (TSPO), which can be measured and located in the brain using positron-emission tomography (PET) and anatomical magnetic resonance imaging (MRI). The MGH study, led by Nicole Zurcher, PhD, an investigator in MGH's Athinoula A. Martinos Center for Biomedical Imaging, was the first to use a new generation of PET "tracers," which more accurately detect TSPO, to examine the brains of people with ASD.

In the study, Zurcher and her colleagues scanned the brains of 15 young adult males (average age, 24) with ASD. The group included both high- and low-functioning subjects with varying degrees of intellectual abilities. For comparison, Zurcher's team scanned the brains of 18 healthy control subjects who were similar in age. The investigators hypothesized that the scans would show increased levels, or expression, of TSPO in subjects who have ASD.

"To our surprise, that's not what we saw," says Zurcher. Instead, the scans showed that the brains of males with ASD had lower levels of TSPO than those of the healthy subjects. In fact, the men with the most severe symptoms of ASD tended to have the lowest expression of TSPO. When the tests were repeated several months later, the pattern persisted. The brain regions found to have low expression of TSPO have previously been linked to ASD in earlier studies, and are believed to govern social and cognitive capacities such as processing of emotions, interpreting facial expressions, empathy, and relating to others. "We know these brain regions are involved in autism," says Zurcher.

To understand this unexpected finding, Zurcher notes that TSPO does more than serve as a marker of inflammation. "It has multiple complex roles," she says, and some actually promote brain health. For example, adequate TSPO is necessary for normal functioning of mitochondria, which are the "power houses" in cells that produce energy. Earlier research has linked malfunctioning mitochondria in brain cells to ASD.

Zurcher and her colleagues next plan to study brains from deceased donors with the goal of determining which brain cells in people with ASD might experience mitochondrial dysfunction, which she says may well be occurring alongside neuroinflammation and other mechanisms to cause ASD. "Our study has generated new hypotheses that now need to be investigated," says Zurcher. "There's more work to be done."

When a patient arrives at an American emergency room today, they have a higher chance than ever before of seeing a doctor who's a woman or a person of color. And they're also more likely than ever to get a survey after they go home, asking how satisfied they were with their ER care.

But some have worried that a combination of increased physician diversity, underlying patient biases, and more emphasis on ER satisfaction ratings could create issues - especially if hospitals with low ER patient ratings face public reporting or even financial penalties in future.

A new study by a team from Yale University and the University of Michigan may ease some of those fears.

Published in JAMA Network Open, the study finds that patients rated their satisfaction with a simulated ER visit just as highly if the doctor randomly assigned to them was white or African-American, and man or woman. Confidence in their doctor also didn't vary based on physician gender or race.

This held true even after the researchers took into account variation in respondents' demographic characteristics and attitudes like prejudice and sexism.

Surprise findings

Lead author Rachel Solnick, M.D., M.Sc., notes that the study doesn't mean that emergency physicians won't ever face individual situations where a patient expresses bias against them because of race, gender, age or other factors.

In fact, it was her own experience with such biases as an emergency medicine resident, as well as previous research by others, that led Solnick to do the study.

The fact that ER patients don't get to choose which doctor they see, unlike with most other fields of medicine, adds to the potential for bias to creep into the doctor-patient interaction.

So, she says, "We were really surprised that even after looking at these data in many different ways, we did not see evidence of racial or gender bias affecting patient satisfaction or confidence. This is not to say that people are bias-free, but it did not appear to enter into their ratings of care in surveys. This is good news, with a grain of salt."

More about the study

Solnick, now a National Clinician Scholar at the U-M Institute for Healthcare Policy and Innovation, sees patients as an emergency medicine physician at Michigan Medicine, U-M's academic medical center. She's one of the approximately 25% of American ER physicians who are women; 5% of all ER physicians identify as African-American.

Working with Yale colleagues including Kyle Peyton, Ph.D., Gordon Kraft-Todd, Ph.D. (now at Boston College) and Basmah Safdar, M.D., M.Sc., the team designed a study that drew its "patients" from two online platforms commonly used in academic research. More than 1,600 of them were recruited from the Amazon Mechanical Turk interface, and another 1,600 were recruited through Lucid using a quota sample matched to Census demographics.

Each "patient" received the same scenario: they had gone to the ER for stomach symptoms, and received tests, a diagnosis of viral gastroenteritis and supportive treatment plan from the simulated physician randomly assigned to them.

Alongside the physician diagnosis was a contradictory diagnosis from an online symptom checker, which suggested their symptoms might indicate a much more serious issue: an infected appendix. This contrast was meant to instill doubt in the doctor's competence in providing appropriate care.

Assessing patient bias toward or against certain types of ER physicians is especially important at this time, Solnick adds.

The federal Centers for Medicare and Medicaid Services has been testing the feasibility of a new survey tool called the Emergency Department Patient Experiences with Care (EDPEC) for hospitals to use with ER patients who did not get admitted to the hospital.

Such a tool could be used in future to impose financial penalties on hospitals with low ER satisfaction ratings, just as patient ratings for other types of care already do. The new CMS survey tool is in addition to private ones that hospitals already use in-house.

"Patient satisfaction surveys have really altered the fabric of the emergency doctor/patient relationship, because in addition to thinking about the medical treatment we also are considering how we will be 'graded' at the end of the encounter," says Solnick.

This isn't necessarily a bad thing, she emphasizes. In fact, it has made clear communication throughout an ER visit even more important -- even as ERs cope with crowding and have to accept every patient who comes to them.

Next steps

The current research didn't investigate patient assessments of doctors from other racial and ethnic backgrounds, immigration statuses, ages or national origins. Also, the scenario the researchers studied was based in an ER setting, and other areas of the healthcare system where patients have a longer term relationship with their doctor or exercise greater discretion in physician choice may reveal different results. That could be another avenue for follow-up studies.

Although this study did not find that physician race or gender negatively affected patient satisfaction, on average, there is compelling evidence that increasing the diversity of the physician workforce has positive benefits for public health. For example, a recent field experiment in Oakland, CA found that black men treated by black male physicians reported greater satisfaction and took more preventative health measures than black men treated by white male physicians.

