Body

Researchers have discovered key mechanisms and structural details of a fundamental biological process--how a cell nucleus and its chromosomal material reorganizes itself after cell division. The new findings in chromosomal architecture and function may offer important insights into human health and disease.

"During mitosis, as a cell divides into two daughter cells, virtually all the genes are temporarily turned off, and the intricate structures in chromatin fibers, the substance of chromosomes, are disrupted," said study leader Gerd A. Blobel, MD, PhD, who holds the Frank E. Weise III Endowed Chair in Pediatric Hematology at Children's Hospital of Philadelphia (CHOP). "After mitosis, the daughter cells faithfully rebuild the complex chromatin structures within each cell nucleus."

In their study, published Nov. 27 in Nature, Blobel and colleagues describe the biological structures and dynamic forces that drive chromosome reorganization after mitosis.

Blobel said that, despite the critical importance of the cell cycle, in which cells grow and divide, few scientists previously investigated the mechanisms of chromatin rebuilding. "It's long been an open question in biology of exactly how the genome is organized in the nucleus. All the DNA bases in the genome of one cell, if uncoiled into a straight line, would extend for two meters. Yet this material is confined into a tiny space within each cell nucleus, and requires highly organized packaging."

Blobel and co-corresponding author Jennifer E. Phillips-Cremins, PhD, of the Department of Bioengineering at the University of Pennsylvania's School of Engineering and Applied Science, brought their respective teams together with colleagues from Pennsylvania State University, led by Ross C. Hardison, PhD, an expert in gene regulation and Blobel's longtime collaborator. The first author was Haoyue Zhang, PhD, of CHOP.

The research team performed their experiments in blood-forming cells from a well-established mouse model. They used sophisticated techniques called high throughput chromosome conformation capture (Hi-C) that detect and map interactions across three-dimensional space between specific sites in chromosomal DNA. These maps also allowed the scientists to measure such interactions at different time points in the cell cycle. In all, the tools detected roughly 2 billion interactions during mitosis and thereafter, when the daughter nuclei are rebuilt.

The study detected the formation of structures in chromatin: the appearance and expansion of transcriptionally active and silenced compartments; the creation of contact between regulatory regions of the genome; and changes in so-called architectural proteins called CTCF and cohesin that help sculpt the genome. "Our findings describe a dynamic hierarchical framework of the sequence by which chromosomes rebuild themselves after mitosis," said Blobel.

In addition to delineating a crucial process in cell biology, the research delved into what Blobel called "the complicated interplay between chromatin architecture and gene transcription." Transcription, the conversion of information encoded in DNA into its equivalent in RNA, temporarily stops during mitosis, but reactivates thereafter in the daughter cells. Because gene mutations that disrupt normal genome architecture or transcription can play a key role in disease, better understanding of chromatin architecture has potential clinical importance.

To take one example, researchers at CHOP and elsewhere have investigated cohesinopathies--defects in cohesin that cause subtypes of multisystem genetic disorders such as Cornelia deLange syndrome. "Abnormalities in chromatin-related structures are relevant to disease, so one implication of our study is that diseases that affect chromatin structures should be viewed through the lens of the cell cycle," said Blobel.

In summary, added Blobel, "the new study offers important insights into fundamental aspects of a key process in biology---chromatin organization over space and time."

CHICAGO - Artificial intelligence (AI) provides an automated and accurate tool to measure a common marker of heart disease in patients getting chest CT scans for lung cancer screening, according to a study presented today at the annual meeting of the Radiological Society of North America (RSNA).

Low-dose chest CT is approved for lung cancer screening in high-risk people, such as long-time smokers. While these CT scans are intended to diagnose lung cancer, coronary artery calcium, a measure of plaque in the arteries, is also visible on CT. The coronary artery calcium score derived from CT is a well-established measure that helps doctors decide who should get cholesterol-lowering preventive medications called statins.

"The new cholesterol guidelines encourage using the calcium score to help physicians and patients decide whether to take a statin," said study co-senior author Michael T. Lu, M.D., M.P.H., director of AI in the Cardiovascular Imaging Research Center (CIRC) at Massachusetts General Hospital (MGH) in Boston. "For select patients at intermediate risk of heart disease, if the calcium score is 0, statin can be deferred. If the calcium score is high, then those patients should be on a statin."

Despite its prognostic value, coronary artery calcium is not routinely measured in low-dose CT lung screening, as the measurements require dedicated software and add time to the interpretation.

"If our tool detects a lot of coronary artery calcium in a patient, then maybe we can send that patient to a specialist for follow up," said lead author Roman Zeleznik, M.Sc., B.Sc., from the Artificial Intelligence in Medicine (AIM) Program at Boston's Brigham and Women's Hospital (BWH) and Dana-Farber Cancer Institute. "This would make it easier for patients to get appropriate treatment."

The research team, which represents a close collaboration between MGH's CIRC and AIM at BWH, recently developed and tested a technique that uses deep learning, a sophisticated type of AI, to automatically measure coronary artery calcium on chest CT images. They trained the deep learning system on cardiac CTs and chest CTs in which the coronary artery calcium had been measured manually. They then tested the system on CT scans from thousands of heavy smokers, age 55-74, who were part of the National Lung Screening Trial (NLST), a major study that established CT's value in providing early detection of lung cancer.

The results showed that the deep learning-derived coronary artery calcium scores corresponded closely to those of human readers. In addition, there was a significant association between deep learning calcium scores and cardiovascular death over follow-up of 6.5 years.

"There's information about cardiovascular health on these CT scans," Dr. Lu said. "This is an automated way to extract that information, which can help patients and physicians make decisions about preventative therapy."

