Body

BOSTON -- A paper published today in Science Translational Medicine describes a simple, minimally invasive new tool for viewing differences in the nasal airways of cystic fibrosis patients in vivo at a cellular level. The new technique provides high-resolution images of the hair-like structures called cilia that line nasal airways as well as detailed features of the clearance of mucus, which is impaired in people with CF, causing significant morbidity.

The imaging catheter, which is about 2-millimeters in diameter, uses optical coherence tomography with a resolution of about 1 micrometer -- a 50th the size of a human hair -- allowing researchers to probe the nasal passages of patients without even sedating them.

"We've done a lot of benchtop imaging with micro-OCT but this is the first time we've been able to use it in people," said co-principal investigator Guillermo Tearney, MD, PhD, a pathologist and investigator for the department of Pathology and Wellman Center for Photomedicine at Massachusetts General Hospital (MGH), the Remondi Family MGH Research Institute Chair, and professor of pathology at Harvard Medical School (HMS). "It's unprecedented to see this pathophysiology dynamically in living patients. It will allow us to begin to understand things we never even knew were there."

Among the researchers' findings were that in CF patients, the mucus contained more inflammatory cells than in control subjects and it was dehydrated, moving slowly and impacting cilia speed. The researchers were surprised that they were even able to measure the mucus's reflective quality, which they determined was an indicator of viscosity, and that patches of CF patients' cilia and epithelium were ablated. "We thought they were there but just not functioning well," said Tearney, "but in places they were completely gone."

The approximately 30,000 cystic fibrosis patients in the United States have an average life expectancy of about 45 years. The new technique will allow clinicians to earlier diagnose diseases that affect the airways, monitor them and optimize drug therapies for individual patients. "Visualizing abnormal mucus will be a powerful tool," said co-principal investigator Steven M. Rowe, MD, MSPH, director of the Gregory Fleming James Cystic Fibrosis Research Center and a professor of medicine at the University of Alabama at Birmingham. "Now we'll be able to see how various treatments affect the airway -- not only agents intended to fix abnormal mucus, which is applicable to many diseases, but also treatments that repair the basic CF defect itself."

The researchers expect micro-OCT to have many applications beyond cystic fibrosis -- from diagnosing and treating respiratory ailments like primary ciliary dyskinesia, chronic sinus disease, and chronic obstructive pulmonary disease (COPD) to screening the GI tract for diseases and imaging coronary artery cells. "The goal is to figure out who else it can be used to help," said Rowe, "and make it more broadly accessible as a device."

The thump, thump of a baby's heartbeat is a milestone in any pregnancy. Now, researchers at Stevens Institute of Technology have developed a technique that could allow expectant parents to hear their baby's heartbeat continuously at home with a non-invasive and safe device that is potentially more accurate than any fetal heartrate monitor currently available in the market.

The device, which uses the same commercial sensors used in smartphones to horizontally or vertically orient the device, can record vibrations sent through a mother's abdomen when her baby's heart beats or when the fetus squirms and kicks. Lauded by physicians, the device could potentially reduce an estimated 2.6 million stillbirths per year worldwide.

"Almost a third of stillbirths occur in the absence of complicating factors," said Negar Tavassolian, an associate professor who led the work at Stevens. "Our device could let a pregnant woman know if her fetus is compromised and she needs to go to the doctor."

Many stillbirths are preceded by variations in fetal movement and heartrate, so affordable, lightweight monitors that detect vibrations generated from a heartbeat could be worn continuously in the final weeks of pregnancy to ensure that distressed fetuses receive prompt medical attention. The work is reported in the July 24 early access issue of IEEE Sensors Journal.

Tavassolian and first author Chenxi Yang, a graduate student at Stevens, teamed up with Bruce Young and Clarel Antoine, two OB-GYNs at New York University-Langone Medical Center to test their sensors. In experiments on 10 pregnant women, they found the device could detect fetal heartrate with about the same accuracy as fetal cardiotocograms (f-CTG), which measures the baby's heart electrical activity (ECG) together with mother's uterine contractions -- and considered the current standard for fetal monitoring.

A vibration monitor offers important advantages over existing tools based on ECG or Doppler ultrasound technology, which require specialized knowledge to use, and can be bulky and expensive. One leading monitor system currently on the market weighs more than 11 pounds and has a battery life of four hours; by contrast, the Stevens team's sensors are barely a fifth-of-an-inch long, weigh next to nothing, and can run off a 3-volt battery for more than 24 hours.

Yang's previous work has shown that chest vibrations could be used to track an adult's heartbeat, but measuring the fetal heartbeat is an order of magnitude more difficult, with the faint vibrations of the fetus's tiny heart muffled by the movements of the maternal host. To solve that problem, the Stevens team combined signals from three different sensors, and used algorithms to isolate the fetal heartbeat.

The new monitor also poses no risk to the fetus -- a concern with ultrasound monitors, which can heat tissue if used continuously for long periods. The Stevens team's monitor simply detects existing vibrations, like a doctor listening with a stethoscope. "Our monitors are completely passive, so there's no health concern," Tavassolian said.

Vibration monitors can also offer an objective measure of fetal movement, which is currently assessed simply by asking moms to count the times their baby kicks. Combining heart-rate and movement data could provide vital insights into fetal health, surpassing anything that's currently available, Yang explained. "That's the big plan -- to fuse these different modalities into a single device," he said.

