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U.S. physicians are increasingly ordering medications for children for conditions that are not approved by the Food and Drug Administration, according to a Rutgers study.

The findings highlight the need for more education, research and policies addressing effective, safe pediatric drug prescribing.

The study, published in the journal Pediatrics, analyzed data collected from 2006 to 2015 in the Centers for Disease Control and Prevention's National Ambulatory Medical Care Surveys, which provide information on doctor office visits across the U.S. The researchers analyzed the frequency, trends and reasons why doctors ordered unapproved medications for children under 18.

It is the first study in a decade to look at how U.S. doctors outside of hospitals order a broad range of medicines off-label to children. This study focused on systemic drugs, which work throughout the body and have a greater potential for toxicity.

Many drugs prescribed for children have not been rigorously tested in children, according to the Food and Drug Administration. "Off-label medications - meaning medications used in a manner not specified in the FDA's approved packaging label - are legal. We found that they are common and increasing in children rather than decreasing," said senior author Daniel Horton, assistant professor of pediatrics and a pediatric rheumatologist at Rutgers Robert Wood Johnson Medical School. "However, we don't always understand how off-label medications will affect children, who don't always respond to medications as adults do. They may not respond as desired to these drugs and could experience harmful effects."

The study found, for about 19 percent of the estimated two billion office visits for children studied, doctors ordered one or more off-label systemic drugs, often for common conditions such as respiratory infections, asthma or mental health disorders. In visits with at least one drug order, doctors ordered drugs off-label in about 83 percent of newborn visits, 49 percent of infant visits and about 40 percent of visits for other ages. The study also found that, among visits with at least one ordered drug, the rates of ordering off-label increased from 42 percent in 2006 to 47 percent by 2015.

Rates of off-label drug orders were higher for girls and for children with chronic conditions. Physicians in southern states ordered off-label drugs more often than physicians in other regions of the country. Specialists ordered them more commonly than general practitioners.

The most frequently ordered off-label drugs were antihistamines for respiratory infections, several classes of antibiotics for respiratory infections and antidepressants for attention-deficit/hyperactivity disorder.

"Despite the laws in this country and Europe that encourage and require research on medications for children, we found that physicians are increasingly ordering certain medications off-label for children," said Horton.

"Use of some off-label drugs is supported by high-quality evidence. For example, drugs approved to prevent vomiting caused by chemotherapy also work quite well in treating more common causes of vomiting in children, such as from viruses. We need this kind of evidence to determine the appropriateness of use of many other drugs currently used off-label to treat a wide range of conditions in children," Horton said.

A group of forager-farmers in Bolivia's tropical forests -- known for having remarkable cardiovascular health and low blood pressure -- experienced changes in body mass and diet over a nine-year period, with increased use of cooking oil the most notable dietary change.

The Tsimane' people, a pre-industrial society, traditionally hunt, fish, farm and gather food for their subsistence, said Baylor University anthropologist Alan F. Schultz, Ph.D., M.P.H., co-author of a study published in the journal Obesity. Their diet, traditionally higher in carbohydrates, fiber and protein and lower in fat than the average United States diet, includes plantains, rice, manioc, maize and fruit as well as lean game, freshwater fish and occasional honey.

But recent population growth, along with encroachment on their territory, has put pressure on supplies of game and fish, while more opportunities to attend school and earn wages correspond with reductions in traditional cultural knowledge and lifestyle practices. With these changes have come greater access to and reliance on market foods, such as refined grains, refined sugar, cooking oil and domesticate foods, like pigs, chickens and eggs, according to the study, conducted from 2002 to 2010.

"Objective measures suggest this group is astonishingly heart-healthy, with low average blood pressure and little heart disease. But that's only one part of their story," Schultz said. "It's still a puzzle how these attributes fit with high rates of infectious disease, high death rates in children under 5 and moderate-to-high physical activity levels. Is their overall well-being also high? Or just certain health measures? Our findings of a trend in weight gain and increased consumption of high-calorie foods suggest that the benefits of change are not so clear-cut."

Researchers who conducted a 2017 study funded by the NIH National Institute on Aging reported that the Tsimane' had better cardiovascular health based on coronary artery calcium scoring done with CT scans than ever has been measured in any other population and continued low blood pressure. But they also reported less healthy lipid and glucose levels than previous research.

Using data from 365 men and 330 women older than age 20 who live in Amazonian lowlands, researchers found changes from 2002 to 2010, a time frame that reflects growing access to market food but a majority diet of cultivated crops. Researchers measured body mass index (BMI), body fat percentage, waist circumference and fat-free mass.

Changes included:

Tsimane' women's prevalence of overweight and obesity increased from 22.6 percent and 2.4, respectively, to 28.8 percent and 8.9 percent.

Men's prevalence of overweight and obesity trended similarly from 16.2 percent and 0.7 percent to 25 percent and 2.2 percent, respectively.

More use of cooking oil was associated with increased BMI among females, while consumption of domesticated animal products did not change significantly but was positively associated with female BMI and male waist circumference.

Household calories did not increase to a statistically significant degree, and homegrown crops still accounted for the bulk of household calories. But the odds of cooking oil use increased by 24 percent each year, nearly doubling the number of study households using it. By 2010, this included 30 percent of households, much lower than in industrialized populations.

While sugar intake increased by about 13 percent annually, neither it nor refined grains had detectable associations with changes in body fat.

Because shifts from subsistence diets to market-based ones often are accompanied by livelihood and lifestyle change, it can be hard to separate the effect of diet versus other health factors, Schultz said.

But "we found that even small increases in market-based foods that are high in calories even in small servings, contributed to fat gain in this active, subsistence-based population," he said. "Cooking oil adds so much flavor -- we use it for a reason -- but at 120 calories/14 fat grams per tablespoon, few foods can so easily alter your diet."

