Body

What The Study Did: Researchers report on a randomized clinical trial that compared two strategies (proton pump inhibitors vs. histamine-2 receptor blockers) to prevent stress ulcers among adult patients in intensive care units who needed mechanical ventilation. The trial was conducted at 50 ICUs in five countries to compare in-hospital death rates using the two strategies. The study is being released to coincide with presentation at the Critical Care Reviews Meeting 2020 in Belfast, Northern Ireland.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

Authors: Paul J. Young, Ph.D., of the Medical Research Institute of New Zealand in Wellington, is the corresponding author.

(doi:10.1001/jama.2019.22190)

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

University of Manchester scientists investigating a possible treatment for foetal growth restriction (FGR), a condition in which babies grow poorly in the womb, have urged further caution on the use of Viagra.

The drug, commonly used to treat erectile dysfunction, as it enhances blood flow - has been undergoing trials as a potential treatment for FGR. However, in a recent study in mice, Viagra showed no improvement in foetal growth but did result in high blood pressure in the pups as they reached maturity.

Babies with Foetal Growth Restriction (FGR) are at increased risk of stillbirth and are more likely to suffer from developmental problems and other conditions such as heart disease and diabetes in adulthood.

FGR affects around 3 in every 100 pregnancies and most cases are caused by poor function of the placenta, affecting blood flow and thus nutrient transfer from mother to the baby.

No treatments are available for FGR and often the only option for obstetricians is to deliver the baby early so they can be cared for outside the womb.

The Manchester team are the first to report the long-term effects of the drug, on both male and female offspring, when given to mice during pregnancy and publish their results in the American Journal of Physiology - Heart and Circulatory Physiology.

An international clinical trial of Viagra on severe cases of human FGR called STRIDER, and carried out at the same time as the Manchester study, also found the drug had no significant benefit on foetal growth or prolongation of pregnancy.

The Dutch arm of the STRIDER trial was halted after 11 babies of mothers using the medication died from lung complications, though this did not happen to babies in the New Zealand-Australia or the UK-Ireland trials.

In the Manchester study, over 90% of mice whose mothers were given Viagra during their pregnancy experienced a significant increase in their blood pressure. This increase was in the range of values equivalent to those used to diagnose high blood pressure in humans.

The effect was similar in both wild type (normally grown) and growth restricted mice and was consistent in both females and males.

Female mice also experienced a modest increased weight gain after birth and a minor reduction in glucose tolerance after 8 weeks.

The study was carried out by former PhD student Dr Lewis Renshall. He said "This, and other studies have shown Sildenafil - otherwise known as Viagra - may not be a suitable treatment for FGR unless life-saving benefits can be demonstrated."

"So there is still much work to do if we are to eventually find a treatment for this distressing condition."

Dr Mark Dilworth, who led the study, added: "The evidence from this study and others suggest that caution should be used for the use of Viagra in foetal Growth Restriction. Our study suggests there may be long-term risks associated with its use in mice and importantly, there is a lack of beneficial effect in recent human clinical trials."

"We do feel, however, that it is important to continue to conduct studies which look at longer term impacts of giving medication during pregnancy as there is surprisingly little research on this."

Clinical trials suggest treatment that involves psychedelics can be more effective than psychotherapy alone.

More than three million people in the United States are diagnosed each year with post-traumatic stress disorder, whose symptoms include nightmares or unwanted memories of trauma, heightened reactions, anxieties, and depression--and can last months, or even years.

People with PTSD--difficulty recovering from experiencing or witnessing a traumatic event--have traditionally been treated with a combination of trauma-focused psychotherapy and a regimen of medications. Many sufferers have not responded well to that treatment, but new research to be presented by the Medical University of South Carolina's Dr. Michael Mithoefer and colleagues, at the annual meeting of the American College of Neuropsychopharmacology, suggests that the combination of some psychedelic drugs and traditional psychotherapy holds promise.

Psychedelic substances are often found in nature and have been used in various cultures over thousands of years. Formal medical research into their medicinal uses starting in the 1950s produced promising results published in major journals but was largely halted in the 1970s for political rather than medical or scientific reasons. More recent studies argue that, when administered in a controlled clinical setting, MDMA (more commonly known as ecstasy) and psilocybin (the active ingredient in "magic mushrooms") have acceptable risk profiles --and patients who experienced temporary adverse reactions did not require additional medical intervention.

In the past few years the FDA has granted both MDMA and psilocybin Breakthrough Therapy Designations for PTSD and depression respectively, acknowledging they may improve upon existing therapies, and agreeing to expedite their development and review.