But at the same time, minority physicians and women physicians often experience higher rates of burn out from their job and some report higher rates of job turnover due to discrimination.

Solnick and colleagues feel that this new data points the research spotlight towards other sources of potential workplace discrimination- colleagues, superiors, and policies- and the need for institutions to identify and evolve in order to sustain and encourage a diverse workforce.

February 21, 2020 - The first set of comprehensive, evidence-based clinical guidelines for surgical treatment of thyroid disease - developed by an expert panel assembled by the American Association of Endocrine Surgeons (AAES) - was published today by Annals of Surgery. The journal is published in the Lippincott portfolio by Wolters Kluwer.

The guidelines provide an expert perspective on current approaches to surgical management for patients with benign and malignant thyroid disease. "To help provide safe, effective, and appropriate care of patients, these AAES-sponsored multidisciplinary clinical guidelines analyze the conduct, indications, and outcomes of adult thyroid surgery guided by a comprehensive evidence-based review of the medical literature," according to the guideline statement. The lead author was Kepal N. Patel, MD, of NYU Langone Health, New York, N.Y.

Emphasis on Evidence-Based, Personalized Care for Patients Undergoing Thyroidectomy

The guidelines consist of a total of 66 specific recommendations, identified by a search of the medical literature from 1985 to 2018 and review by a multidisciplinary panel of 19 experts in thyroid disorders. Recommendations are graded according to the strength and quality of the supporting evidence; the full guidelines document provides guidance on how to best apply the recommendations to individual patients. The project was coordinated by Sally E. Carty, MD, of University of Pittsburgh School of Medicine and Christopher R. McHenry, MD, of Case Western Reserve University, Cleveland.

Thyroidectomy, referring to any type of thyroid surgery, is a common procedure - more than 100,000 thyroidectomies are performed each year in the United States. While thyroidectomy is "typically a definitive and often curative procedure," ongoing advances in diagnosis and management have led to variability and even controversy in the treatment of thyroid disease.

While other specialty societies have published recommendations addressing the management of thyroid nodules and thyroid cancer, the new AAES guidelines focus on surgical management of thyroid disease in adults. Specific objectives include:

Helping surgical team members understand the epidemiology and pathogenesis of thyroid disease. Thyroidectomy is most frequently performed for thyroid dysfunction, symptomatic benign thyroid nodules, and thyroid cancer, including the newer category of "borderline" thyroid tumors.
Outlining the diagnosis of thyroid disease, including the clinical findings; imaging, including ultrasound examination; thyroid function tests; voice assessment, reflecting the risk of vocal fold dysfunction related to thyroid disease and surgery; and the use of fine-needle aspiration biopsy, a key test for evaluation of suspicious thyroid nodules and lymph nodes.
Defining the indications for thyroidectomy, including recommendations related to the extent and outcomes of surgery for patients with different categories of thyroid disease. One recommendation states that, when possible, thyroidectomy should be performed by surgeons who perform a high volume of such procedures.
Detailing methods for safe and effective perioperative management, including steps to prevent complications and the use of thyroid tissue diagnosis during surgery.
Analyzing the optimal management of thyroid cancer - emphasizing a personalized, evidence-based approach tailored to the patient's situation and preferences.

On behalf of the AAES, the members of the expert panel hope their efforts will meet the need for evidence-based recommendations to "define practice, personalize care, stratify risk, reduce health care costs, improve outcomes, and identify rational challenges for future efforts." They conclude: "Throughout the writing process, [our] intent was to advise surgeons about the right thing to do for the patient" in need of surgical treatment for thyroid disease.

Click here to read "The American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults."
DOI: 10.1097/SLA.0000000000003580

A Polygenic Risk Score -- a genetic assessment that doctors have hoped could predict coronary heart disease (CHD) in patients -- has been found not to be a useful predictive biomarker for disease risk, according to a Vanderbilt study published in the Journal of the American Medical Association.

Lead author Jonathan Mosley, MD, PhD, assistant professor of Medicine and Biomedical Informatics, and senior author Thomas Wang, MD, former director of the Division of Cardiovascular Medicine and now chair of the Department of Internal Medicine at the University of Texas Southwestern Medical Center in Dallas, conducted a retrospective cohort study of the predictive accuracy of polygenic risk scores in 7,306 adults of European ancestry ages 45-79. The patients were taken from two large cohort studies, the Atherosclerosis Risk in Communities (ARIC) study and the Multi-Ethnic Study of Atherosclerosis (MESA).

Mosley found that the polygenic risk score didn't significantly improve prediction of CHD risk in this generally white, middle-age population. It was no more useful than the conventional method of determining CHD Risk -- assigning a patient a clinical risk score based on factors including age, gender, cholesterol levels and tobacco use, Mosley said.

Physicians have long sought to reduce cardiovascular mortality by early identification of CHD.

Though his findings suggest a genetic biomarker has not been discovered for this general population of CHD patients, Mosley said further study is needed to determine whether special populations may benefit from a polygenic risk score.

"Genetic methods are getting better and people are developing these risk scores that are performing better than they have in the past," he said. "There are a lot of calls to see whether these can be converted to clinical tools. A critical piece of this process is to conduct a rigorous evaluation of any risk score, as has been done for other proposed cardiac biomarkers."

Mosley said the study suggests that polygenic risk scores should not be added to the standard of care for identifying high-risk CHD patients at this time. "Essentially, they are more likely to add costs than benefits at this point," he said.

Wang emphasized, "This study does not minimize the importance of genetic contributors to cardiovascular risk. What it does show is that genetic factors provide limited information about who will actually have a cardiovascular disease event."

"I think it's possible that we could develop better-performing scores," Mosley added. "I think you could develop more rigorous methodologies that may enhance the degree to which these predict."

Researchers at Johns Hopkins Bloomberg School of Public Health have demonstrated the use of stem-cell-derived "mini-brains" to detect harmful side effects of a common drug on the developing brain. Mini-brains are miniature human brain models, developed with human cells and barely visible to the human eye, whose cellular mechanisms mimic those of the developing human brain.