For instance, automated coronary calcium quantification could be used to segregate people into high- and low-risk groups.

The deep learning system runs in the background and adds no time to the exam. The system's ability to automate coronary calcium assessment could be a boon to research, as it can evaluate large numbers of patients in a much less time than it would take human readers.

It could also have value outside of the lung screening population. The research team has already demonstrated its effectiveness in people with stable and acute chest pain.

"We have a tool that in the future can be used on almost every chest scan to generate very clinically relevant information for a large number of patients," said study co-senior author Hugo Aerts, Ph.D., director of the AIM Program at BWH.

The research team has already demonstrated similar results in clinical trial populations in patients with stable (PROMISE Trial) and acute (ROMICAT trial) chest pain.

CHICAGO - Damage from concussion alters the way information is transmitted between the two halves of the brain, according to a new study presented today at the annual meeting of the Radiological Society of North America (RSNA).

Research has shown that the corpus callosum, a bundle of nerve fibers that carries signals between the brain's left and right hemispheres, is vulnerable to damage from mild traumatic brain injury, commonly known as concussion. Less is known about the impact of this damage on cognitive function.

To learn more, researchers at New York University (NYU) School of Medicine in New York City compared the condition of the corpus callosum in 36 patients with recent concussion to that of 27 healthy controls. They studied the participants' brains with two innovative advances, including an MRI technique that uses measures of water diffusion to provide a microscopic view of the brain's signal-carrying white matter.

"Looking at how water molecules are diffusing in the nerve fibers in the corpus callosum and within the microenvironment around the nerve fibers allows us to better understand the white matter microstructural injury that occurs," said study co-author Melanie Wegener, M.D., resident physician at NYU Langone Health in New York City.

Dr. Wegener and colleagues combined the MRI findings with results from the study's second innovative advance, called an Interhemispheric Speed of Processing Task, a test developed at NYU Langone that evaluates how well the two hemispheres in the brain communicate with each other.

For the test, the participants were told to sit in a chair and focus their gaze on the letter X that was displayed on a screen directly in front of them. The researchers then flashed three-letter words to the right or the left of the X and asked the participants to say those words as quickly as possible. When the researchers evaluated this reaction time in both patients with concussion and healthy controls, they noticed an interesting phenomenon.

"There is a definite and reproducible delay in reaction time to the words presented to the left of the X compared with words presented to the right visual field," Dr. Wegener said. "This shows it takes time for information to cross the corpus callosum from one hemisphere to the other, which is measured by the difference in response time between words presented to different sides of our visual field."

This delay is likely due to the fact that language function is most often located in the brain's left hemisphere. This means that information presented to the left visual field is first transmitted to the right visual cortex in the brain and then has to cross over the corpus callosum to get to the left language center. In contrast, words that are presented to the right visual field do not need to cross the corpus callosum.

Performance on the test correlated with brain findings on MRI. In the healthy controls, reaction time corresponded with several diffusion measures in the splenium, an area of the corpus callosum located between the right visual cortex and the left language center. No such correlation was found in the concussion patients, suggesting microstructural changes relating to injury.

"We saw a correlation between white matter microstructure injury and the clinical status of the patient," Dr. Wegener said. "This information could ultimately help with treatment in patients who have mild traumatic brain injury."

For instance, Dr. Wegener said, patients could undergo MRI immediately after a concussion to see if they experienced any clinically important white matter injury and thus may benefit from early intervention.

"Another thing we can do is use MRI to look at patients' brains during treatment and monitor the microstructure to see if there is a treatment-related response," she said.

CHICAGO - MRI illuminates abnormalities in the brains of people with depression, potentially opening the door to new and improved treatments for the disorder, according to two studies presented this week at the annual meeting of the Radiological Society of North America (RSNA).

Major depressive disorder (MDD) is one of the most common and debilitating mental disorders worldwide. Symptoms include feelings of hopelessness, diminished interest in daily activities, and fatigue. Limited understanding of the brain changes associated with MDD hinders the effectiveness of treatments.

"Unfortunately, with current treatments there is a large chance of relapse or recurrence," said Kenneth T. Wengler, Ph.D., from Columbia University in New York City and co-author of one of the studies. "To develop new, more effective treatments, we must improve our understanding of the disorder."

Dr. Wengler and colleagues at the Renaissance School of Medicine at Stony Brook University in Stony Brook, N.Y., recently studied connections between MDD and disruptions in the blood-brain barrier (BBB), a network of blood vessels and tissue that protects the brain from foreign substances. Using a new MRI technique they developed called intrinsic diffusivity encoding of arterial labeled spins (IDEALS), they looked at BBB water permeability, or the movement of water out of the blood vessels and into the brain tissue.

Comparison of results in 14 healthy individuals and 14 MDD patients found that less water moved from inside the blood vessels to outside in the MDD patients, representing disrupted BBB integrity. This difference was particularly large in two regions of the brain: the amygdala and the hippocampus.

"We observed disruption of the blood-brain barrier in gray matter regions known to be altered in major depressive disorder," Dr. Wengler said. "This study helps improve our understanding of the pathophysiology of depression and can open new avenues of treatment for a disorder that affects over 100 million individuals worldwide."

A second study presented at RSNA 2019 looked at abnormalities in the complex network of connections in the brain known as the connectome for their role in depression. Previous research has focused on characterizing the connections between different brain regions, but this study, from researchers at the University of North Carolina (UNC) in Chapel Hill, N.C., looked deeper within individual brain regions.