The research by Dr. Mithoefer and his team includes six Phase 2 clinical trials conducted by independent investigators in four countries. In the trials, one group of patients was administered MDMA during their psychotherapy sessions, while the other group was administered a placebo or low dose comparator in conjunction with the same psychotherapy. The overall conclusion from these studies was that MDMA-assisted psychotherapy was significantly more effective at treating patients with persistent PTSD than unassisted psychotherapy.

The researchers aim to both review the successes that have been seen in the use of psychedelic drugs to treat trauma-related disorders and depression, as well as address several of the outstanding questions the medical community may still have concerning the safety, efficacy, and neurobiological functions of these novel treatment options.

COLUMBUS, Ohio - Acid reflux drugs that are sometimes recommended to ease stomach problems during cancer treatment may have an unintended side effect: impairment of breast cancer survivors' memory and concentration.

New Ohio State University research shows an association between breast cancer survivors' use of proton pump inhibitors (PPIs) and reports of problems with concentration and memory. On average, cognitive problems reported by PPI users were between 20 and 29 percent more severe than issues reported by non-PPI users. PPIs are sold under such brand names as Nexium, Prevacid and Prilosec.

The study, the first to look at PPI use in breast cancer survivors, used data from three previous Ohio State clinical trials examining fatigue, a yoga intervention and vaccine response in breast cancer patients and survivors. In each of those studies, participants had reported their use of prescribed and over-the-counter medications and rated any cognitive symptoms they had as part of routine data collection.

After controlling for a variety of factors that could affect cognition - such as depression or other illnesses, types of cancer treatment, age and education - the researchers found that PPI use predicted more severe concentration and memory symptoms as well as lower quality of life related to impaired cognition.

"The severity of the cognitive problems reported by PPI users in this study was comparable to what patients undergoing chemotherapy had reported in a large observational study," said Annelise Madison, lead author of the study and a graduate student in clinical psychology at Ohio State. "PPI non-users also reported problems, but were definitely getting better. Based on what we're seeing, we don't know if PPI users might not be able to fully recover cognitively after chemotherapy. It's an area for further investigation."

The study is published online in the Journal of Cancer Survivorship.

Madison pursued this study based on her knowledge of PPIs' known potential to bypass the blood-brain barrier and previous research suggesting that off-label use of PPIs in cancer patients may increase tumors' responsiveness to chemotherapy and protect the digestive system from the ravages of chemo drugs.

"I thought there could be a cognitive effect from taking PPIs, particularly in this population, because breast cancer survivors are already at risk for cognitive decline," she said. "PPIs are over the counter and generally considered safe so there haven't been many long-term trials, especially looking at cognitive outcomes, because nobody was really thinking that would be a downstream effect."

As part of her graduate program, Madison works in the lab of Janice Kiecolt-Glaser, professor of psychiatry and psychology and director of the Institute for Behavioral Medicine Research at Ohio State. For this work, Madison conducted secondary analyses of three of Kiecolt-Glaser's earlier studies examining inflammation's connection to breast cancer treatment and survivorship.

Data from 551 women in those earlier studies, 88 of whom reported taking PPIs, were used in Madison's analysis. The women in the previous studies had provided self-reports of PPI use and cognitive symptoms multiple times over varied periods of time depending on the design of each study.

Women in the studies looking at fatigue in newly diagnosed patients and investigating yoga's effect on inflammation and fatigue in survivors had completed a questionnaire rating the severity of their memory and concentration problems on a scale of 0 to 10 over the previous five days. Madison's analysis found that on average, PPI users' concentration problems in the fatigue study were 20 percent more severe than those reported by non-PPI users. In the yoga study, PPI users' concentration problems were 29 percent more severe than those reported by non-PPI users. There were no differences in reported memory problems.

In the third study, which featured data from the placebo visit of a typhoid vaccine trial, reported memory problems were 28 percent more severe in PPI users than in non-users, with no differences in reports of concentration issues. Breast cancer survivors in this study completed an additional questionnaire measuring the functional implications of their cognitive impairment. PPI users' scores were lower than non-users' scores on this assessment, where PPI users reported a poorer quality of life, greater cognitive impairment and poorer cognitive abilities compared to non-users.

"The fact that this study found similar effects across three different sets of patients who are at different stages of cancer survivorship gives some weight to what we're seeing," said Kiecolt-Glaser, senior author of the paper and an investigator in Ohio State's Comprehensive Cancer Center. "Had it been in only a single study, it could have been a chance effect."

The U.S. Food and Drug Administration has approved PPIs for short-term use to treat common gastric acid conditions and longer-term use for gastric ulcers and disorders involving excessive acid secretion. Madison noted that the off-label maintenance use of PPIs in cancer patients can last a long time: Her analysis showed that at least two-thirds of the breast cancer survivors using PPIs had taken them for between six months and two years.