The scientists, who will publish their findings on February 21 in Frontiers in Cellular Neuroscience, used the mini-brains to determine that the common antidepressant paroxetine suppresses the growth of synapses, or connection points between neurons, and leads to significant decreases in an important support-cell population. Paroxetine is sold under the brand names Paxil and Seroxat, among others.

Paroxetine, which can cross the placenta in pregnant women, currently comes with a warning against use in early pregnancy, largely due to a known risk of heart and lung defects. Some epidemiological studies also have suggested that paroxetine raises the risk of autism. The new findings are likely to heighten concerns about the effects of this drug, and others in its class, on the developing brain.

The study authors say that the findings suggest that lab-grown mini-brains, which they call BrainSpheres, are a good alternative to traditional animal testing. In particular, they can reveal drugs and other chemicals that are harmful to young brains.

"There's a growing concern that we have an epidemic of neurodevelopmental disorders, including autism, and that these might be caused by exposures to common drugs or other chemicals. However, since traditional animal testing is so expensive, we haven't been able to properly investigate this question," says co-senior author Thomas Hartung, MD, the Doerenkamp-Zbinden Chair and Professor in the Department of Environmental Health and Engineering and director of the Center for Alternatives to Animal Testing at the Bloomberg School.

Hartung and colleagues developed the mini-brains to model early brain development. The tiny clumps of brain tissue are made by taking cells from adult humans, often from their skin, and transforming them into stem cells, and then biochemically nudging the stem cells to develop into young brain cells. The mini-brains form a rudimentary brain-like organization over a period of a few months. Because they are made of human cells, they may be more likely to predict effects on the human brain--and because they can be mass-produced in the lab, they are much cheaper to work with than animals.

A set of animal toxicology tests for a single chemical costs about $1.4 million on average, the authors note, which explains why the vast majority of chemicals used in drugs and other consumer products have never been tested for toxicity. In contrast, toxicity testing using mini-brains costs only a few thousand dollars.

In the new study, the scientists used mini-brains to test for neurodevelopmental effects of paroxetine. It and other antidepressants in its class, known as SSRIs or selective serotonin reuptake inhibitors, are among the world's most commonly prescribed drugs, accounting for at least hundreds of millions of prescriptions annually.

The research team exposed mini-brains to two different concentrations of paroxetine over eight weeks as the clumps of tissue developed. Both concentrations were within the therapeutic range for blood levels of the drug in humans. In the experiments, the researchers also used two different sets of mini-brains, each derived from a different stem cell.

The scientists found that while paroxetine didn't seem to have a significant neuron-killing effect, at the higher concentration it reduced levels of a protein called synaptophysin, a key component and marker of synapses by up to 80 percent. Paroxetine reduced levels of two other synapse-related markers as well. Similarly, the team observed that paroxetine reduced the normal outgrowth of structures called neurites, which eventually develop into the output stalks and root-like input branches of mature neurons. Finally, the researchers noted that paroxetine-exposed mini-brains developed with up to 75 percent fewer oligodendrocytes, the support cells that are crucial for the proper "wiring" of the brain, than controls.

These effects suggest that the drug might hinder the normal formation of interconnections among developing neurons--a result that could conceivably underlie autism or other disorders.

The study also shows the broader potential of mini-brains-based testing to detect adverse effects of drugs on the developing brain.

"In this report, we were able to show that testing with mini-brains can reveal relatively subtle neurodevelopmental effects, not just obvious effects, of a chemical," Hartung says. "Whether paroxetine causes autism has been a decade-long debate, which could not be settled with animal tests or epidemiological analyses. So we see mini-brains as technology for broader assessment of the risks of common drugs and chemicals, including those that might be contributing to the autism epidemic."

Hartung and colleagues recently received a grant from the U.S. Environmental Protection Agency to develop their technology as an alternative to animal testing.

Lyme disease, also called borreliosis, is the most common vector-borne disease in the Northern hemisphere. It is caused by the spirochete (corkscrew-shaped) bacterium Borrelia burgdorferi and close relatives and mainly spread through the bite of infected ticks.

Currently, more than 300,000 new cases are reported in the USA each year, compared to 65,000 in Europe, and these numbers are rising due to climate change and urban sprawl. The standard of care for Lyme disease, a course of antibiotics over 2-4 weeks, is not always effective: at least 10-20% of treated patients continue to experience symptoms after treatment. Late-stage Lyme patients may experience many different symptoms, including fatigue, joint pains, memory problems, facial paralysis, aches, stiffness in the neck, heart palpitations, and severe headaches. The discovery of novel treatments against Lyme disease is therefore of great interest.

In a new study published in Frontiers in Medicine, researchers from the Johns Hopkins Bloomberg School of Public Health, with colleagues at the California Center for Functional Medicine and Focus Health, surveyed the power of 14 plant-based extracts to kill Borrelia burgdorferi, compared to the currently used Lyme antibiotics doxycycline and cefuroxime.

The researchers tested these extracts' effectiveness in vitro (outside of a living organism) against the free-swimming "planktonic" form of the bacterium as well as against microcolonies. Microcolonies are aggregates of bacteria, the first stage in the development of biofilms - structured bacterial communities that stick to a surface and are embedded in a slimy extracellular matrix.

The researchers show that plant extracts from black walnut, cat's claw, sweet wormwood, Mediterranean rockrose, and Chinese skullcap had strong activity against B. burgdorferi, outperforming both tested antibiotics.

But by far the strongest performers were Ghanaian quinine (Cryptolepis sanguinolenta; also known as yellow-dye root, nibima, or kadze) and Japanese knotweed (Polygonum cuspidatum).

Ghanaian quinine is a shrub from West Africa containing the antimicrobial alkaloid cryptolepine, and is used in ethnomedicine to treat malaria, hepatitis, septicemia, and tuberculosis. Japanese knotweed is a traditional medicine in India and China that contains the polyphenol resveratrol. In other preclinical studies it has been found to have anti-tumor and anti-inflammatory effects and protect the nervous system and heart. Extracts from both plants were found to kill microcolonies of Borrelia burgdorferi and inhibit division of the planktonic form, even at low concentrations (0.03-0.5%). Remarkably, a single 7-day treatment with 1% Ghanaian quinine could completely eradicate the bacterium - it did not regrow, even under optimal conditions in the drug's absence.