The researchers compared 66 adults with MDD and 66 matched healthy controls during wakeful rest using functional MRI (fMRI) and a newly developed multiscale neural model inversion framework that linked the brain's microscopic circuitry with its larger-scale interactions. As part of the study, the researchers were able to assess excitatory or inhibitory influence between neuronal cell groups. A proper balance between excitation and inhibition is crucial to a well-functioning brain.

Patients with MDD had abnormal patterns of excitation and inhibition at the dorsal lateral prefrontal cortex, a brain area important to cognitive control functions, including the regulation of the amygdala, a key region embedded deep in the brain for expression of emotion. It has long been hypothesized that malfunctioning inhibitory control over the amygdala could result in depressive symptoms.

"In our study, we found that excitation and inhibition in the brain regions in control of executive functions and emotional regulation were reduced in patients with MDD," said study co-author Guoshi Li, Ph.D., from the Image Display, Enhancement and Analysis (IDEA) group at UNC. "This suggests that control functions in MDD are impaired, which may lead to elevated responses in the amygdala, resulting in increased anxiety and other negative moods."

In addition, the researchers found that recurrent excitation in the thalamus, an area of the central brain that is also responsible for emotional regulation, was abnormally elevated in patients with MDD.

Dr. Li said the new approach could open the door for a deeper understanding of the mechanisms behind depression.

"Current methods of studying the brain provide a superficial understanding of connectivity," Dr. Li said. "This method allows us to identify impaired connectivity within each brain region, making it a potentially more powerful tool to study the neuromechanism of brain disorders and develop more effective diagnosis and treatment."

CHICAGO - More than half of people who received X-rays or CT scans after electric scooter accidents were found to have injuries, most commonly to the upper extremities, according to a new study presented today at the annual meeting of the Radiological Society of North America (RSNA). Researchers said the findings underscore the need for more public education on the use of these scooters.

Dockless electric motorized rental scooters, also known as e-scooters, have exploded in popularity in recent years. E-scooters are familiar sights in urban areas and on college campuses, where users value them as an inexpensive, convenient and less strenuous alternative to bicycles.

The rapid growth of rental e-scooters in cities across the U.S. has sparked concerns, as hospital emergency departments have reported a growing number of injuries associated with the vehicles. Earlier this year, the Centers for Disease Control and Prevention (CDC), in association with Austin Public Health, released a study assessing the potential public health impact of e-scooter use.

"E-scooters have a narrow platform, can travel up to 15 to 20 miles per hour and require a level of coordination and skill that is often not native to many users," said study co-author Aiza Ashraf, M.D., diagnostic radiology resident at the Indiana University School of Medicine in Indianapolis. "Whereas physical effort is required to get a bicycle up to speed, e-scooters are self-powering."

Imaging exams for e-scooter accidents spiked at Indiana University Health System after the scooters were legalized in Indianapolis in September 2018. To find out more about this trend, Dr. Ashraf, Mohsin Mukhtar, M.D., and colleagues at Indiana University School of Medicine, studied electronic medical records and radiology archives of people ages 18 and older who had exams ordered for scooter-related injuries over a five-year period.

The researchers identified 69 exams performed on 36 unique Emergency Department patients with involvement of an e-scooter. There were 19 males and 17 females included in the study, and two-thirds were in the 18-30 age range. X-rays of the extremities and CT of the head, face and cervical spine were the most common exams ordered.

Nineteen of the 36 patients were found to have a radiographically apparent injury. The most common injuries involved the upper extremities, particularly the wrist. There were six cases of distal radial fractures, or fracture of the forearm bone close to the wrist, making it the most common injury in the study group. Soft tissue injuries of the head, face, wrist and ankle, were present in five cases.

"We believe that many users are not fully aware of the potential significant injuries that may occur with e-scooter use," Dr. Mukhtar said. "Raising awareness and doing further research on this topic could inform future policy."

The study findings highlight the importance of protective equipment such as helmets and hand/wrist guards, researchers said, along with the potential dangers of riding while under the influence of intoxicating substances. In addition, the study suggests that communities should consider imposing speed limits on e-scooter users.

"Limiting e-scooter speed could reduce the overall incidence and severity of injuries in the event of a fall or collision," Dr. Ashraf said. "And since these e-scooters could be viewed as a potential public health hazard, we would recommend public education on the use of these devices."

The study also found a lack of adequate and specific documentation of scooter type in the emergency medical records. More than 200 instances found in the search may have been e-scooter-related, but lack of documentation in the records prevented the researchers from making a definitive link.

"A robust ability for more systematic data collection and analysis, for example, performed as a multi-institutional public health study, may be of benefit," Dr. Mukhtar said.

A new approach to treating people with cystic fibrosis (CF) has been shown to reduce inflammation, which has the potential to reduce the need for lung transplants and lower the risk of death.

The study, led by researchers at RCSI (Royal College of Surgeons in Ireland), is published in the current edition of the American Journal of Respiratory and Critical Care Medicine.

CF is a genetic disease that affects about 1,300 children and adults in Ireland and 70,000 worldwide. The main cause of death in people with CF is lung disease, which is driven by severe inflammation and chronic infection in the airways.

While recent years have seen the emergence of several new therapies aimed at improving lung function and survival, the lack of effective anti-inflammatory and anti-infective treatments for these individuals continues to represent a significant challenge.

The researchers found that one of the most aggressive bacteria found in the lungs of those with CF caused certain immune cells to change their metabolism. This change caused the immune cells to produce a protein that causes more inflammation. They identified that high levels of the protein were associated with worse lung function and a higher risk of death or need for a lung transplant.