Madison stressed that the study shows a correlation between PPI use and cognitive problems in breast cancer survivors, and that a clinical trial controlling PPI doses and obtaining objective cognitive data would be required to identify any causal effect.

Epigenetic changes occur in the DNA of breast cancer cells that have developed a resistance to hormone therapy, an effective treatment for ER+ breast cancer, which accounts for 70% of all diagnoses.

Reversing these changes, researchers say, has significant potential to help reduce breast cancer relapse.

A team led by Professor Susan Clark at the Garvan Institute of Medical Research showed that the 3D structure of DNA is 'rewired' in hormone resistant ER+ breast cancers, altering which genes are activated and which genes are silenced in the cells. The researchers published the findings today in the journal Nature Communications.

"For the first time, we've revealed crucial 3D DNA interactions that are linked to whether or not a breast cancer is sensitive to hormone therapy," says senior author Professor Clark, who is Garvan's Genomics and Epigenetics Research Theme Leader. "Understanding this process reveals new insights into how ER+ cancers evade hormone therapy, allowing them to grow uncontrolled."

Tackling hormone resistance in breast cancer

The sex hormone estrogen can be an inadvertent driver of cancer growth - ER+ breast cancers grow when estrogen 'docks' to their cells. Treatment that blocks estrogen, known as hormone therapy, is successful at stopping cancer growth and reducing relapse, however many breast cancers become resistant to the treatment over time.

"Treatment resistance is a significant health problem that leads to a third of all ER+ breast cancer patients on hormone therapy relapsing within 15 years," says the study's first author Dr Joanna Achinger-Kawecka.

"We are interested in epigenetic changes to DNA, the layer of instructions that organises and regulates DNA's activity, that underpin the development of hormone resistance in breast cancer. Understanding these fundamental changes may help guide development of future treatments that either prevent resistance from developing, or reverse it once it has occurred."

Uncovering hidden changes to DNA

Using chromosome conformation capture, a cutting-edge technique that provides a snapshot of how DNA is arranged and interacts in three dimensions in the cell, the researchers compared different ER+ breast cancer cells that were either sensitive or resistant to hormone treatment.

"Between breast cancer cells that were still sensitive to hormone treatment and those that had developed resistance, we saw significant changes in 3D interactions of DNA regions that control gene activation. Including at genes that control the estrogen receptor levels in the cells," says Dr Achinger-Kawecka.

"Further, we found that this 3D 'rewiring' occurred at DNA regions that were methylated, which is an epigenetic change that the team has already linked to hormone resistance."

The researchers say that the altered DNA methylation at critical regulatory regions may explain how the 3D structure of DNA is rewired as a cancer cell develops hormone resistance, allowing the cancer to better evade treatment.

A new path for breast cancer treatment

"Cancer cells are always trying to outsmart therapy and it only takes one cell to evolve a different way to bypass a drug to cause a relapse in cancer," says Professor Clark. "Our study shows us just how much impact a change in the epigenome can have on cancer cell behaviour."

The researchers say the next step is to investigate whether epigenetic changes could be reversed to stop hormone resistance, using existing drugs that are already in clinical trials for other cancers, including lung and colorectal cancer.

"Once ER+ breast cancer patients become resistant to hormone therapy, it is more difficult to treat," says Professor Clark. "We hope our research will help lead to combination treatments that allow women to take hormone therapy for longer, giving them better clinical outcomes."

Researchers at the University of Illinois at Chicago report that in Illinois hospital visits associated with homelessness have tripled since 2011.

Their findings, which are published in the American Journal of Public Health, also show that beginning in 2016, annual conservative estimates of homelessness using hospital-based data have exceeded similar estimates from the U.S. Department of Housing and Urban Development, or HUD.

"The data suggests that homelessness may be increasing, despite official HUD estimates showing a substantial decrease in homelessness," said Dana Madigan, a doctoral student at UIC and first author of the study.

Using discharge records from 2011 to 2018, Madigan and her colleagues identified visits to hospital emergency departments in Illinois in which patients indicated they were affected by a lack of housing or homelessness.

Their analysis included more than 200 hospitals, representing 96.5% of all patient admissions statewide in this period.

By matching patient date of birth, gender and race/ethnicity, they estimated the number of unique homeless individuals that visited hospitals in Illinois. They compared their estimates with HUD's annual estimates of homelessness based on Point-in-Time counts for Illinois, taken on a single night in January.

The most conservative estimates of homelessness using hospital data of unique emergency department visitors increased annually from 6,613 in 2011 to 15,815 in 2018. HUD estimates showed some year-over-year increases, but an overall 24% decrease from 14,009 in 2011 to 10,643 in 2018.

"At the very least, this suggests that state and national estimates of homelessness will be more accurate if they also take into account readily available information from hospitals," Madigan said.