"This study provides the first convincing evidence that some of the herbs used by patients such as Cryptolepis, black walnut, sweet wormwood, cat's claw, and Japanese knotweed have potent activity against Lyme disease bacteria, especially the dormant persister forms, which are not killed by the current Lyme antibiotics," says Dr Ying Zhang from the Johns Hopkins Bloomberg School of Public Health.

"These findings are exciting as they offer opportunities for improved treatment of persistent Lyme disease, which is not helped by the current standard treatment. We are interested in further evaluating these potent herbal medicines through animal studies as well as clinical trials."

However, not all tested compounds or herbs yielded positive results against the bacterium. Extracts of grapefruit seeds, green chiretta, ashwagandha, candy leaf (also known as stevia), fuller's teasel, and Japanese teasel had little or no effect, and neither did the chemicals colloidal silver, monoglyceride monolaurin, or antimicrobial peptide LL37 from human immune cells. This was surprising, as anecdotal and preclinical studies suggested that they might be effective, and they are often used in the community of Lyme disease practitioners and patients.

"Many thousands of Lyme patients today, especially those with later-stage symptoms who have not been effectively treated, are in great need of efficacious, accessible treatment options," says Dr Sunjya K. Schweig, CEO and co-Director of the California Center for Functional Medicine and Scientific Advisory Board Member of the Bay Area Lyme Foundation.

Diabetes affects more than 400 million people worldwide and is a major public health problem. Although commonly referred to as a single disease, it actually constitutes a group of metabolic disorders with hyperglycaemia as a common feature. Of all its forms, monogenic diabetes - due to a mutation in one of the genes involved in the management of blood sugar levels - affects 1% to 4% of all cases of diabetes. Often confused with type 1 or type 2 diabetes, more than 90% of monogenic cases are misdiagnosed. A study carried out by scientists from the University of Geneva (UNIGE), the University Hospitals of Geneva (HUG), and the Lithuanian University of Health Sciences in Vilnius with more than 1,200 young diabetics allowed to accurately identify the proportion of monogenic diabetes in the whole pediatric diabetes population. Consequently, treatments were adjusted according to the genetic characteristics of the disease in order to improve patients' quality of life. The results that can be read in the journal Diabetes, highlight the need for precision medicine in the management of metabolic diseases.

Diabetes is defined by chronic hyperglycemia which may lead to dangerous complications. Type 2 diabetes and type 1 diabetes are the best known forms. Type 2 is often associated with obesity, while type 1 is an autoimmune disease where the immune system destroys the insulin-producing pancreatic beta cells. The form of diabetes studied here is called "monogenic", and is caused by a mutation in a single gene. In the majority of cases, these mutations prevent the beta cell from functioning properly and the disease often manifests during adolescence. Sometimes, however, the pancreas simply does not develop, and insulin must be administered to babies as soon as they are born.

Eleven new genes identified

Monogenic diabetes very often goes undiagnosed because its clinical features are quite similar to other forms of diabetes. Even if the symptoms are comparable, the cause is very different. "Lithuania has a register of all diabetic children, which also includes most of the young adults", says Valérie Schwitzgebel, professor at the Department of Paediatrics, Gynaecology and Obstetrics and co-coordinator of the Diabetes Centre of the UNIGE Faculty of Medicine and Head of the Paediatric Endocrinology and Diabetology Unit at the HUG, who led this work. "We have thus carried out a large-scale epidemiological and population study."

The scientists first evaluated the presence of autoimmune antibodies, known markers of type 1 diabetes, in the 1209 children and young adults included in the cohort. A complete genetic analysis was then carried out on the 153 patients who did not have these antibodies or who had only anti-insulin antibodies, which can also develop from insulin treatment. "We were able to identify the gene mutation causing diabetes in 42 of them, a much larger number than expected", says Ingrida Stankute of the Lithuanian University of Medical Sciences. "In addition, almost 10% of the study participants who tested positive for autoimmune anti-insulin antibodies also had monogenic diabetes, indicating the need for accurate diagnosis."

While most patients had only one defective gene, many different mutations were identified, including eleven genes identified for the first time. "But do all these mutations produce the same effects? In the next step of our collaboration, we will therefore perform co-segregation studies in the patients' families and, and conduct experiments to analyse gene functions", says Valérie Schwitzgebel.

Adapting treatments adapted to mutations- a step towards precision medicine

In general, young diabetic patients, particularly when affected by type 1 diabetes, must follow a strict treatment based on insulin injections. "In many gene mutations however, beta cells can be stimulated through specific drugs, called sulfonylureas, which are much easier to administer than insulin injections and which have a much better effect on metabolism", explains Valérie Schwitzgebel. "Many of the patients diagnosed, even the youngest, were thus able to switch to a lighter oral treatment, and some even stopped treatment altogether. This proves the need for precision medicine where treatment is tailored to the causes of the disease, not just the symptoms it triggers."

Towards a much more systematic diagnosis

"In Geneva, we have already put this new evidence into practice", explains Jean-Louis Blouin, researcher at the Department of Genetic Medicine and Development at UNIGE Faculty of Medicine and at the HUG Department of Genetic Medicine. "We have developed a diagnostic test that includes the 40 plus genes that can lead to monogenic diabetes, and all diabetic children, who don't have autoimmune antibodies are tested." Even in adults, such a test would be useful, as monogenic diabetes is often falsely identified as type 2 diabetes, with important consequences in terms of management, comfort of life and costs for the health care system.

"Hyperglycaemia should therefore be considered as a symptom of various diseases, rather than a disease in itself, and different forms of diabetes should be better screened. The earlier the actual cause is identified, the sooner appropriate treatments can be initiated, minimizing the risk for long term complications", concludes Valérie Schwitzgebel.

Surgical treatment of obesity is as effective for individuals who developed the disorder early, by the age of 20, as for those who have developed obesity later in life, a study from the University of Gothenburg shows.