The team then used a small molecule called MCC950 to reduce levels of the protein in a laboratory model of CF. In addition to reducing inflammation, this also helped clear the lungs of bacteria. This marks the first time that researchers were able to stop this protein in CF in vivo by targeting cell metabolism, which could potentially lead to a new approach to treating inflammatory diseases like CF.

"This is an important first step to significantly improving patient outcomes for people with cystic fibrosis. While more testing is required before delivering this to patients, we believe these results are very promising and could make this molecule a candidate for clinical trials," said Professor Gerry McElvaney, the study's joint senior author and Professor of Medicine at RCSI.

RCSI researchers, including joint senior and corresponding author Dr Emer Reeves, carried out the study in collaboration with the University of Duisberg-Essen and the Trinity Biomedical Sciences Institute. The research was funded by the StAR (Strategic Academic Recruitment) MD Programme, which aims to transfer impactful research discoveries to clinical practice more quickly for the benefit of patients.

"Previously, people with CF had a very low life expectancy. Due to improvements in medical treatment, these individuals are now living longer. However, they still suffer from a very severe disease. We hope that this advancement can lead to further improvements in outcome, better quality of life and eventually a normal life expectancy for our patients," said Dr Oliver McElvaney, the study's lead author.

SAN DIEGO, December 3, 2019 -- Ultrasound can be used to examine cervix tissue and improve diagnostics, which is essential for predicting preterm births. Ultrasound data is used to compare two techniques for evaluating changes in cervical tissue throughout pregnancy.

Researchers at the University of Illinois at Chicago and the University of Illinois at Urbana-Champaign will discuss ultrasound techniques used during pregnancy at the 178th Meeting of the Acoustical Society of America, held at the Hotel Del Coronado in San Diego. "Comparison of two spectral-based techniques for estimating the attenuation coefficient from human cervix" is part of a session on biomedical acoustics and the application of quantitative ultrasound in humans.

Ziyang Xu, Aiguo Han, Douglas G. Simpson, W.D. O'Brien, Jr. and Barbara L. McFarlin are looking at ultrasonic attenuation coefficients that can help scientists characterize cervical changes throughout pregnancy and in preparation for birth before other symptoms, such as contractions or dilation, occur. Researchers compared two methods of finding the ultrasonic attenuation coefficient: the spectral difference and the spectral log difference techniques.

"Our research is based upon the biology of cervical changes in preparation for labor and childbirth, namely collagen remodeling. Ultrasonic attenuation is sensitive to these changes, as during pregnancy the collagen fibers are tightly packed and have a high attenuation," said McFarlin. "In preparation for labor and birth, there is increased collagen disorganization, increased water content and inflammation of the cervix, with low ultrasonic attenuation."

After gathering data on the two ultrasound techniques, the authors identified which performed better when it came to detecting cervical changes.

"This ASA presentation primarily evaluates the agreement in attenuation coefficient estimates between the two spectral-based techniques without referring to clinical outcomes. Future research is needed to evaluate the two techniques in terms of the ability to improve clinical diagnostics," said Han.

Han's presentation 2pBAb9, "Comparison of two spectral-based techniques for estimating the attenuation coefficient from human cervix," will be at 3:50 p.m. PT, Tuesday, Dec. 3, in the Garden room of the Hotel del Coronado in San Diego.

The number of vitamin D supplement prescriptions written for children in primary care in the UK has surged 25-fold in under 10 years, reveals an analysis of family doctor (GP) prescribing data, published in the online journal BMJ Open.

Increasingly higher doses and an absence of a prior diagnostic blood test featured in a third to more than half of the annual prescriptions written, the analysis shows.

Vitamin D, which is usually sourced from sunlight and diet, is essential for healthy teeth, bones, and muscles. And several studies have linked low levels of the vitamin with various conditions, including diabetes, asthma, and eczema.

Yet most clinical trials have failed to show any meaningful impact of supplementation on improving health.

While severe vitamin D deficiency can cause rickets and seizures in children, it's not clear what impact vitamin D insufficiency has.

To get a handle on prescribing patterns of vitamin D supplements in primary care over time, the researchers drew on information from medical records submitted by GPs to the Health Improvement Network (THIN) between 2008 and 2016 inclusive.

The THIN database contains anonymised data from 744 general practices and around 16 million patients, equivalent to more than 6% of the UK population.

During the study period, 12, 277 children from 723 general practices were prescribed vitamin D supplements for the first time. Girls were more likely than boys to be prescribed these supplements, and prescribing rates were higher in England than elsewhere in the UK.

Older age, social deprivation, and black, Afro-Caribbean and Asian ethnicities were all associated with higher rates of vitamin D prescribing.

By 2016, the prescribing rate was more than 25 times higher than it had been in 2008, rising from 10.8 to 276.8/100,000 person years.* This trend was particularly noticeable among 12-17 year olds, among whom girls were nearly twice as likely to be prescribed a vitamin D supplement as boys.

But increased prescribing rates occurred across all the other age groups: 0-6 months; 6 months-4 years; 4-11 years.

Overall, between 29% and 56% of prescriptions annually had no linked blood test results for vitamin D levels recorded in the 3 months before the prescription was issued.

Less than a third (29.5%) of all children prescribed the supplement had symptoms indicative of vitamin D deficiency, including aches and pains, tiredness or fatigue. Among those with no vitamin D levels recorded beforehand, symptoms were recorded for just one in six.

Prescribed doses varied greatly, with a tendency to increasingly prescribe therapeutic (pharmacological) doses to children, irrespective of their vitamin D levels.

Official guidance recommends prescribing therapeutic doses of supplementary vitamin D only to those actually diagnosed with vitamin D deficiency, note the researchers.