The current device uses commercially available sensors, but the long-term goal is to patent and market a custom-built device. Costing far less than equivalent ECG or ultrasound systems, such a device could capture a significant share of the global market for fetal monitors, which is expected to reach $3.6 billion by 2022.

DES PLAINES, IL -- Opioid use at the three-month follow-up in emergency department patients discharged with an opioid prescription for acute pain is relatively low and not necessarily synonymous with opioid misuse. That is the conclusion of a study to be published in the August 2019 issue of Academic Emergency Medicine (AEM), a journal of the Society for Academic Emergency Medicine (SAEM).

The lead author of the study is Raoul Daoust MD, MSc, a clinical professor and researcher in the Department of Family Medicine and Emergency Medicine at the University of Montreal.

Daoust, et al., found that "...9% of patients discharged from the ED with an acute pain condition still consumed opioids 3 months later and 91% of them did so to manage pain (72% initial pain, 19% new pain). Furthermore, of the whole cohort, less than 1% consumed opioids for other reasons than pain, suggesting misuse."

"The clear and present applied implication for research from Daoust et al is the need to test non-narcotic methods to treat acute pain. The more theoretical research implication is the need to better understand the neurobiology that drives the conversion of acute to chronic pain," commented Jeffrey A. Kline, AEM Editor-in-Chief, in a summary about the paper sent to SAEM members.

The findings are controversial and provocative, as suggested by the following analysis from Gail D'Onofrio, MD, MS, professor of emergency medicine and chair in the department of emergency medicine at Yale University:

"Emergency physicians should not be reassured by the authors' findings. The lack of a denominator, poor response rate (56%), and applied definition of misuse are significant limitations. Shah et al (MMWR 2017) demonstrated the escalating probability of continued opioid use among opioid-naïve patients at one and three year if greater than three days were prescribed."

Dr. D'Onofrio is internationally known for her work in alcohol and other substance use disorders (SUDs). For the past 25+ years she has developed and tested interventions for alcohol, opioids, and other substance use disorders, serving as principal investigator on several large National Institutes of Health, Substance Abuse and Mental Health Services Administration, and Centers for Disease Control and Prevention studies. She is a founding board member of the Board of Addiction Medicine, recently recognized by the American Board of Specialties as a specialty, sub-specialty.

EAST LANSING, Mich. - Michigan State University researchers, in collaboration with the Van Andel Institute, have identified a combination of two gene mutations that is linked to endometrial cancer.

"More than 63,000 women are likely to be diagnosed with endometrial cancer this year, making it the most commonly identified type of gynecologic cancer," said Ronald Chandler, an assistant professor of obstetrics, gynecology and reproductive biology in the College of Human Medicine, who led the study.

The research, published in Nature Communications, found that mutations of the ARID1A and PIK3CA genes are frequently found together in the development of endometrial cancer, as well as in endometriosis-associated ovarian cancer. The findings could mean that better, more targeted treatments can be developed to help fight the disease.

ARID1A is a tumor suppressor. When it mutates, chromatin, cellular material that keeps DNA compacted in cells, loses its structure, allowing cancer to spread. PIK3CA is an instructional gene that tells the body to produce certain proteins and leads to uncontrolled growth of cells when it mutates.

Similarly, these same mutations often are found in women who have endometriosis - a painful condition in which uterine tissue grows outside the uterus - but many of those affected never develop endometrial cancer.

"We're trying to understand why some women with the same set of mutations get cancer and some don't," Chandler said. "There is something else involved."

Endometrial cancer commonly occurs in women after menopause, suggesting that other factors, such as hormonal changes, environmental exposures or obesity, could combine with the mutations to trigger cancer.

"The hardest part of our job is figuring out what's causing it," Chandler said. "Is it something in the environment or it is something else? It's a complex process. These are big questions that we're trying to address."

Through a collaborative effort, Chandler's team provided genetic material to Van Andel Institute. VAI researchers then analyzed the samples with a next-generation sequencer, a machine that rapidly sequences the human genome. This helped MSU researchers identify which gene mutations were associated with the cancer.

"Ten years ago, this research would not have been possible," said Marie Adams, VAI's genomics core manager and a study co-author. "Next-generation sequencers are powerful new tools we can use to process large-scale projects and provide actionable results in weeks as opposed to years."

University of Houston researcher Chandra Mohan is reporting in Arthritis Research and Therapy that clotting proteins, both those that promote blood clots (pro-thrombotic) and those that work to dissipate them (thrombolytic), are elevated in the urine of patients who suffer from lupus nephritis (LN).

"Among the proteins examined, urine plasmin emerged as the strongest independent predictor of kidney function and renal disease status," reports Mohan, Hugh Roy and Lillie Cranz Cullen Endowed Professor of biomedical engineering.

"Urine biomarkers represent promising candidates for the early diagnosis as well as the monitoring of disease activity and therapeutic responses in lupus nephritis." The discovery of the new biomarker for active LN opens the door for clinical monitoring of the disease.

Systemic lupus erythematosus (SLE) is an autoimmune disease that occurs when the body attacks its own tissues and organs. Inflammation from the disease can impact many different parts of the body including joints, skin, kidneys, blood cells, brain and heart. Lupus nephritis is one of the most frequent and severe clinical manifestations of SLE, representing a leading cause of morbidity and mortality.