The results, published in the journal Diabetes Care, are based on data from the Swedish Obese Subjects (SOS) study. Started in 1987, this study is led and coordinated from Sahlgrenska Academy at the University of Gothenburg.

The present substudy covers a total of 4,026 adult individuals who had developed obesity. Half of them had undergone bariatric surgery and the other half were a control group. Each of the groups was divided into three subgroups, based on the participants' body mass index (BMI) at age 20: those of normal weight, those who were overweight, and those with obesity.

The researchers then investigated whether there was any difference in the effects of bariatric treatment for obesity among those who had developed the disorder before age 20, compared with those who developed it later in life.

One of the study's coauthors is Johanna Andersson Assarsson, Ph.D., researcher and study coordinator for SOS.

"We were somewhat surprised at the results. Since the group that had already developed obesity by the age of 20 had been exposed to obesity and its risks for longer periods, we'd expected that bariatric surgical treatment in these participants would be less effective in terms of weight loss and obesity-related sequelae than in the other group. But it wasn't like that," Andersson Assarsson says.

"On the contrary, the group with obesity at age 20 lost a little bit more weight after the operation, and there was no difference in effects on diabetes or its complications, cardiovascular disease or cancer, compared with individuals who developed obesity later in life."

For many diseases, early treatment is advantageous, but individuals with early-onset obesity have often had their disorder for a long time before bariatric surgery is considered. It has sometimes been speculated that bariatric surgical treatment would be less effective in these individuals because of their longer exposure to the adverse health effects of obesity.

"Here, we show that's not the case. And we think it's important that this information reaches people considering bariatric surgery for obesity and also health professionals who treat patients with obesity," says Johanna Andersson Assarsson.

Using a machine-learning algorithm, MIT researchers have identified a powerful new antibiotic compound. In laboratory tests, the drug killed many of the world's most problematic disease-causing bacteria, including some strains that are resistant to all known antibiotics. It also cleared infections in two different mouse models.

The computer model, which can screen more than a hundred million chemical compounds in a matter of days, is designed to pick out potential antibiotics that kill bacteria using different mechanisms than those of existing drugs.

"We wanted to develop a platform that would allow us to harness the power of artificial intelligence to usher in a new age of antibiotic drug discovery," says James Collins, the Termeer Professor of Medical Engineering and Science in MIT's Institute for Medical Engineering and Science (IMES) and Department of Biological Engineering. "Our approach revealed this amazing molecule which is arguably one of the more powerful antibiotics that has been discovered."

In their new study, the researchers also identified several other promising antibiotic candidates, which they plan to test further. They believe the model could also be used to design new drugs, based on what it has learned about chemical structures that enable drugs to kill bacteria.

"The machine learning model can explore, in silico, large chemical spaces that can be prohibitively expensive for traditional experimental approaches," says Regina Barzilay, the Delta Electronics Professor of Electrical Engineering and Computer Science in MIT's Computer Science and Artificial Intelligence Laboratory (CSAIL).

Barzilay and Collins, who are faculty co-leads for MIT's Abdul Latif Jameel Clinic for Machine Learning in Health, are the senior authors of the study, which appears today in Cell. The first author of the paper is Jonathan Stokes, a postdoc at MIT and the Broad Institute of MIT and Harvard.

A new pipeline

Over the past few decades, very few new antibiotics have been developed, and most of those newly approved antibiotics are slightly different variants of existing drugs. Current methods for screening new antibiotics are often prohibitively costly, require a significant time investment, and are usually limited to a narrow spectrum of chemical diversity.

"We're facing a growing crisis around antibiotic resistance, and this situation is being generated by both an increasing number of pathogens becoming resistant to existing antibiotics, and an anemic pipeline in the biotech and pharmaceutical industries for new antibiotics," Collins says.

To try to find completely novel compounds, he teamed up with Barzilay, Professor Tommi Jaakkola, and their students Kevin Yang, Kyle Swanson, and Wengong Jin, who have previously developed machine-learning computer models that can be trained to analyze the molecular structures of compounds and correlate them with particular traits, such as the ability to kill bacteria.

The idea of using predictive computer models for "in silico" screening is not new, but until now, these models were not sufficiently accurate to transform drug discovery. Previously, molecules were represented as vectors reflecting the presence or absence of certain chemical groups. However, the new neural networks can learn these representations automatically, mapping molecules into continuous vectors which are subsequently used to predict their properties.

In this case, the researchers designed their model to look for chemical features that make molecules effective at killing E. coli. To do so, they trained the model on about 2,500 molecules, including about 1,700 FDA-approved drugs and a set of 800 natural products with diverse structures and a wide range of bioactivities.

Once the model was trained, the researchers tested it on the Broad Institute's Drug Repurposing Hub, a library of about 6,000 compounds. The model picked out one molecule that was predicted to have strong antibacterial activity and had a chemical structure different from any existing antibiotics. Using a different machine-learning model, the researchers also showed that this molecule would likely have low toxicity to human cells.

This molecule, which the researchers decided to call halicin, after the fictional artificial intelligence system from "2001: A Space Odyssey," has been previously investigated as possible diabetes drug. The researchers tested it against dozens of bacterial strains isolated from patients and grown in lab dishes, and found that it was able to kill many that are resistant to treatment, including Clostridium difficile, Acinetobacter baumannii, and Mycobacterium tuberculosis. The drug worked against every species that they tested, with the exception of Pseudomonas aeruginosa, a difficult-to-treat lung pathogen.

To test halicin's effectiveness in living animals, the researchers used it to treat mice infected with A. baumannii, a bacterium that has infected many U.S. soldiers stationed in Iraq and Afghanistan. The strain of A. baumannii that they used is resistant to all known antibiotics, but application of a halicin-containing ointment completely cleared the infections within 24 hours.

Preliminary studies suggest that halicin kills bacteria by disrupting their ability to maintain an electrochemical gradient across their cell membranes. This gradient is necessary, among other functions, to produce ATP (molecules that cells use to store energy), so if the gradient breaks down, the cells die. This type of killing mechanism could be difficult for bacteria to develop resistance to, the researchers say.