Lee Friedman, senior author of the study, said that without accurate data, states will not get adequate resources to address homelessness.

"Homelessness is an 'invisible' condition that is undoubtedly hard to measure, but that doesn't mean state and federal agencies get a pass on doing a poor job," said Friedman, UIC associate professor of environmental and occupational health sciences at the School of Public Health. "HUD's numbers, which are the primary driver of public policy, may be seriously flawed, and this study shows that hospital data, which is available in every state, is a feasible data system to incorporate into estimates of homelessness to improve accuracy."

New Zealand media reports on chronic pain are focusing on treatments involving opioids and cannabis at the expense of best practice non-drug treatments, researchers have found.

Chronic pain, defined as persistent or recurring pain present for more than three months, is the leading cause of disability worldwide and affects one in five New Zealanders.

The researchers analysed 240 news articles on chronic pain published in the New Zealand news media between January 2015 and June 2019. Their report is published in the latest issue of the New Zealand Medical Journal.

Lead author Dr Hemakumar Devan, a Postdoctoral fellow at the Centre for Health, Activity and Rehabilitation Research at the University of Otago, Wellington's School of Physiotherapy, says few of the news stories included information about non-pharmaceutical treatments for chronic pain, despite these being the preferred option for most chronic pain conditions.

"Pharmacological strategies are only recommended for some chronic pain conditions, such as cancer pain and neuropathic pain. For other pain conditions, drug treatments are recommended to be used with care and caution because of potential side effects and limited long-term effectiveness."

He says media coverage of pharmaceutical treatments for chronic pain focused almost entirely on opioid-based painkillers and cannabis. Stories on opioids mentioned their ineffectiveness in treating chronic pain and their potential for dependence and addiction, while reports about medicinal cannabis portrayed it as an effective and safe treatment with minimal side effects. This was despite the lack of scientific evidence to support its long-term use for chronic pain.

"The personal experience stories about cannabis focused on its positive effects and fewer side effects compared to opioid-based analgesics. There is, however, limited evidence to suggest cannabis as a substitute for opioids and a lack of high-quality evidence to support the use of cannabis for chronic pain.

"There was no reporting on the potential adverse effects of medicinal cannabis use, such as cognitive deficits, dependency and mood changes, which could particularly affect young people."

The researchers also found media coverage was dominated by the struggle associated with living in chronic pain, with little attention given to the resources available to support people to manage pain successfully and live a meaningful life.

"Non-drug based self-management strategies, which include exercise, relaxation and cognitive behavioural treatments, are a key component of managing chronic pain and are proven to be effective in the long term."

Dr Devan says the difficulties faced by patients in accessing pain services because of the lack of trained multidisciplinary health professionals, and inequities in terms of access for Māori and Pasifika, were accurately reflected by the media coverage.

The researchers found the level of media interest in chronic pain had increased in recent years.

"We expect this will continue to rise, with chronic pain becoming increasingly relevant in the lead up to New Zealand's 2020 cannabis referendum; and as the number of people living with chronic pain increases as the population ages."

Dr Devan says given the high level of interest from media, there is a need for media guidelines for chronic pain similar to those developed by the Mental Health Foundation of New Zealand for mental health issues https://www.mentalhealth.org.nz/get-help/media-guidelines.

Researchers from St. Jude Children's Research Hospital and the Chinese Children's Cancer Group led the first randomized, Phase III clinical trial comparing targeted therapies for acute lymphoblastic leukemia (ALL) driven by the Philadelphia chromosome. Results showed that the drug dasatinib provides more benefit than the standard of care, which led to changes in the way this leukemia is treated. The findings were reported today in JAMA Oncology.

Fusions of the BCR-ABL1 genes, resulting in the formation of the Philadelphia chromosome, underlie 3-4% of cases of childhood ALL. This subtype is high risk and associated with poor outcomes.

"This was a very fruitful collaboration," said corresponding and co-senior author Ching-Hon Pui, M.D., St. Jude Department of Oncology chair. "No single institution could enroll enough patients to do this kind of randomized clinical trial. By working with the Chinese Children's Cancer Group, we were able to answer which targeted therapy provides the most benefit."

Researchers compared the efficacy of imatinib, the first targeted therapy for Philadelphia chromosome-positive (Ph+) ALL, and a next-generation inhibitor called dasatinib. The study showed that dasatinib resulted in an event-free survival rate of 71% compared to 49% with imatinib over four years.

The study enrolled patients with Ph+ ALL at 20 major hospitals throughout China. Of those, 92 patients received dasatinib, and 97 received imatinib. All patients underwent intensive chemotherapy without prophylactic cranial radiation, and only four patients underwent stem cell transplantation.