New immunosuppressive drugs and biologics have brought improvements in recent SLE and LN survival rates, but early diagnosis and monitoring disease flares are still challenges that need to be addressed. Renal biopsy remains the gold standard for the diagnosis and prognosis of LN, but it's invasive and cannot be used for routine monitoring of disease activity and treatment responses. Because of this, several studies focusing on screening and identifying non-invasive biomarkers for the early diagnosis and monitoring of SLE and LN are emerging.

Because coagulation system disorders have been reported in SLE and lupus nephritis patients and the frequency of thrombotic events was documented to be higher in SLE patients than in the general population, Mohan's lab examined urinary proteins related to coagulation.

Finding elevations in both pro-thrombotic and thrombolytic proteins in the urine of patients with lupus nephritis was unexpected.

"When I first saw the presence of both I thought 'This can't be right, so let's look at this in more detail with more urine samples and better assays,'" said Mohan, who describes the presence of both proteins as "a raging war" within the kidneys. If one or the other predominates, he said, there are medicines that can regulate the clotting in balance, but when both processes are equally upregulated, balancing this biological process becomes clinically challenging.

Urine samples for this study were obtained from 113 patients with LN who had previously been recruited from the renal clinic at UT Southwestern Medical Center between 2007 and 2011. Collaborating with Mohan on the study are lead author, Qing Ling, a practicing nephrologist, Michelle A. Petri, director of the Hopkins Lupus Center at Johns Hopkins Medicine, Baltimore, and Ramesh Saxena, professor of internal medicine -nephology at UT Southwestern Medical Center, Dallas.

A new study from researchers at the University of Cincinnati (UC) and Cincinnati Children's looks at the prevalence of abnormal thyroid function in youth with severe mood and anxiety disorder. It is the largest study to date of this population and will help mental health professionals better understand the predictors of abnormal thyroid function, like weight gain, family history or treatment with certain medications.

"I was interested in devising this study because I wanted to better understand any relationship between the physical illness and mood disorder," says Marissa Luft, a third-year medical student at UC, and lead author on the study.

"The American Academy of Child and Adolescent Psychiatry recommends that clinicians consider of hypothyroidism or hyperthyroidism when assessing anxious or depressed youth, given that some thyroid conditions produce anxiety or depressive symptoms. However, until this study, we had limited evidence as to whether routine screening with a laboratory test was the best approach to screen for thyroid disease in kids with anxiety and depression," says corresponding author Jeffrey Strawn, MD, associate professor in the Department of Psychiatry and Behavioral Neuroscience at the UC College of Medicine and director of UC's Anxiety Disorders Research Program, who mentored Luft.

"These results suggest that screening, with a blood test, may be most helpful when the other predictors of thyroid disease are present," added Strawn.

The results are available online in the Journal of Clinical Psychiatry.

The thyroid gland is closely connected to brain function and, with other systems, regulates many systems in the body as well as metabolism. It produces hormones that regulate the rate at which food is converted into energy. An overactive thyroid, or hyperthyroidism, can produce anxiety, weight loss and decreased appetite, and poor concentration. Hypothyroidism (too little hormone production) can cause fatigue, weight gain and increase in appetite, slower motor skills and concentration and may look like depression.

"The study is based on chart review data of pediatric patients that were hospitalized for psychiatric disorders at Cincinnati Children's and had routine thyroid screening tests performed. We looked at the prevalence of thyroid disease in patients hospitalized with psychiatric complaints as well as other factors that may have predicted abnormal thyroid hormone levels," says Luft.

An analysis of 1,319 patients under the age of 19, found that the thyroid-stimulating hormone concentrations were abnormal in just over 6% of the psychiatrically hospitalized youth at Cincinnati Children's.

"This is the largest study to examine the utility of thyroid function screening in psychiatrically hospitalized youth with severe mood and anxiety disorders, and though it relies on existing medical history data, it does help us better understand the predictors of abnormal thyroid function tests," says collaborator, Laura Ramsey, PhD, assistant professor of pediatrics and clinical pharmacology.

Luft notes that from this study and other literature, they determined predictors of elevated thyroid-stimulating hormone levels.

"When considering thyroid assessment in youth with anxiety and mood disorders, targeted screening should focus on patients with a family history of thyroid disease, recent weight gain, treatment with specific medications, and in girls, any history of abnormal uterine bleeding," says Luft.

"The prevalence of thyroid disorders is poorly understood in pediatric populations, particularly in the area of psychiatric disorders," notes Luft, and believes the data can help inform more targeted approaches to screening, and will be of clinical interest to pediatricians, child and adolescent psychiatrists, and other mental health providers.

As an undergraduate, Luft worked with Strawn during the summers of 2016 and 2017 through the UC ROSE program, a unique research internship program which offers high-achieving students early admission to the College of Medicine, while actively engaging them in "Research, Observation, Service, and Education" (ROSE) experiences over two summers. Luft also received the Summer Medical Student Fellowship supported by American Academy of Child and Adolescent Psychiatry's Campaign for America's Kids in 2018, which funded the research.

Pivotal response treatment involving parents works better than other existing therapies at motivating children with autism and significant speech delays to talk, according to the results of a large study by researchers at the Stanford University School of Medicine.

Because children with autism are less socially motivated than typically developing children, parents' instincts about how to engage them often don't succeed, said Grace Gengoux, PhD, clinical associate professor of psychiatry and behavioral sciences. PRT gives parents a way to breach this barrier.