"There has been a marked and sustained increase in vitamin D prescribing in children in UK primary care," write the researchers.

While this may reflect the success of the Department of Health and Social Care's efforts in raising awareness of vitamin D deficiency, findings from our study would suggest that nationally set recommendations on vitamin D supplementation are not consistently followed by GPs, in terms of the number of patients treated, the doses used for supplementation, as well as the practice of prescribing vitamin D without appropriate testing," they conclude.

A single dose of radiotherapy is as "effective" as five doses for end-of-life cancer patients suffering with painful spinal canal compression, finds a large study conducted by UCL.

Spinal canal compression is a common complication in cancer patients when the cancer has spread to their spine. Radiotherapy is used to control pain and alleviate symptoms. Around three to five in 100 people (3-5%) with cancer develop spinal canal compression, which equates to around 4,000 people in the UK each year.

As part of the SCORAD randomised clinical trial, published in JAMA, researchers wanted to find out if giving just one dose (single-fraction) of radiotherapy could be used instead of five doses (multi-fraction) which requires several hospital visits.

The lead trial investigator, Professor Peter Hoskin (University of Manchester, Mount Vernon Cancer Centre (NHS)), said: "In the UK, NICE guidelines do not currently stipulate a standard treatment regimen, though most patients with spinal canal compression or other metastatic bone disease are given several fractions.

"We believe our findings, which show equal clinical effectiveness for single-dose radiotherapy, provide strong evidence for NICE guidelines, and those in other countries, to be changed to stipulate a one-dose one-visit approach, reducing unnecessary discomfort for end of life cancer patients without compromising efficacy."

Co-author Professor Allan Hackshaw (CRUK & UCL Cancer Trials Centre, UCL Cancer Institute) said: "Terminally ill cancer patients with spinal canal compression suffer significant problems such as being unable to walk, and pain. Radiotherapy is an effective treatment for these patients.

"At the moment, with no recommended radiotherapy schedule for these patients, many are given several doses of radiation treatment, and each dose requires a separate visit to the hospital. Patients and their carers have to make multiple journeys, which can be uncomfortable to patients, inconvenient and expensive.

"This is the first large study to assess whether giving a single dose of radiation in one visit is as clinically effective as multiple doses. Our trial showed that one dose was just as good as several doses for a range of patient outcomes."

In total, 686 patients with metastatic cancer and spinal canal compression were recruited from 42 UK and five Australian radiotherapy centres. Half were randomly assigned to be given just one radiotherapy dose, and the other half were given five doses which involved visits to the hospital on five consecutive days.
Effectiveness was assessed by whether patients were able to walk, with or without aids such as walking sticks. This was done at about one, four, eight and 12 weeks after starting radiotherapy.

At week eight, 342 patients were still alive, and among these, 69% who had been given one dose were able to walk compared with 73% who had five doses; results that are considered close enough clinically. At week four, the corresponding percentages of patients who could walk were 67% (one dose) and 68% (five doses); and at week 12 the results were 72% (one dose) and 68% (five doses).

Many other patient outcomes were also similar between patients who had been given either one or five radiotherapy doses. At 12 weeks, 50% of patients were still alive in the group who had been given one dose, close to 55% among patients who had five doses - a difference that was not statistically significant. Having additional cancer treatments, supportive care therapies, quality of life and pain were all similar between having one or five doses.

Radiation therapy is associated with side effects. Fewer patients who had one dose experienced adverse skin reactions (12% given one dose compared with 19% who had five doses); and fewer patients also suffered fatigue (49% given one dose compared with 55% who had five doses). But a group of patients who had radiation treatment specifically to the lower part of their spinal cord (called the cauda equina), were more likely to have bladder problems, and one radiotherapy dose might not be enough treatment for these particular patients.

The study was funded by Cancer Research UK and the Cancer Council Queensland, with support from the National Institute for Health Research.

About half of patients who took part in the trial died before eight weeks, which is when the main measure of efficacy was assessed. Having a lower number of patients than expected meant that one statistical criterion was not strictly met for determining whether a single radiotherapy dose was as effective as having five doses, when comparing the percentage of patients who could walk. Although this was mentioned in the published article (as per JAMA requirements), the conclusion makes clear that the one statistical criterion needs to be interpreted carefully, because it has no meaningful impact on the clinical findings.

The conclusion that one dose of radiotherapy should be used instead of five doses for most patients with spinal canal compression, is supported by all of the other statistical criteria and multiple patient outcomes.

When they said their wedding vows, many of them promised to stand by one another in sickness and in health.

But a new study suggests that as married couples age and develop chronic conditions, the daily demands of coping with their own health demands and those of their spouse may take a mental toll.

Depression symptoms increased over time among married men and women who themselves had two or more chronic conditions that need different types of self-care - such as a special diet and medications for heart disease or diabetes along with pain-reducing therapy for arthritis.

When husbands and wives both had chronic health conditions, and needed different kinds of self-care from their partners, husbands fared worse. Their depression symptoms were significantly higher, but this effect was not found for wives.

The new findings, made by a team from the University of Michigan using data from a long-term study of more than 1,110 older opposite-sex married couples from 2006 to 2014, are published in Journals of Gerontology Series B: Psychological Sciences and Social Sciences.

While less than 10% of the women and less than 7% of the men in the study had levels of depression symptoms serious enough to suggest a need for treatment, lower-level depression is important for older people, clinicians, caregivers and adult children to understand, says Courtney Polenick, Ph.D., who led the study.

In both husbands and wives, the rise of depressive symptoms didn't begin until a few years after the first assessment of their health and well-being.