For the Tsimane', access to market products is shifting along with economics. They are one of the most isolated of 36 Bolivian indigenous groups, generally living in communities of 50 to 250 people. But their population is growing rapidly -- from an estimated 6,000 people in the late 1990s to an estimated 16,000 in 2015, according to national censuses.

They still have limited access to running water, electricity and sanitation. But as migrants and ranchers continue to move into the area, there is more chance for income from contracts to extract forest products and work as day-laborers. That money is spent partly on processed foods and medical care.

Travel to the nearest market town on foot or by dugout canoe can take between two hours and several days. "They also can buy from traders who travel the river by motorboat, but many families have recently bought small, inexpensive outboard motors to speed trips to market," Schultz said. "Travel is changing dramatically."

Tsimane' livelihood remained almost entirely subsistence-based even years after the first road was built into their territory in the 1970s, initiating an intense period of logging for hardwood by outsiders and expansion of missionary activities. As change in environments and livelihoods accelerates, many exceptional attributes of Tsimane' health identified across numerous academic studies appear threatened.

"Future research should focus on the ultimate causes and consequences of recent changes," Schultz said. "This includes, among other things, diet, physical activity and infectious disease experience as well as sociocultural health determinants like lifestyle expectations and social support."

"Does market-based living condemn most of us to obesity, stress and poor heart-health? Will it have this effect on Tsimane'? If Tsimane' livelihoods are changing, we want to understand the causes and ultimate effects of that change for their health -- and for ours."

New research presented at this year's annual meeting of the European Association for the Study of Diabetes (EASD) in Barcelona, Spain (16-20 September) shows that specialist analysis of the lens in the eye can predict patients with type 2 diabetes and impaired glucose tolerance (IGT) (also known as prediabetes, a condition that often leads to full blown of type 2 diabetes).

This early pilot study is by Dr Mitra Tavakoli, University of Exeter Medical School, Exeter, UK. Her study showed that measuring the level of autofluorescence in the lens of the eye can predict who will develop type 2 diabetes in future, and prediabetes, caused by impaired glucose tolerance. Prediabetes often leads to the development of type 2 diabetes.

Other studies have shown that there can be a lag of up to ten years between the onset of type 2 diabetes and diagnosis, so earlier detection and timely intervention could help prevent complications.

The study used a newly developed biomicroscope which can detect advanced glycation end-products (AGEs) in the eye via a simple scan. The increased level of AGEs in the body contributes to development of many diseases, including complications of diabetes such as retinopathy (eye nerve damage) and neuropathy (general nerve damage).

The new biomicroscope focuses a beam of blue light onto the lens non-invasively, and measures the autoflouresence in the reflected green light, which provides a measure of the level of AGEs.

In this pilot study, 20 people with type 2 diabetes, 20 people with prediabetes and 20 healthy age-matched control subjects underwent comprehensive medical and neurological assessments including measurement of lens autofluorescence by using the biomicroscope.

The study found a significant increase in AGE levels in the eyes of people with type 2 diabetes. It also showed an increase levels in people with prediabetes, meaning this could be a robust way to measure those who may go on to develop diabetes in future.

Dr Tavakoli says: "The results of this preliminary study showed the lens autofluorescence is significantly greater in patients with prediabetes and type 2 diabetes. The level of AGE products were correlated with the levels of blood sugar."

She concludes: "Lens autofluorescence could be a robust marker of long-term diabetes control predicting future complication risks. This supports the feasibility of non-invasive lens autofluorescence to screen subjects for undiagnosed type 2 diabetes and prediabetes subjects. Although this is a pilot study, is an exciting emerging new tool for early detection and monitoring the treatment of patients. It could improve the lives of people with type 2 diabetes by reducing complications. However larger and long-term clinical studies are needed to confirm these findings."

The research published today (Monday 16 September) in Paediatric and Perinatal Epidemiology examined whether there were any effects of taking paracetamol in mid-pregnancy and the behaviour of the offspring between the ages of 6 month and 11 years, with memory and IQ tested up until the age of 17. Paracetamol is commonly used to relieve pain during pregnancy and is recommended as the treatment of choice by the NHS.

Using questionnaire and school information from Bristol's Children of the 90s study researchers examined 14,000 children. When they were seven months pregnant 43 per cent of their mothers said they had taken paracetamol 'sometimes' or more often during the previous three months. Researchers examined results of the children's memory, IQ and pre-school development tests, temperament and behaviour measures.

They found an association between paracetamol intake and hyperactivity and attention problems as well as with other difficult behaviours with young children that were not accounted for by the reasons why the medication was taken or social factors. However, this was no longer the case by the time the children reached the end of primary school. Boys appeared to be more susceptible than girls to the possible behavioural effects of the drug.

The study was led by Professor Jean Golding OBE who also founded the University of Bristol's Children of the 90s study. She commented:

"Our findings add to a series of results concerning evidence of the possible adverse effects of taking paracetamol during pregnancy such as issues with asthma or behaviour in the offspring. It reinforces the advice that women should be cautious when taking medication during pregnancy and to seek medical advice where necessary.

"It is important that our findings are tested in other studies - we were not in a position to show a causal link, rather an association between two outcomes. It would also be useful now to assess whether older children and adults are free of difficult behavioural problems if their mother had taken paracetamol."

Researchers experimentally determined a property of cadmium called the magic wavelength which is considered essential for the development of the most accurate clocks ever envisaged. The researchers hope this may permit simple and robust atomic clocks so accurate they could be used to improve our understanding of current theories and even test for new physics.