"This study demonstrates the importance of global medicine," said Carlos Rodriguez-Galindo, M.D., St. Jude Department of Global Pediatric Medicine chair. "Results from studies run in one country can save the lives of children around the world by informing changes in the standard of care."

Findings from this clinical trial were reported at the European Society for Paediatric Oncology and American Society of Hematology annual meetings in 2019. This data helped inform decisions by other national study groups in the U.S. and Europe to include dasatinib for the treatment of Philadelphia chromosome-positive ALL in clinical protocols going forward.

Zika virus infection can stunt neonatal brain development, a condition known as microcephaly, in which babies are born with abnormally small heads. To determine how best to prevent and treat the viral infection, scientists first need to understand how the pathogen gets inside brain cells.

Employing different approaches to answer different questions, two research teams at University of California San Diego School of Medicine independently identified the same molecule -- αvβ5 integrin --as Zika virus' key to entering brain stem cells.

In a pair of papers published January 16, 2020 by Cell Press, the researchers also found ways to take advantage of the integrin to both block Zika virus from infecting cells and turn it into something good: a way to shrink brain cancer stem cells.

Integrins are molecules embedded in cell surfaces. They play important roles in cell adherence and communication, and are known to be involved in cancer progression and metastasis. Several other integrins are known entry points for other viruses, including adenovirus, foot-and-mouth disease virus and rotavirus, but αvβ5 was not previously known for its role in viral infections.

Finding the key

One team, led by Tariq Rana, PhD, professor and chief of the Division of Genetics in the Department of Pediatrics at UC San Diego School of Medicine and Moores Cancer Center, used CRISPR gene editing to systematically delete every gene in a 3D culture of human glioblastoma (brain cancer) stem cells growing in a laboratory dish. Then they exposed each variation to Zika virus to determine which genes, and the proteins they encode, are required for the virus to enter the cells. The virus was -- for the first time -- labeled with green fluorescent protein (GFP) to allow the researchers to visualize viral entry into the cells.

Their study, published in Cell Reports, uncovered 92 specific human brain cancer stem cell genes that Zika virus requires to infect and replicate in the cells. But one gene stood out, the one that encodes αvβ5 integrin.

"Integrins are well known as molecules that many different viruses use as doorknobs to gain entry into human cells," Rana said. "I was expecting to find Zika using multiple integrins, or other cell surface molecules also used by other viruses. But instead we found Zika uses αvβ5, which is unique. When we further examined αvβ5 expression in brain, it made perfect sense because αvβ5 is the only integrin member enriched in neural stem cells, which Zika preferentially infects. Therefore, we believe that αvβ5 is the key contributor to Zika's ability to infect brain cells."

Blocking Zika virus infection

The second study, published in Cell Stem Cell, was led by Jeremy Rich, MD, professor in the Department of Medicine at UC San Diego School of Medicine and director of neuro-oncology and of the Brain Tumor Institute at UC San Diego Health. Knowing that many viruses use integrins for entry into human cells, Rich's team inhibited each integrin with a different antibody to see which would have the greatest effect.

"When we blocked other integrins, there was no difference. You might as well be putting water on a cell," said Rich, who is also a faculty member in the Sanford Consortium for Regenerative Medicine and Sanford Stem Cell Clinical Center at UC San Diego Health. "But with αvβ5, blocking it with an antibody almost completely blocked the ability of the virus to infect brain cancer stem cells and normal brain stem cells."

Rich's team followed up by inhibiting αvβ5 in a glioblastoma mouse model with either an antibody or by deactivating the gene that encodes it. Both approaches blocked Zika virus infection and allowed the treated mice to live longer than untreated mice. They also found that blocking the αvβ5 integrin in glioblastoma tumor samples removed from patients during surgery blocked Zika virus infection.

Rana's team also blocked αvβ5 in mice, treating them daily with cilengitide or SB273005, two experimental cancer drugs that target the integrin. Six days after Zika virus infection, the brains of their drug-treated mice contained half as much virus as mock-treated mice.

"The neat thing is that these findings not only help advance the Zika virus research field, but also opens the possibility that we could similarly block the entry of multiple viruses that use other integrins with antibodies or small molecule inhibitors," Rana said.

Rana and team are now engineering a mouse model that lacks αvβ5 integrin in the brain -- a tool that would allow them to definitively prove the molecule is necessary for Zika viral entry and replication.

Leveraging Zika to treat brain cancer

Rich is a neuro-oncologist who specializes in diagnosing and treating patients with glioblastoma, a particularly aggressive and deadly type of brain tumor. When he first saw how the Zika virus shrinks brain tissue, it reminded him of what he hopes to achieve when he's treating a patient with glioblastoma. In 2017, he and collaborators published a study in which they determined that Zika virus selectively targets and kills glioblastoma stem cells, which tend to be resistant to standard treatments and are a big reason why glioblastomas recur after surgery and result in shorter patient survival rates.