"We were teaching parents how to set up situations where their child would be motivated to communicate," Gengoux said. "The results of our study are exciting because we found that children in the PRT group improved not just in their communication skills, but also in their broader social abilities."

Heidi Pim of Palo Alto, California, participated in the study with her son, James, who was diagnosed as a toddler with autism and speech delays.

"I was really worried and anxious about not knowing if he would ever be able to talk," Pim said. She was impressed by the changes she saw in James, who was 3 at the time of the study. "I feel so grateful now to see how many words and phrases he knows," she said. "He's able to speak clearly and socialize as well, to go up to people and ask them questions."

A paper describing the study will be published online Aug. 5 in Pediatrics. Gengoux is the lead author. The senior author is Antonio Hardan, MD, professor of psychiatry and behavioral sciences.

Six-month study

The six-month study enrolled 48 children who were 2 to 5 years old and had autism and significant language delays. Half the children received PRT treatment from therapists and their parents, while the remaining children continued to receive whatever autism treatments they had been getting before the study began, which included other types of applied behavior analysis and conventional speech therapy.

For the first 12 weeks of the study, children in the PRT group underwent 10 hours per week of PRT from a trained therapist, and their parents received training for one hour per week in how to use the treatment's techniques during everyday interactions with their children. For the second 12 weeks of the study, children in the PRT group received five hours per week of therapist treatment, and their parents had monthly instruction sessions.

In PRT, the therapist or parent notes what the child is interested in, and uses the object to encourage speech. For example, if James wanted a toy car, Pim, his mother, learned to pick up the car, hold it where he could see it and encourage him to say "car." When he tried to say the word, he was rewarded with the toy.

At first, James learned single words. He then progressed to phrases such as "green car" and "ready, set, go." Pim also used PRT to help James learn to express his needs, such as by saying "bottle" if he was thirsty.

"He used to not be able to point to something or ask," Pim said. "PRT really improved his vocabulary skills and communication back and forth. It helped us understand what he needs and wants."

As the trial progressed, Pim also saw James' frustration levels decrease. "Before, he didn't know how to express his feelings," she said. "When I would leave for the day and come back, he didn't know how to say 'Mommy, I missed you,' so instead he would hit me or cry. That has lessened."

Today, James, now 8, is a happy kid who attends school in a mainstream classroom and enjoys playing with his twin sister, Jessica. Pim still uses PRT techniques to engage James in conversation on his favorite topics, such as elevators.

Speaking more

At the end of the study, the children in the PRT group spoke more than those in the comparison group, and were using common words that could be recognized by others, an important marker of progress given that many children spoke unintelligibly at the start of the trial. The children in the PRT group also showed greater improvement in a measure of their overall social communication, which is critical for an optimal long-term outcome, the researchers reported.

They also found that children who began with lower developmental abilities benefited more from the intervention, a surprising finding since many autism therapies are of greater benefit to higher-functioning children.

"It's discouraging for parents of lower-functioning kids if we tell them that higher-functioning kids do better, because higher-functioning kids are already doing better," Gengoux said. The new findings suggest that parents can play an especially valuable role in assisting children who have the greatest needs, she said, adding, "This provides a lot of hope."

Stanford researchers believe that findings from this trial are promising but that they need to be replicated in larger investigations. They are also currently recruiting young children with autism for a new study of how the brain changes in PRT. Interested parents can call (650) 736-1235 or e-mail autismdd@stanford.edu for more information.

Parents and teachers who want to learn PRT techniques can attend a one-day conference being held at Stanford in September. More information about the conference is available at http://med.stanford.edu/autismcenter.html.

Asbestos-related cancers include lung cancer and malignant mesothelioma (MM) for which there is no cure. Most patients with MM die within two years of diagnosis and despite the banning of asbestos in many countries MM related deaths are predicted to rise in both industrialised and developing countries.

A University of Technology Sydney (UTS) led pilot study found that the zeolite clinoptilolite reduced asbestos-induced cellular damage in cell lines (in vitro) and significantly reduced MM development in mouse models (in vivo).

Clinoptilolite is a naturally occurring mineral used for a variety of purposes including as an odour absorber and as both a food and feed additive. The mineral has GRAS status under the USFDA.

The research team also included scientists from the University of Otago, University of Western Australia, University of Sydney and Medical University of Vienna. The results are published in the journal FASEB BioAdvances.

Chief Investigator, UTS Associate Professor Tony George said that the research tested the theory that the metal-binding properties of zeolites would trap iron molecules released from asbestos fibres and thus "reduce asbestosis toxicity".

"This is the first report of success in delaying or preventing MM in an animal model," he said.

The scientists say that new treatments for MM and asbestosis have been slow to progress and is a factor in underlining the potential of the current study.

"The study is preliminary data only and the team recognises the difficulty in reproducing animal studies in humans. However, we expect that due to the incurable nature of MM, we might be able to fast-track a Phase I trial."

A study published in Cell Reports Aug. 6 describes the generation of a new mouse model developed at Hollings Cancer Center that could lead to a better understanding of the cachexia syndrome. This wasting condition, characterized by excessive weight loss, has one of the highest incidences in pancreatic cancer patients.

Denis Guttridge, Ph.D., Hollings Cancer Center associate director of Translational Sciences and principal investigator of the study, says the study found that the newly genetically engineered mouse model, called KPP, better mimics the human phenotype of cancer cachexia.