"Our results suggest that there's a window where, if one or both of you are managing complex conditions that don't have similar self-management goals, it may be possible to intervene and prevent the development or worsening of depression," says Polenick, who is part of the U-M Department of Psychiatry and Institute for Social Research. "This might be the time for couples, and those who care for them, to emphasize broadly beneficial lifestyle behaviors that help to maintain both mental and physical health."

For instance, a woman coping with both high blood pressure and arthritis needs to make changes to her exercise routine, but her husband without such conditions could commit to making those changes along with her. Or a wife with diabetes who does most of the cooking and has a husband with prostate cancer could adopt a healthier menu for both of them.

Polenick and her colleagues from U-M's Institute for Healthcare Policy and Innovation looked at data from the Health and Retirement Study, which repeatedly interviews and surveys thousands of American adults in their 50s and beyond over time.

They focused on conditions that have similar treatment goals focused on reducing cardiovascular risk -- diabetes, heart disease, hypertension and stoke - and those with treatment goals and needs that are different from each of the other conditions- cancer, arthritis and lung disease.

When one person in the couple had at least one condition with different treatment goals and needs, they're considered to have "discordant" conditions. When one member of a couple had at least one condition that has different treatment goals and needs from the other partner, the couple is considered to have discordant conditions.

"Research has focused on how individuals with multiple conditions, also called multimorbidity, manage their chronic health needs," says Polenick. "But most people in later life are partnered, with similar health-related habits, and we need to understand how changing health affects the couple dynamic."

The fact that both wives and husbands experienced significant increases in depressive symptoms as the years passed, when they were coping with discordant conditions in themselves, is by itself important to understand, Polenick notes.

But the fact that wives whose husbands' health needs differed from their own didn't experience an even greater rise in depression is a bit surprising, she adds.

Meanwhile, husbands whose conditions had self-care needs that were different from their wives' conditions did experience an additional rise in depression symptoms.

Among individuals who are baby boomers or older, wives may be more used to taking the lead in caring for the health and emotional well-being of both themselves and their husbands, she says. But when husbands have wives who are coping with different health demands than their own, the husbands may experience less of this support than usual, worsening their stress and mental health.

Polenick and her colleagues continue to explore these intra-couple dynamics, and their consequences for mental and physical health. They also hope to expand the range of chronic health conditions they examine, and to look at shorter timeframes in conditions that can be managed with lifestyle changes.

But in the meantime, she notes that middle-aged and older couples may want to do more now to understand the factors that they can control as they age, and those they cannot, and talk about how they feel as a result.

"This is a reminder to step back and look at what your partner is coping with, to learn about their health conditions, to be conscious of it on a daily basis, and for grown children and clinicians to do the same," she says. "Having that awareness, and helping one another manage health problems while watching for signs of depression, may help both members of a couple over time."

Philadelphia, December 3, 2019 - According to a new report in The American Journal of Medicine, published by Elsevier, aspirin can be considered an effective and safe option to other, more expensive medications to treat acute migraines as well as prevent recurrent attacks. A review of randomized evidence suggests efficacy and safety of high dose aspirin in doses from 900 to 1,300 milligrams taken at the onset of acute symptoms. The data also support a lower dose of from 81 to 325 milligrams as a possible preventive option.

"Aspirin provides a possible clinical option for primary healthcare providers to relieve the debilitating symptoms of acute migraine headaches and prevent recurrent attacks. Aspirin's side effect profile and low cost may also favour its use," noted senior author Charles H. Hennekens, MD, DrPH, the first Sir Richard Doll Professor & Senior Academic Advisor to the Dean of the Charles E. Schmidt College of Medicine at Florida Atlantic University, Boca Raton, FL, USA. The investigators reviewed the randomized evidence for high dose aspirin in treatment and low dose aspirin in prevention of migraine headaches.

Migraine headache is the third most common disease in the world affecting about one in seven people. More prevalent than diabetes, epilepsy, and asthma combined, migraine headaches are among the most common and potentially debilitating disorders encountered by primary healthcare providers. Migraines are also associated with an increased risk of stroke. There are effective prescription medications available to treat acute migraine headaches as well as to prevent recurrent attacks. Nonetheless, in the United States many patients are not adequately treated for reasons that include limited access to healthcare providers, lack of health insurance, or high co-pays, which make expensive medications of proven benefit unaffordable. The rates of uninsured (or underinsured) have been estimated to be 8.5 percent nationwide and 13 percent in Florida. Furthermore, for all patients, the prescription drugs may be poorly tolerated or contraindicated.

Professor Hennekens mused that, "If aspirin were only half as effective, 10 times more expensive, and available by prescription, then perhaps patients and, possibly some of their healthcare providers, would take it more seriously."

"Despite the fact that aspirin is an over-the-counter drug," Dr. Hennekens cautioned, "as is the case for any drug used long term, it should be prescribed by a healthcare provider."

Joseph S. Alpert, MD, Editor-in-Chief of The American Journal of Medicine and Professor of Medicine, University of Arizona Department of Medicine, Tucson, AZ, USA, commented in an accompanying editorial, "My take home message from this thoughtful and carefully researched review is that physicians should always try the simple and inexpensive high dose aspirin regimen as the initial therapeutic attempt for migraine headache control. If aspirin works to abort or ameliorate the headaches, then it should be tried as a prophylactic measure to see if it can prevent the occurrence of these debilitating headaches. Hopefully, this would lead to less disability and loss of employment time for these patients who are so common in the US and throughout the world."