"When you're dealing with a molecule that likely associates with membrane components, a cell can't necessarily acquire a single mutation or a couple of mutations to change the chemistry of the outer membrane. Mutations like that tend to be far more complex to acquire evolutionarily," Stokes says.

In this study, the researchers found that E. coli did not develop any resistance to halicin during a 30-day treatment period. In contrast, the bacteria started to develop resistance to the antibiotic ciprofloxacin within one to three days, and after 30 days, the bacteria were about 200 times more resistant to ciprofloxacin than they were at the beginning of the experiment.

The researchers plan to pursue further studies of halicin, working with a pharmaceutical company or nonprofit organization, in hopes of developing it for use in humans.

Optimized molecules

After identifying halicin, the researchers also used their model to screen more than 100 million molecules selected from the ZINC15 database, an online collection of about 1.5 billion chemical compounds. This screen, which took only three days, identified 23 candidates that were structurally dissimilar from existing antibiotics and predicted to be nontoxic to human cells.

In laboratory tests against five species of bacteria, the researchers found that eight of the molecules showed antibacterial activity, and two were particularly powerful. The researchers now plan to test these molecules further, and also to screen more of the ZINC15 database.

The researchers also plan to use their model to design new antibiotics and to optimize existing molecules. For example, they could train the model to add features that would make a particular antibiotic target only certain bacteria, preventing it from killing beneficial bacteria in a patient's digestive tract.

CHICAGO--February 20, 2020--Patients who have taken antidepressants for years should consider coming off the medication. However, researchers say they will likely face difficult and even dangerous withdrawal symptoms due to a physical dependence.

The best process is to follow a tapering schedule while consulting with a physician, according to research in The Journal of the American Osteopathic Association. Stopping medication outright is almost never advisable.

"I understand that many people feel safe in that their depression or anxiety is continuously managed by medication. However, these are mind-altering drugs and were never intended as a permanent solution," says Mireille Rizkalla, PhD, Assistant Professor, Department of Clinical Integration at Midwestern University Chicago College of Osteopathic Medicine, and lead author on this research. "Once the patient's depression or anxiety has been resolved, the physician should guide them toward discontinuation, while providing non pharmacologic treatments to help them maintain their mental health."

Hard to quit

Patients who stop taking their medication often experience Antidepressant Discontinuation Syndrome (ADS), which includes flulike symptoms, insomnia, nausea, imbalance, sensory disturbances often described as electric shocks or "brain zaps", and hyperarousal.

Older, first-generation antidepressants often come with additional risks for more severe symptoms, including aggressiveness, catatonia, cognitive impairment, and psychosis. Discontinuing any antidepressant also carries a risk for gradual worsening or relapsing of depression and anxiety, as well as suicidal thoughts.

Indefinitely medicated

A recent report from the CDC said a quarter of people taking antidepressants had been using them for a decade or more. Rizkalla says this data makes the case that patients and physicians are overly reliant on medication without concern for long-term consequences.

"I think we have a real problem with patient care management, when it comes to prescribing antidepressants," says Rizkalla. "We tend to put patients on an SSRI and more or less forget about them."

She adds that, while relatively safe, antidepressants still carry side effects, including weight gain, sexual dysfunction and emotional numbing. She also urges caution as the evidence for antidepressant risk factors is based on short-term usage, and says there are no sufficient longitudinal studies on the neurologic impact of taking antidepressants for decades.

Rizkalla and her coauthors included the following tapering schedule for varying classes of antidepressants. However, she insists patients consult their physician before and throughout the process to monitor their symptoms and progress.

Walter and Eliza Hall Institute researchers have revealed a new vulnerability in lymphomas that are driven by one of the most common cancer-causing changes in cells.

The team revealed that the protein MNT is required for the survival of lymphoma cells that are driven by the protein MYC. Up to 70 per cent of human cancers - including many blood cancers - have high levels of MYC, a protein which forces cells into abnormally rapid growth.

The research, led by Professor Suzanne Cory, Dr Hai Vu Nguyen and Dr Cassandra Vandenberg, suggests that potential therapies targeting MNT could be effective new treatments for MYC-driven cancers.

At a glance

The majority of human cancers are driven by high levels of the protein MYC, but it has been challenging to develop new medicines that directly inhibit MYC.

Our researchers revealed that MYC-driven lymphoma cells rely on the protein MNT for their survival, and without MNT the cells rapidly die.

The results suggest that inhibiting MNT might be an effective new approach for treating MYC-driven cancers.

A new target

High levels of the MYC protein are found in up to 70 per cent of human cancers. MYC controls hundreds of genes, driving rapid cell production, said Professor Cory, who has studied MYC-driven cancers since the early 1980s.

"For many years we hoped for a drug that could directly target MYC as a potential cancer treatment, but to date such inhibitors have been disappointing in the clinic," she said. "It became clear we needed to look for other vulnerabilities in MYC-driven cancers."

The team successfully identified a new target for tackling MYC-driven cancers by homing in on the role of a protein related to MYC, called MNT. Their research was published in the journal Blood.

By deleting the gene encoding MNT from MYC-driven lymphocytes - the type of immune cell from which lymphomas arise - the team found that MNT played a significant role in MYC-driven lymphoma development, Dr Vandenberg said.

"In our laboratory models, the incidence of MYC-driven lymphomas was greatly reduced when MNT was absent. This showed us that MNT had a vital role at some stage during lymphoma development," she said.

"That role became clear when we found that pre-cancerous cells lacking MNT had high levels of apoptotic cell death," said Dr Nguyen. "Thus, MNT is required to keep MYC-driven cells alive."

Towards better treatments

Dr Nguyen said that the team went on to examine the impact of depleting MNT from fully malignant MYC-driven lymphomas. "When we did this, we saw that the tumour cells rapidly died," he said. "This suggests MNT could well be a promising new therapeutic target for MYC-driven lymphomas."

Professor Cory said the researchers would now look at whether MNT was important in other MYC-driven cancers.

"Inhibiting MNT may also make tumours more susceptible to other drugs such a BH3-mimetics which directly target the cell's death machinery.

"Although a lot of work remains to be done to develop and test a new MNT-inhibiting therapy, our discovery opens up a new front in tackling MYC-driven cancers," Professor Cory said.