What time do you make it? How about now? Time is constantly changing but it is not changing constantly. It sounds confusing, but since Einstein's time we've known that time progresses at different rates depending on where you are. This is mainly due to the effect of gravity, the stronger gravity is in your vicinity the slower time progresses relative to where gravity is weaker. To us this difference is imperceptible, but highly accurate atomic clocks can measure it.

These imperceptible differences in the rate of the passage of time are far from trivial however. Accurate measurements of time can actually help researchers measure other corresponding quantities which relate to how time flows at a specific location. For example given the way increased gravitational strength alters the passage of time, the density of material below your feet could be accurately measured with a sufficiently accurate clock. And this kind of information could be useful to those who study volcanoes, plate tectonics and earthquakes.

However, to measure time at the accuracies required for such purposes is an immensely complex challenge. State of the art atomic clocks based on the vibration of atoms such as caesium, for example, operate with an uncertainty - the opposite of accuracy - in the region of 1x10-16 or to 16 decimal places. This is extremely accurate for the measurement of distance and is thus used in current global positioning system (GPS) technology. But researchers strive for even greater accuracy, and one kind of clock may be able to offer uncertainties as low as 1x10-19 or to 19 decimal places. The optical lattice clock promises to offer such accuracy.

First proposed by Professor Hidetoshi Katori from the Department of Applied Physics in 2001, the idea is to trap a large number of atoms in a lattice of lasers. With many atoms trapped their vibrations can be measured simultaneously, which greatly improves the accuracy of the measurement of time. Isotopes of Cadmium are ideal as they have some properties which help to reduce noise in this kind of quantum system. But in order to create a clock based on this principle there are several hurdles to overcome, and researchers have just jumped one.

"We experimentally determined the so-called 'magic wavelength' for cadmium which is one of the essential parameters to operate the optical lattice clock," said research scientist Atsushi Yamaguchi from RIKEN. "In a lattice clock the optical lattice created by interference patterns of laser light, the wavelength of which is related to the atoms the lattice needs to hold. The optimal or 'magic' wavelength to construct a lattice around Cadmium isotopes is around 419.88 nanometers, which is almost exactly the value of 420.10 nanometers we originally predicted."

One important feature of Cadmium isotopes which makes them ideal for lattice clocks is that they are more robust to changes to their environment than many other atoms and isotopes. An application researchers aim for is the ability to make measurements in different locations with the same device, meaning it must be relatively portable, so it helps to be robust. With the theory in place, researchers now wish to evaluate the performance of such a clock.

"Careful and detailed evaluation is required so scientists in different fields can make use of this high precision instrument," explained Katori. "Such a device will afford us the chance to study and maybe one day challenge established ideas in cosmology such as general relativity and perhaps even the fundamental constants of nature."

Heart failure is an important potential complication of type 2 diabetes that occurs frequently and can lead to death or disability. Earlier this month, late-breaking trial results revealed that a new class of medications known as SGLT2 inhibitors may be helpful for patients with heart failure. These therapies may also be used in patients with diabetes to prevent heart failure from occurring in the first place. However, a way of accurately identifying which diabetes patients are most at risk for heart failure remains elusive. A new study led by investigators from Brigham and Women's Hospital and UT Southwestern Medical Center unveils a new, machine-learning derived model that can predict, with a high degree of accuracy, future heart failure among patients with diabetes. The team's findings are presented at the Heart Failure Society of America Annual Scientific Meeting in Philadelphia and simultaneously published in Diabetes Care.

"We hope that this risk score can be useful to clinicians on the ground -- primary care physicians, endocrinologists, nephrologists, and cardiologists -- who are caring for patients with diabetes and thinking about what strategies can be used to help them," said co-first author Muthiah Vaduganathan, MD, MPH, a cardiologist at the Brigham.

"Our risk score provides a novel prediction tool to identify patients who face a heart failure risk in the next five years," said co-first author Matthew Segar, MD, MS, a resident physician at UT Southwestern. "By not requiring specific clinical cardiovascular biomarkers or advanced imaging, this risk score is readily integrable into bedside practice or electronic health record systems and may identify patients who would benefit from therapeutic interventions."

To develop the risk score -- called WATCH-DM -- the team leveraged data from 8,756 patients with diabetes enrolled in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. These data included a total of 147 variables, including demographics, clinical information, laboratory data and more. The investigators used machine-learning methods capable of handling multidimensional data to determine the top-performing predictors of heart failure.

Over the course of almost five years, 319 patients (3.6 percent) developed heart failure. The team identified the 10 top-performing predictors of heart failure, which make up the WATCH-DM risk score: weight (BMI), age, hypertension, creatinine, HDL-C, diabetes control (fasting plasma glucose), QRS duration, myocardial infarction and coronary artery bypass grafting. Patients with the highest WATCH-DM scores faced a five-year risk of heart failure approaching 20 percent.

The study draws strength from its large sample size and the high rate of heart failure, but the authors note that their findings may be constrained by certain limitations. ACCORD was conducted between 1999 and 2009, and predictors of heart failure may have evolved since the trial's conclusion. In addition, while the risk score was accurate in predicting one form of heart failure -- that with reduced ejection fraction -- it fell short for predicting a second form of heart failure -- that with preserved ejection fraction. Future studies will be needed to develop specific risk scores for predicting the latter among the general population and among patients with diabetes.

Importantly, the WATCH-DM risk score is now available as an online tool for clinicians to use. As a next step, the research team is working to integrate the risk score into electronic health record systems at both the Brigham and UT Southwestern to facilitate its practical use.

In addition to the tool's usefulness for clinicians, Vaduganathan also sees a key message from the study for patients with diabetes who are concerned about their risk of heart failure.

"It's important to look at these 10 variables and reflect on them," said Vaduganathan. "For individual patients, these are important messages to think about when assessing personal risk. BMI was one of the top predictors of heart failure risk, which reinforces the idea that long-term excess weight may increase future risk for heart failure. We hope this work highlights ways to intervene -- both through lifestyle changes and through the use of SGLT2 inhibitors -- to delay or even entirely prevent heart failure."