"We believe that the KPP mouse model better captures what patients go through when afflicted with pancreatic cancer and suffer from cachexia," he says. "Approximately 70% of patients diagnosed with pancreatic cancer lose significant weight."

Cachexia depletes patients' quality of life by causing the loss of skeletal muscle-, the most abundant tissue in humans. It affects cancer treatment by decreasing treatment tolerance and making patients weak and more resistant to treatment, Guttridge says. Actor Patrick Swayze, who died of pancreatic cancer in 2009, suffered from cachexia.

"I got the chance to speak with Patrick Swayze's wife, and she shared with me how much of a fitness nut her husband was. She remembered that he would go in for his checkup and was always more concerned about why he was losing so much weight rather than the progression of his cancer, because maintaining a quality of life and his fitness was so important to him," Guttridge says. "Although we understand that cachexia is a consequence of cancer, for such cancers like pancreatic, an effective treatment does not yet exist. So trying to combat cachexia to provide the patient a better quality of life is a big deal."

Guttridge, a specialist in cachexia, estimates that nearly one-third of all cancer deaths can be attributed to this wasting syndrome, which is devastating for not only the patient but their families as well.

It occurs in many cancers, usually at the advanced stages of disease, and is most commonly seen in a subset of cancers, led by pancreatic, but also present in lung, esophageal and colon cancers.

This study, funded by the National Institutes of Health, is novel because the KPP model overcomes certain limitations present in current animal models, such as the high tumor burden, which is not a common feature of patients.

One nuance of the new model is that it is inducible, thus allowing researchers to control when pancreatic cancer can be triggered through the expression of mutant cancer genes.

"When we turn on these cancer genes, tumors take two months to develop rather than two weeks, as seen in the current models. So we have that extra opportunity to look at events that are happening sequentially," Guttridge says.

Features in KPP mice showed a better reflection of cachexia symptoms typically seen in humans, than did tradition models, he says. This was evident when researchers compared the gene expression pattern of muscles from pancreatic cancer patients with cachexia and compared them to KPP versus the traditional models of cachexia.

"The match was much more similar with our new model," Guttridge says. "That's another level of confidence we can have in trying to recapitulate a model that mimics the human condition."

Guttridge emphasizes that this is only the first generation of the model, recognizing the need to adjust for particular outcomes such as a level of inflammation that surpasses what they detect in patients.

However, Guttridge is confident that their KPP model will have a positive impact on the future of cachexia research.

"We're hoping that we will be able to identify new mechanisms that drive muscle wasting and weight loss in cancer patients," he says. "And because of the timescale of the model, we believe the model will be useful for performing preclinical studies that possibly lead to identifying new drugs that can be translated to the clinic."

While the study was a team effort, Guttridge credits first author Erin Talbert, Ph.D., a postdoctoral fellow in his lab, for leading the project and creating the KPP model. The project also features Hollings collaborators, including Hollings Cancer Center Director Gustavo Leone, Ph.D.; Maria Cuitiño, D.V.M., Ph.D.; Michael Ostrowski, Ph.D.; Cynthia Timmers, Ph.D.; and other collaborators from The Ohio State University Comprehensive Cancer Center.

"We're satisfied that we've contributed to the field, and we're eager to see our colleagues use the model and give us feedback," Guttridge says. "This is a shared resource for the entire scientific community."

Guttridge is optimistic that the new model will lead to novel discoveries among researchers, including those at Hollings Cancer Center.

"We're hoping that the KPP mouse will give us new insights into what's driving cachexia because the more we know about what's driving this syndrome, the more we're going to be able to identify viable therapeutic targets," he says.

NEW YORK, August 6, 2019-- Researchers from TARA Biosystems, Inc. and GlaxoSmithKline (GSK) today published data demonstrating that TARA's engineered heart-on-a-chip system replicated drug responses found in adult humans. The findings, published in the Journal of Toxicological Sciences, show TARA's 3D-cardiac tissue platform can predict how human hearts will respond to a wide range of drugs, something that has been a challenge in pre-clinical models until now.

"The cardiac tissues generated in the study are the first to provide high-fidelity human drug responses and demonstrate the potential for evaluating the safety and efficacy of new therapies in preclinical development," said Michael P. Graziano, PhD, study author and Chief Scientific Officer of TARA Biosystems.

Cardiac toxicity is responsible for almost half of new medicine recalls. Regulations mandate that new drugs undergo a rigorous cardiac safety assessment before human testing, but predicting how human hearts will respond to potential drug toxicity has been difficult. Traditional in vitro systems and animal models do not fully capture the physiology of the human heart.

Human induced pluripotent stem cells (iPSCs) hold great promise as a foundation to bridge the human translation gap. However, experimental models which rely on iPSCs alone lack relevant physiological hallmarks and drug responses seen in human heart muscle.

TARA leverages the power of iPSCs and subjects them to a rigorous maturation process on its patented Biowire™ II system, producing 3D human cardiac tissues called Cardiotype™ tissues. In a study published earlier this year in Cell, TARA scientific founders validated the ability of the Biowire™ II platform to create physiologically relevant human cardiac tissues. Unlike models that rely solely on iPSCs, researchers can measure the force with which Cardiotype™ tissues contract, which better reflects human heart physiology by offering a measure of how well the heart can pump blood. The research also showed how the platform could be used to model different heart diseases by using iPSCs from patients.