Rich's latest study helps account for the virus' preference for glioblastoma stem cells over healthy brain cells. The αvβ5 integrin is made up of two separate subunits -- αv and β5. The team found that glioblastoma stem cells produce a lot of both the αv subunit (associated with stem cells) and β5 subunit (associated with cancer cells). Together, these units form the αvβ5 integrin, which, the team discovered, plays an important role in glioblastoma stem cell survival. Those high levels of αvβ5 integrin also help explain why, in the study, glioblastoma stem cells were killed by Zika virus at much higher rates than normal stem cells or other brain cell types.

"It turns out that the very thing that helps cancer cells become aggressive cancer stem cells is the same thing Zika virus uses to infect our cells," Rich said.

To see how this might play out in a more realistic model of human disease, Rich's team partnered with an expert in human brain disease modeling -- Alysson Muotri, PhD, professor at UC San Diego School of Medicine, director of the UC San Diego Stem Cell Program and a member of the Sanford Consortium for Regenerative Medicine, and team. Pinar Mesci, PhD, a postdoctoral researcher in Muotri's lab, generated a new brain tumor model, where human glioblastoma tumors were transplanted into human brain organoids, laboratory "mini-brains" that can be used for drug discovery. The researchers discovered that Zika virus selectively eliminates glioblastoma stem cells from the brain organoids. Inhibiting αvβ5 integrin reversed that anti-cancer activity, further underscoring the molecule's crucial role in Zika virus' ability to destroy cells.

Now Rich's team is partnering with other research groups to perform targeted drug studies. In addition to searching for drugs to block Zika virus, as Rana's group is doing, Rich is interested in genetic modifications to the virus that could help better target its destruction to brain cancer cells, while leaving healthy cells alone.

"While we would likely need to modify the normal Zika virus to make it safer to treat brain tumors, we may also be able to take advantage of the mechanisms the virus uses to destroy cells to improve the way we treat glioblastoma," Rich said. "We should pay attention to viruses. They have evolved over many years to be very good at targeting and entering specific cells in the body."

Zika virus was perhaps best known in 2015-16, when a large outbreak affected primarily Latin America, but also several other regions of the world. While that particular epidemic has passed, Zika virus has not gone away. Smaller, local outbreaks continue and this past summer, the first few cases of native Zika virus infection were recorded in Europe. Scientists warn Zika could continue to spread as climate change affects the habitat range of the mosquito that carries it. The virus can also be transmitted from pregnant mother to fetus, and via sexual contact. More than half of all people on Earth are at risk for Zika virus infection, and there is no safe and effective treatment or vaccine.

A study of families in Singapore with terminally ill children found that parents tend to defer discussing their psychological pain with their spouses to protect them from emotional distress.

The study, conducted by psychologists at Nanyang Technological University, Singapore (NTU Singapore) through interviews, revealed the parents' preference to support each other in pragmatic and solution-oriented ways such as discussing treatment options, arranging care plans and sharing caregiving responsibilities.

Informed by the research findings and supported by the Singapore Millennium Foundation Research Grant, lead author Associate Professor Andy Ho Hau Yan from the Psychology division at the NTU School of Social Sciences, and his PhD student, Ms Oindrila Dutta, developed a therapist-facilitated online therapy app known as Narrative e-Writing Intervention (NeW-I) to help parents whose children are in need of palliative care.

Studies from Western countries have suggested that sharing thoughts and feelings with one's spouse is key to the emotional adjustment of both partners when faced with a terminal diagnosis in the family. However, this approach was not reported by participants in the Singapore study.

"We propose that in-depth sharing of thoughts and feelings may not be the priority for Asian couples," reported the authors in the journal BMJ Open in November last year, in what is believed to be the first study to look at how interpersonal exchanges and communication patterns evolve between spouses among Asian parents of children facing chronic life-threatening diseases.

Supported by Singapore's Ministry of Education Academic Research Fund and working closely with HCA Hospice Care's paediatric palliative programme Star PALS, the Children's Cancer Foundation, and Club Rainbow (Singapore), the NTU-led research team conducted 1 to 1½-hour long in-depth interviews with 20 family units who had lost their child to a terminal or chronic life-threatening illness.

All the family units who took part - either as a lone parent or as a couple - were married at the time of the child's diagnosis and interview, and at least six months had passed between the child's death and the interview.

In the interviews, the research team observed that after the death of their child, the way that the parents interacted with each other changed, and they described giving each other space to grieve, before engaging in honest and in-depth sharing of their thoughts and emotions surrounding their child's death, and the meaningful memories of the life that had been lived, say the authors.