"This risk tool is an important step in the right direction to promote prevention of heart failure in patients with type 2 diabetes. It can be readily used as part of clinical care of patients with type 2 diabetes and integrated with the electronic medical records to inform physicians about the risk of heart failure in their patients and guide use of effective preventive strategies," said Ambarish Pandey, MD, MSCS, a preventive cardiologist at UT Southwestern and the senior author of this study.

New technological devices are prioritizing non-invasive tracking of vital signs not only for fitness monitoring, but also for the prevention of common health problems such as heart failure, hypertension, and stress related complications, among others. Wearables based on optical detection mechanisms are proving an invaluable approach for reporting on our bodies inner workings and have experienced a large penetration into the consumer market in recent years. Current wearable technologies, based on non-flexible components, do not deliver the desired accuracy and can only monitor a limited number of vital signs. To tackle this problem, conformable non-invasive optical-based sensors that can measure a broader set of vital signs are at the top of the end-users' wish list.

In a recent study published in Science Advances, ICFO researchers have demonstrated a new class of flexible and transparent wearable devices that are conformable to the skin and can provide continuous and accurate measurements of multiple human vital signs. These devices can measure heart rate, respiration rate and blood pulse oxygenation, as well as exposure to UV radiation from the sun. While the device measures the different parameters, the read-out is visualized and stored on a mobile phone interface connected to the wearable via Bluetooth. In addition, the device can operate battery-free since it is charged wirelessly through the phone.

"It was very important for us to demonstrate the wide range of potential applications for our advanced light sensing technology through the creation of various prototypes, including the flexible and transparent bracelet, the health patch integrated on a mobile phone and the UV monitoring patch for sun exposure. They have shown to be versatile and efficient due to these unique features", reports Dr. Emre Ozan Polat, first author of this publication.

The bracelet was fabricated in such a way that it adapts to the skin surface and provides continuous measurement during activity (see Figure 1). The bracelet incorporates a flexible light sensor that can optically record the change in volume of blood vessels, due to the cardiac cycle, and then extract different vital signs such as heart rate, respiration rate and blood pulse oxygenation.

Secondly, the researchers report on the integration of a graphene health patch onto a mobile phone screen, which instantly measures and displays vital signs in real time when a user places one finger on the screen (see Figure 2). A unique feature of this prototype is that the device uses ambient light to operate, promoting low-power-consumption in these integrated wearables and thus, allowing a continuous monitoring of health markers over long periods of time.

ICFO's advanced light sensing technology has implemented two types of nanomaterials: graphene, a highly flexible and transparent material made of one-atom thick layer of carbon atoms, together with a light absorbing layer made of quantum dots. The demonstrated technology brings a new form factor and design freedom to the wearables' field, making graphene-quantum-dots-based devices a strong platform for product developers. Dr. Antonios Oikonomou, business developer at ICFO emphasized this by stating that "The booming wearables industry is eagerly looking to increase fidelity and functionality of its offerings. Our graphene-based technology platform answers this challenge with a unique proposition: a scalable, low-power system capable of measuring multiple parameters while allowing the translation of new form factors into products."

Dr. Stijn Goossens, co-supervisor of the study, also comments that "we have made a breakthrough by showing a flexible, wearable sensing system based on graphene light sensing components. Key was to pick the best of the rigid and flexible worlds. We used the unique benefits of flexible components for vital sign sensing and combined that with the high performance and miniaturization of conventional rigid electronic components."

Finally, the researchers have been able to demonstrate a broad wavelength detection range with the technology, extending the functionality of the prototypes beyond the visible range. By using the same core technology, they have fabricated a flexible UV patch prototype (see Figure 3) capable of wirelessly transferring both power and data, and operating battery-free to sense the environmental UV-index. The patch operates with a low power consumption and has a highly efficient UV detection system that can be attached to clothing or skin, and used for monitoring radiation intake from the sun, alerting the wearer of any possible over-exposure.

"We are excited about the prospects for this technology, pointing to a scalable route for the integration of graphene-quantum-dots into fully flexible wearable circuits to enhance form, feel, durability, and performance", remarks Prof. Frank Koppens, leader of the Quantum Nano-Optoelectronics group at ICFO. "Such results show that this flexible wearable platform is compatible with scalable fabrication processes, proving mass-production of low-cost devices is within reach in the near future."

Boston, MA -- Three-quarters of older adults with a serious illness visit the emergency department during the last six months of their lives. Many will be admitted to the hospital. Some will never leave. But only a minority of patients have a conversation with their physician about preferences for end-of-life care before it is too late in their disease course for their wishes to be expressed. Identifying patients at greatest risk of near-term death early enough to engage in these conversations could both improve patients' experiences and drive down health care costs. Investigators from Brigham and Women's Hospital have analyzed whether the "surprise" question, which elicits a clinician's overall clinical impressions about a patient, can help emergency clinicians identify older patients at greatest risk of death. Worded as, "Would you be surprised if this patient died in the next month?" this question was required of emergency clinicians treating patients at Maine Medical Center. Investigators found a strong correlation -- if a physician or physician assistant answered that they would not be surprised, the patient was twice as likely to die in the next month. But they also found low sensitivity, meaning that clinicians only captured a small proportion of patients who actually died in the next month using the "surprise" question. Despite its low sensitivity, the "surprise" question may be a valuable tool for helping identify at-risk patients and prompting end-of-life conversations. The study's findings are published in JAMA Network Open.