A new study published as "Editor's Choice" in The Journal of Infectious Diseases found that expansion of HIV treatment eligibility to include those under age 15 led to large and significant increases in initiation of antiretroviral therapy (ART) within 30 days of enrollment in care among 10- to 14-year-olds living with HIV.

Led by Olga Tymejczyk and Ellen Brazier of the Institute for Implementation Science in Population Health (ISPH) at the CUNY Graduate School of Public Health and Health Policy, the study used real-world longitudinal service delivery data from HIV clinics in seven countries in sub-Saharan Africa, all members of the global IeDEA research consortium: Burundi, Democratic Republic of the Congo (DRC), Rwanda, Kenya, Uganda, Malawi, and Zambia. All of the countries in the study adopted general universal test and treat, or Treat All, policies in 2016--policies that made all people living with HIV eligible for immediate treatment, regardless of CD4 count or clinical symptoms. Prior to adopting general Treat All policies in 2016, Uganda and Zambia had also adopted pediatric-specific Treat All policies in 2013, which extended treatment eligibility to all children younger than 15 years.

Using a regression discontinuity design, the study found large increases in rapid ART initiation among young adolescents following the adoption of Treat All policies. In Burundi, Democratic Republic of the Congo, Kenya, Malawi, and Rwanda, where "Treat All" policies were adopted in 2016, there was a 23.4 percentage point increase in rapid ART initiation among young adolescents. In Uganda and Zambia in 2013, there was a 11.2 percentage point increase in rapid ART initiation following the adoption of pediatric Treat All policies.

Given the study design, these increases in rapid ART initiation can be interpreted as the effect of expanded treatment eligibility guidelines for a population that has proven hard to reach with HIV care.

"Our findings are clinically important because young adolescents living with HIV in these settings often do not initiate ART until they are at advanced stages of HIV disease," said Tymejczyk. "Getting them on treatment faster after they enroll in HIV care could help lower disproportionately high HIV mortality rates in this age group."

The researchers emphasize, however, that as more follow-up data become available, it will be important to assess whether these young adolescent patients remain on treatment and achieve viral suppression.

"We also need to do more to shorten the time from HIV infection to diagnosis and enrollment in HIV care," said Brazier. "Most of those enrolling into HIV care between the ages of 10-14 years are thought to have acquired the infection perinatally. While it is encouraging that Treat All has improved their access to HIV treatment, we need to understand and address barriers to timely diagnosis and enrollment in HIV among this age group."

Sophia Antipolis, 2 December 2019: Brushing teeth frequently is linked with lower risks of atrial fibrillation and heart failure, according to a study published today in the European Journal of Preventive Cardiology, a journal of the European Society of Cardiology (ESC).1

Previous research suggests that poor oral hygiene leads to bacteria in the blood, causing inflammation in the body. Inflammation increases the risks of atrial fibrillation (irregular heartbeat) and heart failure (the heart's ability to pump blood or relax and fill with blood is impaired). This study examined the connection between oral hygiene and occurrence of these two conditions.

The retrospective cohort study enrolled 161,286 participants of the Korean National Health Insurance System aged 40 to 79 with no history of atrial fibrillation or heart failure. Participants underwent a routine medical examination between 2003 and 2004. Information was collected on height, weight, laboratory tests, illnesses, lifestyle, oral health, and oral hygiene behaviours.

During a median follow-up of 10.5 years, 4,911 (3.0%) participants developed atrial fibrillation and 7,971 (4.9%) developed heart failure.

Tooth brushing three or more times a day was associated with a 10% lower risk of atrial fibrillation and a 12% lower risk of heart failure during 10.5-year follow up. The findings were independent of a number of factors including age, sex, socioeconomic status, regular exercise, alcohol consumption, body mass index, and comorbidities such as hypertension.

While the study did not investigate mechanisms, one possibility is that frequent tooth brushing reduces bacteria in the subgingival biofilm (bacteria living in the pocket between the teeth and gums), thereby preventing translocation to the bloodstream.

Senior author Dr. Tae-Jin Song of Ewha Womans University, Seoul, Korea noted that the analysis was limited to one country and as an observational study does not prove causation. But he added: "We studied a large group over a long period, which adds strength to our findings."

An accompanying editorial states: "It is certainly too early to recommend tooth brushing for the prevention of atrial fibrillation and congestive heart failure". It adds: "While the role of inflammation in the occurrence of cardiovascular disease is becoming more and more evident, intervention studies are needed to define strategies of public health importance."2

A major new analysis of the non-opioid medications, gabapentin and baclofen, shows "worrying" increases in related suicide attempts and hospital admissions in US adults since 2013 - coinciding with a decrease in opioid prescriptions.

With the risks of opioid medications widely publicised, there has been a dramatic decline in prescriptions in the United States since they peaked in 2010-2012. But with millions of US adults still living with chronic pain, non-opioid medications are widely viewed as safer alternatives for pain management. Prescriptions for gabapentin have increased 64% from 39 million in 2012 to 64 million by 2016 when it was the 10th most commonly prescribed medication in the US.

In this latest study, published in Clinical Toxicology, researchers from the University of Pittsburgh looked at over 90,000 cases of exposure to the medications and saw large increases in misuse and toxicity - with isolated abuse instances of using gabapentin (from 2013 to 2017) rising by 119.9%, and baclofen (2014-2017) 31.7%.

Reviewing the data, collected in the National Poison Data system of trends in exposures reported to US Poison Centers, their results show that all US states have seen increases in gabapentin exposures. Most also saw increases in baclofen exposures, gabapentin misuse/abuse, and baclofen misuse/abuse over the study period:

During the five-year period (2013-2017), there were 74,175 gabapentin exposures. All gabapentin exposures increased by 72.3%; isolated exposures by 67.1% and isolated abuse/misuse by 119.9%.