Huntington's disease is a hereditary neurodegenerative disorder caused by a gene of chromosome 4 that affects a very important area of the brain, the striatum. People are born with the defective gene but symptoms do not appear until the age of 30 or 40.

This disease, in addition to motor impairments, cognitive and affective problems, also involves changes in language. A study shows that the first symptoms of the disease are revealed through linguistic changes in spontaneous speech.

So reveals a study published in Journal of Communication Disorders by Antonia Tovar as first author, led by Wolfram Hinzen, ICREA research professor, both researchers with the Department of Translation and Language Sciences at UPF, involving researchers from the universities of Paris-Saclay (Orsay, France), the UAB, the UB, together with the Hospital Mare de Déu de la Mercè in Barcelona and FIDMAG Sisters Hospitallers Research Foundation (Barcelona).

"Linguistic impairments in Huntington's disease arise before the onset of motor impairment and even when neuropsychological tests prove normal. This suggests that language may be a biomarker for the progression of Hungtinton's", Tovar and Hinzen explain.

Specific language patterns of Huntington's disease

In addition to showing that linguistic impairments in Huntington's disease arise before the onset of motor impairment, the authors have sought to characterize the nature of these specific changes in Huntington's disease. Thus "language needs to be assessed as a multi-dimensional construct organized at multiple levels (phonology, morphology, syntax, semantics, discourse), which are re-fitted together into an integrated functional whole", the authors point out.

The few existing linguistic studies on spontaneous speech in Huntington's disease have reported language shortcomings. For example patterns of reduced syntactic complexity, with fewer words and syntactic structures formed in short, simple sentence constructions, more paraphasic and grammatical errors, etc. These language deficits may form a distinctive signature profile of Huntington's as compared with Parkinson's disease or people with cerebral lesions.

To study the language profiles of Huntington's disease, the authors designed an experiment with 20 HD gene-carriers, all native Spanish speakers; 10 in the early stages of the disease and another 10 with pre-manifest Huntington's disease, and their respective neurotypical controls not carrying the gene, and compared them regarding the structure and function of language in spontaneous speech. The researchers also studied the relationship between language and non-linguistic cognitive impairment.

"This disease is generally accepted to begin with the onset of motor symptoms, but we have found differences in the language profile of subjects without motor symptoms", says Tovar, first author of the article.

In addition to proving that in Huntington's disease linguistic changes precede other cognitive and motor impairments, it has been shown that language impairments are in the areas of basic grammar organization and cannot be detected with standard neurocognitive tests. This study is important because it has managed to capture subtle changes in the patient's linguistic profile that could not be detected using the tests generally conducted in this population.

A more detailed and differentiated profile of the linguistic phenotype of this disease

The results showed that while the patients mentioned have "pauses" in their speech, at the beginning of Huntington's disease they tend to be filled through prolongations and repetitions. Therefore, the study provides further support for the disintegration of language in Huntington's disease and contributes to a more detailed and differentiated profile of the linguistic phenotype of the disease.

Since language skills mainly have an impact on communication skills, the authors conclude that special attention must be paid to the early detection of Huntington's disease by means of clinical linguistic tests and the sensitivity and specificity of language as a marker for the progression of the disease must continue to be systematically investigated.

About 8 percent of West Virginia newborns are exposed to alcohol two to four weeks before birth, according to a new study.

"Alcohol exposure during the last trimester is associated with a range of developmental problems that may not be overtly expressed as cranio-facial deformities, but when these children go to school, you see that there are learning, cognitive, behavioral and so many other deficits--from memory to communicating, socializing and performing daily life skills," said Amna Umer, a research assistant professor in the West Virginia University School of Medicine.

Umer, a researcher in the Department of Pediatrics, is part of a team that investigated the prevalence of prenatal alcohol exposure among babies born in West Virginia.

The team was led by Stefan Maxwell, a neonatologist with Charleston Area Medical Center. It also included:

Candice Hamilton and Collin John from the WVU Department of Pediatrics.

Christa Lilly from the WVU School of Public Health's Department of Biostatistics.

Aileen Baldwin from United States Drug Testing Laboratories, Inc.

Janine Breyel and Amy Tolliver from the West Virginia Perinatal Partnership.

Christina Mullins from the West Virginia Department of Health and Human Resources.

A PETH forward for newborn screenings

The study comprised 1,729 newborns. The researchers analyzed dried blood spots for phosphatidylethanol--or PETH--a byproduct of metabolizing alcohol. PETH levels in the blood are biomarkers of alcohol exposure in the past two to four weeks.

The researchers matched the PETH levels with data from Project WATCH, which collects demographic information and health statistics for every infant born in West Virginia.

The team discovered that, on average, 8.10 percent of births involved PETH levels consistent with late-pregnancy alcohol use. The prevalence varied across the state, from 2.3 percent in the Eastern Panhandle to 17.1 percent in and around the Mid-Ohio Valley.

The study also found that prenatal alcohol exposure was associated with maternal smoking during pregnancy. And babies exposed to alcohol prenatally were more likely to be born premature (less than 37 weeks) and have a low birth weight (less than 2,000 grams).

As part of Project WATCH, all West Virginia birth hospitals use the Birth Score tool to gather data on newborns' exposure to substances in utero. These substances include cannabinoids, tobacco, stimulants and opioids.

This month, the Birth Score tool began capturing alcohol exposure data as well.

"Importantly, the new maternal substance use data won't be used for any purpose other than public health surveillance," said Hamilton, assistant director of Project WATCH.

She predicts that--with the collection of this new information--West Virginia's official rates of prenatal substance exposure will increase overall.

Exposure in utero, problems in childhood

The actual incidence of drinking during late pregnancy is probably even greater than this study indicates.

"The PETH test won't pick up just one glass or wine or one beer," Maxwell said. "It's sensitive only for what we call binge drinking, which would be three or four regular drinks in a day."

And the blood samples that the researchers worked with weren't tested for PETH immediately after collection. Six to eight months had elapsed.

"We think that the prevalence rate is even higher than 8 percent because of the degradation of our sample," Umer said.