"In order to best help our patients nearing the end of life, we need ways to identify patients who should be offered palliative care consultation or have serious illness conversations as soon as they are admitted," said corresponding author Kei Ouchi, MD, MPH, a physician in Emergency Medicine at the Brigham. "One of the advantages to the 'surprise' question is that it can provoke a conversation about palliative care -- if a physician answers, 'No, it would not surprise me if my patient died,' the next thought naturally is, 'What am I going to do about that?'"

Ouchi and colleagues analyzed data from a prospective cohort of 10,737 older adults. Their data included answers from 16,223 visits (some patients were seen more than once). Patients were 65 years or older, received care in the Emergency Department and were subsequently admitted to Maine Medical Center from Jan. 1, 2014 to Dec. 31, 2015. Of these patients, 8 percent (893) died in the next month.

Emergency clinicians stated that they "would not be surprised" if the patient died in the next month for 2,104 of the patients. Controlling for age, sex, race, diagnosis and other variables, these patients were 2.4 times as likely to die as those for whom clinicians had said that they would be surprised.

The surprise question demonstrated 20 percent sensitivity and 93 percent specificity: clinicians accurately predicted death 685 times in the next month and inaccurately predicted death 2,639 times for that same timeframe; they accurately predicted that patients would live beyond one month 12,003 times and inaccurately predicted they would live that long 896 times. Overall, clinicians were 78 percent accurate in their predictions.

The authors note that their data are from a single, urban academic medical center with a largely white patient population, which may limit the generalizability of the findings. They also note that the study included physicians and physician assistants, and that looking more broadly to include other members of the clinical team, such as nurses, may help to improve the reliability and scalability of the surprise question.

"We need to shift our thinking about end-of-life care," said Ouchi. "Having earlier conversations with our patients has the potential to change downstream care. Patients who have serious illness conversations experience a 36-percent reduction in the cost of end-of-life care, with an average cost savings of $1,041 in the last week of life. Having tools at our disposal to identify patients at greater risk could allow us to have these conversations sooner and change what end-of-life care looks like in this country."

Researchers at the Complutense University of Madrid (UCM) have identified changes in retinal layer thickness, inflammation or thinning in patients with mild Alzheimer's disease, confirming that the retina is one of the most important biomarkers for early diagnosis of the disease.

For the first time, researchers have determined the shape and size of the areas that present significant thinning in each retinal layer, which tend to occur in the same locations.

They also observed that in some patients already diagnosed with Alzheimer's disease, the retinal layers presented neurodegeneration, whereas in others they presented neuroinflammation, the stage prior to neurodegeneration, a finding which can be used to diagnose the disease before other tests.

"The novelty of our results is that in the early stage of the disease represented by our patient sample, neural layer thinning systematically predominated over thickening, as regards both percentage of thinned surface and neural volume lost", announced Luis Jáñez, a researcher at the Knowledge Technology Institute at the Complutense University of Madrid and first author of the study.

The results of this investigation, which have recently been published in Scientific Reports, confirm that due to the retina's features in common with the brain and accessibility using non-invasive techniques, it constitutes one of the most important and promising biomarkers for further study of this complex neurodegenerative disease.

"In recent years, ground-breaking studies have used the eyes as a window onto the brain to detect the changes that occur during the early stages and progression of Alzheimer's disease", explained Elena Salobrar-García, a scientist at the Ramon Castroviejo Ophthalmology Research Institute at the Complutense University of Madrid and co-author of the study.

The macular zone is the first to present changes

Researchers at the Knowledge Technology Institute and the Ramon Castroviejo Ophthalmology Research Institute --both at the Complutense University-- have developed new techniques and analytical tools that have enabled them to confirm that "the first changes appear in the macular zone, which is the most sensitive area and controls central vision and colour perception", noted José Manuel Ramírez, director of the Ramon Castroviejo Institute.

The study was conducted with a group of 19 patients selected from 2124 clinical histories at the San Carlos Hospital Clinic Geriatric Service in Madrid. These patients had very early stage Alzheimer's disease and did not present any other disease that affected the retina. The study also included a control group comprising 24 volunteers similar in age and other characteristics but without any relevant disease.

A three-dimensional image of a square region measuring 6x6 mm was obtained for each participant's retina, using optical coherence tomography (OCT). "With OCT, a light beam can sweep this area of the retina in 2.5 seconds. This frequently used technique is non-invasive, very fast and low-cost", Salobrar indicated.

Afterwards, using software designed specifically for this study, the thickness of each retinal layer was measured at 262,144 points distributed over a grid of 512 columns and as many rows. "Using statistical techniques based on Gaussian random field theory, we determined for the first time the exact shape, size and location of the areas affected by the disease in each retinal layer", added Jáñez.

In order to compare changes in thickness in different layers, the researchers developed software capable of performing exact arithmetic operations with the huge whole numbers generated by combining the hundreds of thousands of points sampled in each layer.

"The results of our study represent a breakthrough for the diagnosis and follow-up of Alzheimer's disease and confirm that the retina is a good biomarker", the researchers concluded.

Certain drugs used to treat retinal diseases are excreted into breast milk, raising possible safety concerns for developing infants, suggests a first-of-its-kind study led by St. Michael's Hospital in Toronto and published in Ophthalmology.

Ranibizumab and aflibercept are medications used to treat several retinal diseases. They contain an agent called anti-vascular endothelial growth factor (anti-VEGF), which blocks the eye's production of vascular endothelial growth factor (VEGF). VEGF is a protein that stimulates the development of blood vessels but is associated with retinal diseases in high quantities.

VEGF is present in breast milk and plays an important role in the development of an infant's digestive system. As a result, anti-VEGF drugs in a nursing mother raise concerns about possible adverse events in a developing infant if the drugs were to pass into breast milk and suppress VEGF.