During the four-year period (2014 to 2017), there were 15,937 baclofen exposures. All baclofen exposures increased by 36.2%; isolated exposures by 35% and isolated misuse/abuse increased by 31.7%.

They also showed that admissions to a healthcare facility were required in 16.7% of isolated gabapentin exposures and 52.1% of isolated baclofen exposures. Intentional suspected suicide attempts increased by 80.3% for isolated gabapentin exposures over a five-year-period and 43% for baclofen over a four-year-period. Co-ingestion of sedatives and opioids were common for both medications.

Lead author Kimberly Reynolds, of the University of Pittsburgh, said: "We are seeing a worrying increase in harmful exposures to gabapentin and baclofen in US adults over recent years, which may be an unintended consequence of the move away from opioid prescriptions for pain management.

"Building a better understanding of the risks carried by these non-opioid medications is necessary so that providers and patients can make better-informed decisions about their role in pain management - and could also lead to the introduction of new public health measures."

Due to growing concerns related to the misuse of gabapentin, new measures have been introduced in several US states during the final year or after the data collection period of the study - either re-classifying the drug as a Schedule V controlled substance or mandating the reporting of prescriptions. Re-evaluations of prescribing and exposure trends in these states may provide insight into the effects of such programs.

The authors recommend that patients who are prescribed these medications should be screened for substance use disorders, mood disorders, and suicidal ideation utilizing validated screening tools and the prescription drug monitoring program.

A pioneering precision medicine already licensed for breast and ovarian cancer can also slow or stop tumour growth in some men with advanced prostate cancer, a new clinical trial shows.

The phase II trial found that over 80 per cent of men with prostate cancer whose tumours had mutations in the BRCA genes responded well to treatment with the targeted drug olaparib.

Men in the study had already received chemotherapy and their disease was advanced. Patients treated with olaparib whose prostate cancers had DNA repair defects lived for more than 13 months on average - and nearly 18 months among those with BRCA mutations - raising the prospect that it could become the first ever gene-targeted drug to be approved for prostate cancer.

The TOPARP-B trial was led by a team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust. It is published in The Lancet Oncology today (Friday) and was funded in part by olaparib's manufacturer, AstraZeneca, plus by Cancer Research UK, Prostate Cancer UK, the Prostate Cancer Foundation, Movember and the Experimental Cancer Medicine Centre (ECMC) Network.

An initial trial, TOPARP-A, tested use of olaparib in a group of men with advanced prostate cancer who weren't selected for treatment based on gene mutations, and suggested that those whose tumours had mutations in a range of genes involved in repairing damage to DNA could benefit most.

That led to TOPARP-B, which was the first study to direct olaparib specifically at men whose prostate cancers had mutations in their DNA repair systems. The researchers used olaparib to treat 98 men, at 17 UK hospitals, with mutations in DNA repair genes, and who all had advanced cancer which had been heavily pre-treated. Overall, they found that 47 per cent of men with these DNA repair defects responded to olaparib, halting disease progression for an average of 5.5 months.

The most common DNA repair defects were mutations in the BRCA1 and BRCA2 genes, but various other mutations were also detected including those in the PALB2, ATM and CDK12 genes.

Men with BRCA mutations responded best to olaparib, with more than 80 per cent responding and 40 per cent remaining free of disease progression for more than a year. Additionally, over half of patients carrying PALB2 mutations responded to olaparib, as well as 37 per cent of those with ATM mutations. Some 20 per cent of patients with other DNA repair gene alterations also responded to olaparib.

The median overall survival with olaparib was 17.7 months for patients with BRCA mutations, compared with 16.6 for men with ATM mutations, and 13.9 months for those with PALB2 mutations.

Olaparib is one of a class of drugs called PARP inhibitors which are licensed for women with ovarian and breast cancer who have mutations in the BRCA genes. Scientists at The Institute of Cancer Research (ICR) were the first to discover how to genetically target olaparib, and they went on to develop the drug in clinical trials with colleagues at The Royal Marsden.

The researchers believe men with advanced prostate cancer should now routinely have their tumours tested for DNA repair defects such as BRCA mutations, so that where appropriate they can benefit from PARP inhibitors.

The ICR is seeking to discover novel gene-targeted medicines and innovative ways of combining them within its pioneering new Centre for Cancer Drug Discovery - a £75 million investment focused on finding new 'anti-evolution' treatments that can overcome drug resistance.

Study leader Professor Johann de Bono, Regius Professor of Cancer Research at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said:

"Our trial has shown that men with prostate cancer who were selected for faults in DNA repair genes responded very well to the targeted drug olaparib, especially where they had BRCA mutations in their tumours.

"This study and another phase III trial place olaparib on the verge of becoming the first genetically targeted treatment in prostate cancer. I'm excited by these findings, and keen to see further research assessing how we can combine olaparib with other treatments to extend patients' lives even more dramatically."

Professor Paul Workman, Chief Executive at The Institute of Cancer Research, London, said:

"Precision medicines targeted to specific genetic faults are transforming treatment for many different cancers, and with this new research it looks like we will soon be able to add prostate cancer to that list. It's exciting to see a drug which the ICR helped pioneer having such widespread benefits for both women and men with cancer.

"The next step is to work out how to combine olaparib with other drugs to keep cancer at bay for much longer. That's the kind of research we will be carrying out in our new Centre for Cancer Drug Discovery, which aims to create innovative new treatments designed to overcome cancer evolution and drug resistance."