Still, the PETH test has an advantage over more conventional blood tests: it can detect biomarkers for alcohol use weeks after the drinking occurred. A regular blood test for the presence of alcohol may only produce valid results within a day of the alcohol exposure.

Because of the PETH test's larger window of opportunity, it may prove useful for clinicians who want to screen newborns for alcohol exposure.

"The early detection of prenatal alcohol exposure and early diagnosis of fetal alcohol spectrum disorder means that interventions can be targeted at an earlier age to reduce the cognitive and behavioral deficits in later life," Umer said.

"The problem is that when children at the age of 6 or 7 start to have these neuro-developmental disorders--leaning disabilities or whatever it may be--they get misdiagnosed," Maxwell said. "They could be misdiagnosed with ADHD or autism or something else, or the diagnosis could be missed altogether. You could imagine these kids in kindergarten, getting bullied or put in the corner or made to sit outside.

"It becomes important to know that there was prenatal alcohol exposure," he said. "That would be a differential diagnosis. Because the actual approach to therapy may be a little bit different."

Medulloblastoma, the most common brain cancer in children, may arise from biological abnormalities in neural stem cells or neuronal precursors during embryonic development. Indeed, the clinical challenges of treatment resistance and tumor recurrence in patients with medulloblastomas appear to be related to the presence of cancer stem cells within medulloblastoma tumors.

Brazilian researchers working in the Cancer and Neurobiology Laboratory at the Federal University of Rio Grande do Sul (Universidade Federal do Rio Grande do Sul, UFRGS), its university hospital (Hospital de Clínicas de Porto Alegre, HCPA), and the Children's Cancer Institute (Instituto do Câncer Infantil, ICI) in Porto Alegre, in collaboration with Canadian scientists working at the Hospital for Sick Children and the University of Toronto, analyzed gene expression in medulloblastoma tumors from patients. They demonstrated that all medulloblastoma tumor subtypes express two stem cell markers, namely the proto-oncogene protein BMI1 and the cell surface protein CD133. When DNA is in a tightly compacted chromatin state, the expression of genes that promote cell differentiation is reduced, thereby keeping cancer cells in a stem cell-like state. Accordingly, this team of researchers treated medulloblastoma cells with an epigenetic compound that inhibits histone deacetylase (HDAC) activity, leading to chromatin relaxation, and found that they could thereby reduce BMI1 and CD133 expression and hinder tumor cell viability.

Further analysis of tumor samples revealed that expression of these "stemness" markers appeared to be associated with activity of the mitogen-activated protein kinase (MAPK)/ERK intracellular signaling pathway. To test the importance of MAPK/ERK signaling in carcinogenesis, the researchers examined the effects of inhibiting MAPK/ERK in medulloblastoma cells. They found that MAPK/ERK inhibition reduced the cellular content of stemness markers and decreased cancer stem cell formation in culture. Importantly, these antitumor effects were potentiated when the tumor cells were exposed to HDAC inhibitors and MAPK/ERK inhibitors at the same time.

According to the lead author of the article reporting these findings, Dr. Mariane da Cunha Jaeger, "these findings suggest that combining HDAC and MAPK/ERK inhibitors may be a novel and effective approach to preventing medulloblastoma cell proliferation by altering the tumor stem cell phenotype".

The study findings will be reported in an upcoming issue of the Journal of Molecular Neuroscience. Preprints of the report are available at http://www.biorxiv.org. Professor Rafael Roesler, senior author of the study, underscores that this work demonstrates how "integrating gene expression data from patient tumors with cell culture experiments can enable the identification of novel potential therapy combinations".

Commenting on the research team's research outlook in light of these promising findings, the ICI Research Director Dr. André T. Brunetto has said, "We are focusing on finding translational opportunities that can be explored in innovative clinical studies on childhood cancers".

A new study in the journal Family Practice shows that intensive behavioral therapy from dietitians may be a very effective ways for older Americans to lose weight.

Some 39.8% of the general adult population is obese. The economic consequences of obesity are high, with estimated $1,429 greater annual healthcare expenditures per obese person and $147 billion overall per year. Obesity is also associated with increased risk of type 2 diabetes, stroke, certain cancers, and cardiovascular disease.

The primary objectives of this study were to examine the integration of registered dietitian nutritionist-provided intensive behavioral therapy for obesity into a primary care setting and evaluate clinic outcomes for Medicare patients.

Patients undergoing intensive behavioral therapy for obesity met with a registered dietitian once every week for the first month, and once every other week for the next six months, and then (if the patient lost weight) once a month for an additional six months to discuss challenges and lifestyle changes. The patients and the dietitians discussed behavioral health risks and factors affecting their choices. The dietitians recommended clear, specific, and personalized advice and the dietitians and the patients worked together to pick goals and methods to achieve them, and the two arranged follow up meetings to discuss progress and challenges.

This study was a retrospective chart review of therapy sessions conducted at a rural family medicine clinic in eastern North Carolina for patients between 2016 and 2019. Patients were female, had Medicare insurance, and a Body Mass Index above 30. A total of 2,097 female patients met the criteria for eligibility for the therapy.

Analysis showed statistically significant improvements in clinical outcomes from intensive behavioral therapy treatment. Patients in the treatment group lost, on average, 2.66 lbs, roughly 1.22 lbs per intensive behavioral therapy visit, compared to patients in the control group who gained an average of 0.5 lbs. Body Mass Index and A1C (average blood sugar) declined for intensive behavioral therapy patients. Patients also took prescription medication an average of six days less than the control group.

This study suggests that the advantages of dietitian-provided intensive behavioral therapy extend beyond weight loss to include associated benefits for Medicare patients. The researchers involved in the study believe that the results indicate it may be time for primary care physicians to expand their use of dietitians given their proven effectiveness.

"We are excited about our findings, which demonstrated registered dietitian nutritionist delivered intensive behavioral therapy for obesity to Medicare beneficiaries is effective and beneficial for patients," said Lauren Sastre, one of the paper's authors. "This particularly important in light of the growing pressure on providers to track and demonstrate improved Medicare patient outcomes, which include weight status."