"As retina specialists, we often tell our pregnant or nursing patients that there's a risk of a small amount of these drugs making its way into the breast milk, but we can't be sure," said Dr. Rajeev Muni, co-lead author, a vitreoretinal surgeon at St. Michael's and a project investigator at the hospital's Li Ka Shing Knowledge Institute.

"We don't want these patients to lose their vision so we make a decision, despite limited information."

Hoping to change this, Dr. Muni and Dr. Verena Juncal, co-lead author and a retinal fellow at St. Michael's, measured the concentrations of retinal medications in the breast milk of three lactating patients following injection of anti-VEGF therapy. Each patient represented a different scenario - one continued to breastfeed while receiving therapy, one discontinued breastfeeding, and one never started.

The team found that the drugs were excreted into the breast milk within the first couple days following injection, with a corresponding reduction in VEGF levels.

They also found that the amount of medication detected in the patient who continued to breastfeed was significantly lower than the other two patients, suggesting that the medication was constantly excreted and ingested by the infant.

"These results definitively show us that the drug reaches the breast milk," said Dr. Juncal. "We realize that some readers may question the small sample size, but if the drug reaches the breast milk in three patients, it'll reach in 30 patients because it's the same biological process."

As the first study to evaluate the presence of Health Canada approved anti-VEGF therapy in human breast milk, these results provide a resource for ophthalmologists and retina specialists counselling pregnant and nursing patients.

"I'm comforted knowing that other pregnant or nursing mothers with retinal diseases will have the information needed to make an educated decision about whether to consider nursing while receiving these medications," said Lisa, one of the three study participants, who didn't want to reveal her surname.

Next, the researchers hope to collaborate with a team of paediatricians to find out whether the drug passes from the breast milk through the infant's digestive system and into the blood stream.

"If we can measure the levels of these drugs in the infant's blood, we can figure out the exposure over a long period of time," said Dr. Muni. "That's what's really important here - the possible effect of these drugs on the infant over a long period of time."

An international research team has developed a new strategy that can predict the potential clinical implications of new therapeutic compounds based on simple cellular responses. This discovery was partly led by scientists affiliated with Université de Montréal (UdeM), and represents a major step forward in developing more effective drugs with fewer side effects, much faster than before. The researchers conducted their work at Centre de Recherche de l'Hôpital Ste-Justine and published their findings in the prestigious journal Nature Communications.

Developing new drugs is a long, complex and costly process. It starts with identifying the molecule or "ligand" (such as a drug, hormone or neurotransmitter) that can activate or block the target or "receptor" involved in a disease. Compound identification and validation is one of the most important steps in ensuring that a new drug provides an effective clinical response with the fewest possible side effects.

"Most new drugs tested on human subjects fail in clinical trials because the therapeutic response is insufficient. Developing a strategy that infers potential clinical responses early in the drug discovery process would significantly improve drug candidate selection," said Besma Benredjem, the study's co-lead author and a doctoral student in pharmacology at UdeM.

Finding the needle in a haystack

"Our main goal was finding a way to categorize a large number of drug candidates based on similarities in their effectiveness in triggering a multiplicity of cellular responses that help identify the therapeutic action of new compounds," said Professor Graciela Piñeyro, co-senior author of the study and a researcher at CHU Sainte-Justine. To accomplish this, she worked with Dr. Olivier Lichtarge of Baylor College of Medicine, who uses advanced bioinformatic analysis to compare and group ligands according to fairly comprehensive signalling profiles.

Drugs produce desired or undesired clinical actions by changing basic signals within cells. By grouping drugs with known clinical actions and new ligands, we can infer the clinical actions of new compounds by comparing the similarities and differences in their signals with known drugs to promote desired clinical responses and avoid side effects.

This method of analysis was developed by using opioid analgesics as prototypes. This made it possible for the team to associate simple cellular signals produced by opioids such as oxycodone, morphine and fentanyl with the frequency with which respiratory depression and other undesirable side effects of these drugs were reported to the Food and Drug Administration's pharmacovigilance program. At the height of the opioid epidemic, when the risk of death by respiratory depression is at its highest, the team believes this new analytical strategy could lead to the development of safer opioids.

"Thanks to our findings, we can now classify a large number of compounds while taking a multitude of cellular signals into account. The wealth of comparisons this provides increases this classification's predictive value for clinical responses," said Professor Michel Bouvier, the study's co-senior author and a principal investigator of molecular pharmacology and Chief Executive Officer of UdeM's Institute for Research in Immunology and Cancer. "We think we can help patients by speeding up the drug discovery process so clinical trials can start earlier."

"Our next goal is to use a similar approach to test cannabis products that may produce harmful neuropsychiatric actions among young people, and identify which cannabis extracts are most effective at treating chronic pain," added Besma Benredjem.

Boston - A new study identifies specific locations where medication and harm reduction services for people with opioid use disorder should be available in order to have the greatest impact on reducing opioid overdose deaths. Led by researchers at Boston Medical Center's Grayken Center for Addiction, the data show that more than half of those who died of an opioid overdose in Massachusetts encountered the health care, public health and/or criminal justice systems within the 12 months prior to their fatal overdose. These results, published in Drug and Alcohol Dependence, provide a roadmap to better reach these individuals at high risk of overdose and provide treatment and harm reduction services in order to reduce the number of overdose deaths.

For this retrospective cohort study, researchers set out to determine how and where individuals encounter the health care, criminal justice and public health systems in the 12 months prior to their fatal overdose. In collaboration with Massachusetts Department of Public Health, researchers examined eight data sets for persons over the age of 11 in Massachusetts between January and December 2014 with health insurance, as identified in the All-Payer Claims Database.