In the current study, researchers from GSK worked with TARA to select a panel of clinically relevant drugs with known efficacy and toxicity profiles in the heart, for screening in the Cardiotype™ platform. These drugs, and their concentrations, were chosen to assess the predictivity of the Cardiotype™ assay in comparison to current methods for preclinical drug screening in pharmaceutical R&D.

The tissues responded to the range of cardiotherapeutic and cardiotoxic drugs selected as expected, replicating for the first time the human-like response to the drugs that other laboratory models failed to capture. The researchers also confirmed the findings at the molecular level, showing that the drugs were acting along the same molecular pathways seen in human heart tissue.

"At TARA we are proud to tackle cardiac safety in a meaningful way that will ultimately improve the quality of new medicines delivered to patients," said Misti Ushio, PhD, Chief Executive Officer of TARA Biosystems. "By using TARA's cardiac engineered tissue, drug development companies are able to obtain human relevant data earlier in the drug development cycle."

High blood pressure is the most important treatable risk factor for diseases of the heart and the arterial system. Blood pressure recorded over 24 hours predicts these complications more accurately than blood pressure measured on a single occasion. That is the conclusion of an international study coordinated by Professors Jan A. Staessen and Zhen-Yu Zhang of KU Leuven in Belgium. Dr. Gladys Maestre from the University of Texas, Rio Grande Valley School of Medicine, supervised the study in Venezuela, one of the participating countries. The study was published in the Journal of the American Medical Association.

An international consortium of scientists followed 11,135 individuals for 14 years. Study participants included residents of twelve countries in Europe, East Asia, and Latin America. The researchers compared the predictive accuracy of blood pressure measurements made by a healthcare provider in an office setting, to repeated blood pressure measurements recorded for 24 hours, during both day and night. The results showed that the probability of heart and vascular disease during follow-up was closely associated with the blood pressure measured over a 24-hour period.

"Although heart and vascular disease are strongly associated with blood pressure, irrespective of how it is measured, until now we did not know which type of blood pressure measurement captured risk in the most accurate way," Dr. Maestre said.

At the start of the study, investigators made individual blood pressure measurements using all available approaches, and determined other risk factors. Blood pressure was also recorded over a 24-hour period using automated portable blood pressure monitors. The number of blood pressure measurements averaged 30 during daytime and 10 during sleep. One of the advantages of measuring blood pressure during sleep, with individuals lying down in bed, is that the results are not influenced by daytime activities or meals. This at least partly explains the accuracy of nighttime blood pressure in predicting cardiac and vascular illness.

High blood pressure is the leading treatable risk factor for diseases of the heart and vascular system. Worldwide, high blood pressure causes 10 million deaths each year, with more than half of that mortality attributable to cardiovascular disease. The present study is unique in its large sample size and long follow-up period. The characteristics of participants were similar to those of the populations from which they were enrolled, so the results can be generalized.

"Our research highlights the necessity of using 24-hour measurements to diagnose high blood pressure and to institute and fine tune its treatment," said Dr. Maestre. "Nevertheless, most health insurers in the US reimburse 24-hour ambulatory blood pressure monitoring only when blood pressure is found to be high in the clinical setting, but is suspected to be normal otherwise, or if undetected or masked hypertension is suspected. However, 24 hour ambulatory blood pressure monitoring is cost effective: It enables the prevention of cardiovascular disease by starting treatment in a timely manner."

Prevention and improved control of high blood pressure is also cost effective, because hospital-based treatment of the complications of high blood pressure, such as chest pain caused by narrowing of the arteries of the heart, myocardial infarction, and stroke, is expensive. Furthermore, prevention reduces the risk of premature disability and death, thereby avoiding suffering of patients and their families. About 30% of all adults and 60% of people age 60 and over have high blood pressure. Therefore, ambulatory blood pressure monitoring should be available at all levels of the healthcare delivery chain.

WASHINGTON --Researchers for the first time have combined a powerful microscopy technique with automated image analysis algorithms to distinguish between healthy and metastatic cancerous tissue without relying on invasive biopsies or the use of a contrast dye.
This new approach could one day help doctors detect cancer metastasis that is otherwise difficult to see via standard imaging technologies during operations.

"Existing techniques are invaluable but suffer from low spatial resolution and often require the use of exogenous contrast agents," said research team co-leader Thomas Schnelldorfer from Lahey Hospital, Burlington, Mass., U.S.A. "The method utilized in this work identifies in a completely label-free manner cellular and tissue features at the microscopic level, essentially acting like a biopsy without a knife," added Dimitra Pouli from Tufts University, Medford, Mass., U.S.A., lead author of the study.

In The Optical Society (OSA) journal Biomedical Optics Express, researchers demonstrate the use of multiphoton microscopy along with automated image and statistical analysis algorithms to examine freshly excised biopsies from the peritoneal cavity, a part of the abdomen that is frequently affected by metastatic cancers, especially for patients with ovarian cancer. It is the first time healthy and metastatic human peritoneal tissue has been successfully evaluated by combining this microscopy modality with image texture analysis techniques.

Because the approach evaluates cellular and extracellular tissue features at the microscopic level, it could identify cancer metastasis at an earlier stage when it may be easier to treat. By using algorithms to classify tissues, the approach could also help reduce bias in interpreting images and complement methods that rely on human expertise.

"This could ultimately help surgeons identify suspicious or diseased areas directly in the operating room in real-time, which in turn would directly affect patient management," said Schnelldorfer.