Assoc Prof Ho said: "Our findings serve as a caution to healthcare professionals who may overemphasise the need to openly express feelings and emotions soon after prognosis, and in the early stages of end-of-life caregiving among Asian parent-caregivers of children with terminal and chronic life-threatening illnesses."

He added that although the sample is made up of Singaporeans and permanent residents, the Chinese, Malay and Indian ethnicities of the parents interviewed - a reflection of Singapore's multicultural society dominated by major Asian racial and religious groups - imply that findings from this Singapore-based study may be extended to other Asian societies as well.

The authors believe that it would be more useful for healthcare professionals to employ a time-efficient approach when working with couples for whom functional needs such as providing care to their child take precedence.

Findings led to development of therapeutic app

With NeW-I, the therapist-facilitated online therapy app developed based on the study findings, Assoc Prof Ho and Ms Dutta hope that it will help plug an important service gap in the support available for caregivers here.

Comprising a weekly structured writing task, it allows caregivers to reflect on the emotional, practical and financial demands of caregiving and examine how their children can rise above illness-related challenges and live their lives as fully as possible.

Accompanying the writing exercise is psycho-socio-emotional support from a therapist, who reviews, responds to and restructures the written narratives into a legacy document that helps bring comfort, meaning and wellbeing to parents and their families.

Assoc Prof Ho said: "Interventions that empower caregiving resilience and enhance death preparedness have shown to alleviate psychological distress among family caregivers of dying patients, yet there is no known programme designed specifically to address the psychological, emotional and spiritual needs of parents facing child loss, especially in the local context."

NeW-I is currently being piloted in a trial in collaboration with non-profit organisations providing compassionate services to chronically ill children and their families: Club Rainbow (Singapore), Muscular Dystrophy Association (Singapore), and Rare Disorders Society (Singapore).

Parent-caregivers who agree to be part of the trial are randomly assigned to the intervention group or the control group, with the latter still offering psychosocial support. The team is still recruiting participants through their NeW-I app, available now through the Apple App store and the Google Play store.

Assoc Prof Ho said: "Through this trial, we hope to examine the efficacy of the intervention model we have developed in enhancing the quality of life, well-being, perceived social support, as well as reducing depressive symptoms, caregiver burden and anticipatory grief among our parent-caregivers."

Ms Dutta added: "The findings will form the foundation for a full-scale trial for advancing holistic paediatric palliative care and parental bereavement support locally, and around the world."

The use of antipsychotics is associated with increased risks of head and brain injuries among persons with Alzheimer's disease, according to a recent study from the University of Eastern Finland. The risk increase was highest at the initiation of antipsychotic use. The results were published in the Journal of the American Geriatrics Society (JAGS).

"As adverse effects, antipsychotics may cause sedation, orthostatic hypotension, and arrhythmias which all may lead to falls. Among older persons, falls are the most common reason for traumatic brain injuries," Researcher Vesa Tapiainen from the University of Eastern Finland explains as a possible mechanism for the association.

Community-dwellers with Alzheimer's disease who used antipsychotics had a 29% higher risk of head injuries and a 22% higher risk of traumatic brain injuries when compared to community-dwellers with Alzheimer's disease who did not use antipsychotics. Among persons with Alzheimer's disease, antipsychotics are commonly used to treat neuropsychiatric symptoms of Alzheimer's disease. According to clinical care guidelines, treating the cause of these symptoms, such as pain, is the first line option and secondly non-pharmacological treatments should be prioritized. The use of antipsychotics should be restricted to most severe symptoms (such as severe aggression, agitation or psychosis). Following care guidelines and by carefully considering benefits and risks of adverse effects and events could possibly lower the incidence of head injuries and traumatic brain injuries.

The study was conducted using the nationwide register-based MEDALZ cohort which includes Finnish community dwellers with a newly diagnosed Alzheimer's disease in 2005-2011 (70,719 persons). Persons were excluded if they had a prior head injury, antipsychotic use within one year prior to antipsychotic initiation or if they fulfilled other exclusion criteria of this study. The final study population was 21,795 persons who initiated antipsychotic use and 21,795 persons who did not use antipsychotics. Medicine use was extracted from the Finnish Prescription Register. Chronic diseases, use of other medications and socioeconomic position were taken into account.

A new study, published in PeerJ, shows how University of Liverpool researchers have used a newly developed eye movement test to improve the understanding of how parts of the brain work.

Healthy, older adults are widely reported to experience cognitive decline, including impairments in inhibitory control (the ability to stop ourselves thinking or doing things). However, because ageing effects on inhibitory control are highly variable between individuals, vary depending on tests used, and are sometimes not distinguished from general age-related slowing, this general view is a matter of debate.