The researchers determined the relative mortality risk related to opioid overdose deaths through eight potential "touchpoints." Four opioid prescription touchpoints included individuals: taking high doses of opioids; co-prescribed opioids and benzodiazepines; and receiving or filling opioid prescriptions from multiple providers or multiple pharmacies. Four critical encounter touchpoints included individuals who: attended an opioid detoxification program; received medical attention for a nonfatal opioid overdose; sought treatment for an infection related to their injection drug use; or were recently released from incarceration.

Of 1,315 individuals who died from opioid overdose in 2014, 51.8 percent had at least one of the eight potential touchpoints with the health care, criminal justice or public health system in the 12 months prior to their death. Specifically, 20.5 percent of those who died of an overdose had an opioid prescription touchpoint encounter, and 37.3 percent had a critical encounter touchpoint. Of importance, the researchers note, is that overdose death was 12.6 times and 68.4 times more likely for individuals who had an opioid prescription and critical encounter touchpoint, respectively, compared to individuals who did not have a touchpoint.

"These data show that while opioid prescribing stewardship is an important goal, there are additional missed opportunities to provide harm reduction services and treatment for individuals at high-risk of opioid overdose death," said Marc Larochelle, MD, MPH, the study's lead author and a primary care physician specializing in addiction at Boston Medical Center. "We need to focus our efforts on ensuring that on-demand medication and harm reduction services, including overdose education and naloxone distribution, is available in these locations during these critical times so that we have the opportunity to reduce their risk of death by overdose."

In particular, individuals who were taking a high-dose of an opioid prescription had the highest mortality rates in the opioid prescription group, and those who experienced a nonfatal overdose had the highest risk of death by a future opioid overdose in the critical encounter group.

"If we can effectively deploy more targeted interventions that can reach those at highest risk of opioid overdose, we have the potential to eliminate up to 50 percent of those deaths in Massachusetts," said Larochelle, who also is assistant professor of medicine at Boston University School of Medicine.

"The opioid epidemic is claiming far too many lives in Massachusetts and across the country," said Public Health Commissioner Monica Bharel, MD, MPH. "We must continue to use data to focus our efforts where they are most effective, in partnership with researchers from academic, nonprofit, private and government agencies to respond to the opioid crisis."

Systemic lupus erythematosus, a chronic autoimmune disease commonly referred to as lupus or SLE, has been compared to volatile, unprovoked brawls within the body.

The disease, which has no cure, operates much like an allergic reaction gone awry: When activated, the immune system also attacks the body's healthy cells, tissues, and organs, causing inflammation and producing a host of symptoms that, though unique to each person, are universally called flares.

A highly gender-biased disease, lupus afflicts females some nine times more than males. Because of the disease's unpredictable turns and debilitating flares -- the risks of which are elevated in postpartum women -- females with the disease are often advised to avoid pregnancy altogether.

To understand this higher risk of severe flares and ultimately help women with lupus experience healthy pregnancies and successful outcomes, a team of researchers in the Department of Biomedical Sciences and Pathobiology (DBSP) at the Virginia-Maryland College of Veterinary Medicine explored the possible role of gut microbiota in the link between pregnancy and the exacerbation of lupus. The team's findings, "Pregnancy and lactation interfere with the response of autoimmunity to modulation of gut microbiota," were recently published in the online journal Microbiome.

"There are 38 trillion bacteria living in the gut of an average person, collectively called the gut microbiota," said Xin M. Luo, associate professor of immunology in DBSP and lead author of the paper with Qinghui Mu, formerly a DBSP postdoctoral fellow and now a postdoctoral research fellow in immunology and rheumatology at Stanford University School of Medicine. "Disturbance of the gut microbiota exists in the pathogenesis of many autoimmune diseases, including lupus." Identifying gut microbiota's role in heightened flares among pregnant women with lupus, however, was uncharted territory.

Working with the lead authors as members of the DBSP research team were Ph.D. student Xavier Cabana-Puig; visiting scholar Jiangdi Mao; Ph.D. student Leila Abdelhamid; clinical associate professor of anatomic pathology Thomas E. Cecere; Translational Biology, Medicine, and Health Graduate Program Ph.D. student Brianna Swartwout; Professor Haifeng Wang of the College of Animal Science at Zhejiang University, China; and Professor Christopher M. Reilly, discipline chair for cellular biology and physiology at the Edward Via College of Osteopathic Medicine.

Supported by the National Institutes of Health grants AR073240 and AR067418, the research team examined the changes of gut microbiota structure with or without the experience of pregnancy, as well as the differential responses of the immune system to the same microbiota-modulating strategies in unaffected versus postpartum lupus-prone mice. The results indicate that the strategies benefitting the unaffected mice actually worsened lupus disease in postpartum mice.

"Our findings suggest that the gut microbiota may regulate lupus flares in pregnant women," Luo said of the team's research. "Our work helps to uncover the mechanisms underlying pregnancy-induced disease flares and offers the possibility of developing new therapeutic strategies for pregnant women with lupus."

The ultimate goal of her team's research, Luo explains, is to identify beneficial and pathogenic gut bacterial species and to develop therapeutic strategies that modulate the gut microbiota community toward a beneficial effect.

"For patients with autoimmune lupus, diet and probiotics are the two relatively easy and acceptable approaches that can potentially improve disease management through modulating the gut microbiota," Luo said. "But it is challenging to achieve this goal due to the complexity of the disease pathologies, the complexity of gut microbiota, and the differences of gut microbiota communities among individuals."

For its next steps, the research team plans to investigate the interaction between sex hormones and gut microbiota in regulating lupus pathogenesis. "Women experience hormonal changes, which include sex hormones, during pregnancy and postpartum," said Luo. "In addition, lupus has a strong female bias, suggesting a role for sex hormones in the disease."

According to Luo, future investigations will focus on lupus nephritis, the leading cause of mortality in lupus patients, to further delineate the role of gut microbiota in the link between pregnancy and exacerbated lupus.