"As the method exploits inherent tissue signals present almost ubiquitously in tissues, it can be applied to other types of cancer and other applications altogether, such as fibrosis and cardiovascular disease where tissue structure and extracellular matrix remodeling are altered by the underlying disease processes," added Irene Georgakoudi, study co-leader from Tufts University.

Finding clues in tissue texture

Multiphoton microscopy works by delivering laser light to tissue. Though the laser has high peak intensity, it is delivered in very short pulses in order to keep the average power small and not cause tissue damage. As different tissue components interact with the laser light, they emit signals that are then retrieved by the microscope to create an image. Once the images are acquired, automated image processing algorithms can be used to reveal unique textural features. These features, which are not visible in the images acquired with standard operative imaging tools, can be analyzed with statistical models to classify the tissue as healthy or diseased.

A key strength of the approach is that the image acquisition and analysis are based on components of the tissue itself - such as cells or collagen, a protein that forms connective tissue - rather than on contrast dyes that have been added to it. This allows analysis of inherent features related to form and function in a completely noninvasive and nondestructive manner.

In this work, the researchers for the first time applied this combined microscopy and analysis technique to healthy and metastatic human parietal peritoneal tissues. Because parietal peritoneal tissue is replete with collagen, part of the analytical implementation was focused on evaluating the micro-structural patterns of collagen fibers and their intermolecular cross-linking signals.

The researchers found that healthy and diseased tissue showed distinctive patterns in terms of contrast (a measure of intensity dissimilarities from pixel to pixel) and correlation (a measure of pattern repetitiveness). While healthy tissues showed greater variation in these features, metastatic tissue images showed more uniform intensity patterns and smaller fibers. These changes reflect the destruction of the native connective tissue by the cancer cells, providing a hallmark of cancer metastasis.

Improving cancer staging

Determining the extent and locations of cancerous spread - known as staging - is crucial to effective cancer treatment. Cross-sectional radiographic imaging and white light laparoscopy are tools used to identify abdominal metastases, but often fall short when it comes to detecting smaller lesions buried within healthy tissue. Biopsies and microscopic evaluation also play a key role in determining whether cancer cells have metastasized and started to invade the tissue microenvironment.

When ovarian cancer begins to spread, it most often appears first in the peritoneum, a membrane that lines the abdominal cavity. To test their new method, the researchers used it to analyze peritoneal biopsies collected from eight patients with confirmed or suspected ovarian malignancy.

Analyzing 41 images acquired from the biopsies, the technique correctly classified 40 out of 41 images (an accuracy of 97.5 percent). A total of 11 samples were correctly classified as metastatic (100 percent sensitivity) and 29 of 30 were correctly classified as healthy (96.6 percent specificity).

The researchers plan to continue to test the method in a larger sample of images from a broader patient population. While the analysis method was optimized for detecting ovarian cancer that has metastasized in parietal peritoneal tissue, the same technique could be adapted for analyzing other tissue types and other cancer types.

Although biopsies were used to test the method, researchers say the ultimate goal is to apply it directly to areas of the body where cancer is found or suspected, without the need for biopsies or dyes. Before the technique can be used for real-time tissue analysis during surgery, additional work will be needed to miniaturize the microscopy components, integrate the microscope with surgical instrumentation and enable real-time analysis of the acquired images directly at the operating room.

New York, NY--August 6, 2019--By adding electronics and computation technology to a simple cane that has been around since ancient times, a team of researchers at Columbia Engineering have transformed it into a 21st century robotic device that can provide light-touch assistance in walking to the aged and others with impaired mobility.

A team led by Sunil Agrawal, professor of mechanical engineering and of rehabilitation and regenerative medicine at Columbia Engineering, has demonstrated, for the first time, the benefit of using an autonomous robot that "walks" alongside a person to provide light-touch support, much as one might lightly touch a companion's arm or sleeve to maintain balance while walking. Their study is published today in the IEEE Robotics and Automation Letters.

"Often, elderly people benefit from light hand-holding for support," explained Agrawal, who is also a member of Columbia University's Data Science Institute. "We have developed a robotic cane attached to a mobile robot that automatically tracks a walking person and moves alongside" he continued. "The subjects walk on a mat instrumented with sensors while the mat records step length and walking rhythm, essentially the space and time parameters of walking, so that we can analyze a person's gait and the effects of light touch on it."

The light-touch robotic cane, called CANINE, acts as a cane-like mobile assistant. The device improves the individual's proprioception, or self-awareness in space, during walking, which in turn improves stability and balance.

"This is a novel approach to providing assistance and feedback for individuals as they navigate their environment," said Joel Stein, Simon Baruch Professor of Physical Medicine and Rehabilitation and chair of the department of rehabilitation and regenerative medicine at Columbia University Irving Medical Center, who co-authored the study with Agrawal. "This strategy has potential applications for a variety of conditions, especially individuals with gait disorders."

To test this new device, the team fitted 12 healthy young people with virtual reality glasses that created a visual environment that shakes around the user--both side-to-side and forward-backward--to unbalance their walking gait. The subjects each walked 10 laps on the instrumented mat, both with and without the robotic cane, in conditions that tested walking with these visual perturbations. In all virtual environments, having the light-touch support of the robotic cane caused all subjects to narrow their strides. The narrower strides, which represent a decrease in the base of support and a smaller oscillation of the center of mass, indicate an increase in gait stability due to the light-touch contact.