Sept. 13, 2019--In patients with high blood pressure resistant to treatment who also have obstructive sleep apnea (OSA), the more severe their OSA, the higher their blood pressure, according to new research published online in the Annals of the American Thoracic Society.

In "Prevalence, Characteristics and Association of Obstructive Sleep Apnea with Blood Pressure Control in Patients with Resistant Hypertension," Esther Sapiña-Beltrán and colleagues report on a study conducted in 284 patients, ages 18 to 75, who were treated at hospitals in three countries--Spain, Singapore and Brazil--for resistant hypertension (RH). Of all patients with high blood pressure, those with RH, which requires three or more drugs to control, are at greatest risk for a heart attack or other cardiovascular event.

"We believe that OSA plays an important role in the pathogenesis and prognosis of patients with resistant hypertension," said senior author Mireia Dalmases Cleries, MD, a pulmonologist and sleep researcher at the Hospital Universitari Arnau de Vilanova, in Lleida, Spain. "Our study shows a dose-response association between OSA severity and blood pressure, especially during the nighttime period."

The study found:

* 83.5 percent of patients with resistant hypertension had OSA, including 31.7 percent with mild OSA, 25.7 percent with moderate OSA and 31.5 percent with severe OSA.

* OSA was slightly more likely in men than women: 86.3 percent vs. 76 percent; however, the men were twice as likely to have severe OSA.

* As the severity of OSA increased, ambulatory blood pressure increased, particularly at night. The average nighttime ambulatory blood pressure was 5.72 mmHg higher in those with severe OSA compared to those without OSA.

According to the authors, high blood pressure at night is a stronger predictor of cardiovascular risk than those whose blood pressure is high during the day. Because the study is not a randomized, controlled trial it cannot prove cause and effect. The authors also note that because only patients with resistant hypertension were included in the study, the findings cannot be generalized to other patients with high blood pressure.

Dr. Dalmases Cleries said these findings were derived from an ancillary study of the SARAH project. The project is evaluating the impact of OSA and continuous positive airway pressure (CPAP), the gold standard for OSA treatment, on cardiovascular outcomes over five years of follow-up in what is expected to be the largest group of participants with RH and a sleep assessment.

Even before the results of SARAH are known, Dr. Dalmases Cleries said that "considering the high prevalence of OSA in resistant hypertensive subjects and findings from previous studies which show that treating OSA with CPAP can lower blood pressure, clinicians should consider performing a sleep study in patients with resistant hypertension."

Melbourne researchers have discovered that the key to personalised therapies for some types of lung cancers may be to focus on their differences, not their similarities.

More than one in three lung cancers called adenocarcinomas have a common-cancer causing mutation in the gene KRAS, which is a potent cancer driver. Yet decades of attempts to develop a therapy that targets this gene have been unsuccessful.

Now scientists from the Walter and Eliza Hall Institute have shown that co-existing mutations in these cancers can give the tumour distinctive characteristics which they have successfully targeted to inhibit cancer growth. The study suggests this tactic should be investigated for targeted treatment of KRAS-positive human lung adenocarcinomas.

At a glance

Targeted or 'personalised' cancer treatments are not available for people with KRAS-positive lung cancers (adenocarcinomas).

Institute researchers identified that KRAS-positive lung tumours had different 'traits' depending on underlying co-mutations.

Strategies to target and block these cancer-related traits significantly slowed the growth of lung tumours, opening new strategies to target these cancers.

Targeting tumour traits

Lung cancer researchers Dr Kate Sutherland and Dr Sarah Best from the Walter and Eliza Hall Institute led the research, which was published today in the journal Nature Communications.

Dr Best said the researchers were surprised to find that co-existing mutations could play such a significant role in the characteristics of some lung cancers. "In this study, we showed that KRAS-positive lung adenocarcinomas looked and behaved very differently depending on co-existing mutations in the tumour," Dr Best said.

"Cancers with a co-mutation in the gene TP53 were flooded with immune cells, while tumours with a co-mutation in the gene KEAP1 changed their metabolism, how they make energy to fuel the tumour cell. We exploited these unique tumour traits, either by depleting the immune cells in tumour tissue or blocking the energy-producing machinery, and this proved effective in inhibiting tumour progression."

Targeted therapies to deplete immune cells or inhibit metabolic machinery were being explored in human trials for other types of cancers, Dr Best said. "Our study suggests that some patients with KRAS-positive lung adenocarcinomas could benefit from targeted therapies that exploit the differences, rather than the similarities, in these tumours. This could make a real difference for patients with these lung cancers."

Targeted treatments a game-changer

In the past few decades, there has been an explosion in the development of targeted therapies for cancer. Targeted cancer therapies have transformed treatment and survival for people with diseases including breast, blood, skin and bowel cancers.

Unfortunately for people with KRAS-positive lung cancers, targeted therapies have been elusive said Dr Sutherland.

"Researchers and pharmaceutical companies have been searching for decades for an effective therapy that targets KRAS, but have been unsuccessful. KRAS is considered 'undruggable' so we decided to look for alternative ways of attacking these cancers based on other tumour traits," Dr Sutherland said.

Dr Sutherland said understanding the nuances in tumour development was very important when trying to develop personalised therapies. "Our study suggests that a one-size-fits-all therapy would not be effective for all people with KRAS-positive lung cancers," she said.

A unique approach

The researchers studied the cancers in preclinical models and confirmed the findings in donated human lung cancer tissues from patients, in collaboration with Associate Professor Gavin Wright from St Vincent's Hospital.

"We are confident that our models reflect what is happening in patients. And the benefit of the models is that they can be used for preclinical testing of potential therapeutics, to evaluate if they show promise for treating patients," Dr Sutherland said.