"The next phase in our research will be to test this device on elderly individuals and those with balance and gait deficits to study how the robotic cane can improve their gait," said Agrawal, who directs the Robotics and Rehabilitation (ROAR) Laboratory. "In addition, we will conduct new experiments with healthy individuals, where we will perturb their head-neck motion in addition to their vision to simulate vestibular deficits in people."

While mobility impairments affect 4% of people aged 18 to 49, this number rises to 35% of those aged 75 to 80 years, diminishing self-sufficiency, independence, and quality of life. By 2050, it is estimated that there will be only five young people for every old person, as compared with seven or eight today.

"We will need other avenues of support for an aging population," Agrawal noted. "This is one technology that has the potential to fill the gap in care fairly inexpensively."

Children's veins are small and sometimes difficult to access during necessary medical treatment. When caregivers used ultrasound to guide placement of intravenous (IV) lines in children with presumed difficult access, they had higher success rates on their first attempt. Researchers from Children's Hospital of Philadelphia (CHOP) report that this technique reduces the number of needle sticks in their young patients.

The research was published in the July 2019 issue of Annals of Emergency Medicine.

"The need to place an intravenous line is a common but challenging requirement for pediatric healthcare providers," said Alexandra M. Vinograd, MD, an emergency medicine physician at CHOP and the lead investigator of this study. "Our research shows that both the children and their parents are happier with ultrasound-guided line insertion."

The researchers prospectively enrolled 167 patients identified as having difficult IV access that were randomized to receive either traditional IV line or care from a multidisciplinary team trained to place ultrasound-guided IV lines on the first attempt. The children were divided into two groups, age zero to three years old, and over age three.

First-attempt success was higher in the ultrasound-guided IV line placement group (85.4 percent) compared to the traditional intravenous line group (45.8 percent). When asked to score their satisfaction with the IV line placement, parents favored the ultrasonically guided placement over the traditional method.

"In our study, ultrasound-guided intravenous lines remained in place longer than traditional insertion, without an increase in complications," said Joseph J. Zorc, MD, emergency medicine physician at CHOP and senior author of the study. "These results may be used to update guidelines for intravenous line access in children in an effort to limit the number of needle sticks they experience."

Both nurses and physicians had high rates of first-attempt success. The high rate of nurse success led to a training program in CHOP's Emergency Department that broadly trains nurses in ultrasound-guided IV line placement. Ultrasound-guided access is now standard procedure for patients with presumed difficult intravenous access," added Vinograd.

BOSTON -Successful recovery from opioid use disorder appears to be even more challenging than recovery from alcohol use disorder, and individuals with opioid use problems may require more intensive medical, psychological and social support services over a longer period of time, results of the first national study of opioid problem resolution suggest.

An investigation of a nationally representative sample of U.S. adults who reported resolving an opioid problem found that, among those who achieved longer-term recovery (between 1 and 5 years since resolving a problem), individuals who had resolved an opioid problem were more likely than individuals who resolved an alcohol problem to have used formal addiction treatment, pharmacotherapy (that is, drugs to prevent cravings or relapse such as methadone, buprenorphine or naltrexone), recovery support services, and mutual help (such as Narcotics Anonymous and other 12-step programs), found Lauren A. Hoffman, PhD, Corrie Vilsaint, PhD, and John F. Kelly, PhD, from the Recovery Research Institute at Massachusetts General Hospital (MGH) and Harvard Medical School (HMS).

Providing the first national prevalence estimate of opioid recovery, their study suggests that 1.18 million American adults have resolved a primary opioid use problem.

Their findings are published in the Journal of Addiction Medicine.

Although the extent of the opioid crisis in the United States makes headlines daily, there is sparse scientific or clinical information on recovery from opioid use disorders, prompting the MGH investigators to conduct a nationwide study of what appears to work, using recovery from alcohol as a reference point. Alcohol use disorder is the most common type of substance use disorder.

They used data from the 2017 National Recovery Survey that consisted of a sample of adults 18 and older who answered yes to the question "Did you used to have a problem with drugs or alcohol, but no longer do?" They analyzed the estimated prevalence of both opioid and alcohol problem recovery, differences in treatment and recovery services use, and psychological well-being both within the first year of recovery (early recovery period) and from 1 to 5 years (mid-recovery).

"Essentially, those who resolved an opioid problem in mid-recovery were four times as likely to have ever used pharmacotherapies, two-and-a-half times more likely to have used formal treatment, and about two times more likely to use recovery support services and mutual help organizations compared with individuals who reported resolving an alcohol problem and were in mid-recovery," Hoffman says.

"We didn't find those differences in the first year, and this is important because taken together it suggests that individuals with an opioid problem might require additional treatment or additional resources to achieve longer and more stable recovery duration," she added.

The investigators also looked at various measures of psychological well-being and found that whereas levels of self-esteem were higher in the opioid group than the alcohol group in early-recovery, self-esteem levels among the opioid group were lower than the alcohol group in the mid-recovery period. Lower self-esteem in mid-recovery may be related to the extra challenges of opioid recovery, including longer duration or greater use of treatment and recovery services relative to alcohol recovery, more frequent relapses and societal attitudes about opioids, Hoffman says.

Compared with individuals with alcohol use disorder, people with opioid problems tend to be more socially stigmatized, have fewer resources available, and may be less likely to disclose their recovery status to others, which could make them feel more lonely or isolated, the investigators say.