Inhibitory control is also important in conditions like schizophrenia, ADHD and forms of Parkinson's disease; patients can become jumpy, distractible or have problems with unwanted thoughts.

Researchers from the University's Department of Eye and Vision Science, led by Dr Paul Knox, developed a new test, using measurements of eye movements, to provide an improved method of investigating inhibitory control, and have applied to study the effects of ageing on this ability.

Study

In the study two cohorts of healthy people were recruited from two different age groups, 19 to 27 years old and 50 to 72 years old. Participants viewed a dot in the centre of a computer a screen and then had to to look at a second dot that appeared to the left or right not when it appeared, but when it disappeared. As people instinctively look at things when they appear, this requires the inhibition of a normal automatic eye movement. Eye movements were measured precisely using an infrared eye tracker, revealing how often they looked too early.

Results

The results showed that older participants were much more likely to look at the dot when it appeared (not when it disappeared) and were slower compared to younger participants.

Dr Paul Knox, said: "We are designed to react to things appearing in our visual world. It is something we do automatically. However, we also have the ability to stop ourselves responding and this prevents us becoming slaves to our sensory environment.

"This new test allows us to measure inhibitory behaviour precisely. It is clear that older participants found it more difficult to inhibit their actions, even once we had accounted for the general slowing that occurs with ageing.

"This confirms that a decline in inhibitory control is a part of normal ageing. We are doing experiments to refine the test, and then we hope to use it to study inhibitory control in a range of important diseases."

New research has discovered that Down's syndrome, Fragile X syndrome and Williams syndrome are all linked to sleep disruption in very young children, and that sleep plays a crucial role in the development of these children's language skills.

Led by Dr Dean D'Souza of Anglia Ruskin University (ARU) and published in the journal Research in Developmental Disabilities, it is the first cross-syndrome study to examine sleep, and the relationship between sleep and language, in very young children with these neurodevelopmental disorders.

Alongside colleagues from the University of Cambridge; Birkbeck, University of London; The LonDownS Consortium, London; Semmelweis University, Budapest; and the University of Oxford; Dr D'Souza compared the vocabulary size and sleep patterns of 75 infants and toddlers with one of these neurodevelopmental disorders alongside 30 typically developing children of the same age.

The researchers found that sleep was disrupted amongst children with all three neurodevelopmental disorders. On average, typically developing children slept for about 50 minutes longer per night than those with a neurodevelopmental disorder.

They also spent less time awake during the night. Whereas typically developing children spent on average just three minutes awake per night, the children with a neurodevelopmental disorder were awake for around 30 minutes longer.

The study also found that the longer the infants and toddlers with Down's syndrome and Williams syndrome slept at night, the more words they knew. For each additional 10 minutes of sleep, these children would understand the meaning of six additional words. The researchers were unable to test this relationship with children with Fragile X syndrome because of the limited sample size.

The children were tested using a list of 416 words that are commonly acquired in early childhood, with the caregiver indicating whether their child can "understand" or "understand and say" the word. Only one of the 75 children with a neurodevelopmental disorder was able to understand, but not say, all 416 words. This child was 47 months old and had Williams syndrome. Nine of the 30 typically developing children (30%) were able to understand, and say, all 416 words.

Dr D'Souza, Senior Lecturer in Psychology at Anglia Ruskin University (ARU), said: "Children with neurodevelopmental disorders commonly have difficulties with language development. Many different factors are likely to contribute to this, and our study focused on the role of sleep. This is because sleep is important for learning and memory, and individuals with neurodevelopmental disorders often report having problems sleeping.

"Our research demonstrates that sleep is disrupted very early in development across various neurodevelopmental disorders, and the indications are that this is contributing to difficulties with learning language.

"Further research is needed to explore whether early interventions to improve the sleeping patterns of children with Down's syndrome, Fragile X syndrome and Williams syndrome would be as beneficial for their language skills as interventions later in their development that specifically target language learning."

The Akay Lab biomedical research team at the University of Houston is reporting an improvement on a microfluidic brain cancer chip previously developed in their lab. The new chip allows multiple-simultaneous drug administration, and a massive parallel testing of drug response for patients with glioblastoma (GBM), the most common malignant brain tumor, accounting for 50% of all cases. GBM patients have a ?ve-year survival rate of only 5.6%.

"The new chip generates tumor spheroids, or clusters, and provides large-scale assessments on the response of these GBM tumor cells to various concentrations and combinations of drugs. This platform could optimize the use of rare tumor samples derived from GBM patients to provide valuable insight on the tumor growth and responses to drug therapies," reports Metin Akay, John S. Dunn Endowed Chair Professor of Biomedical Engineering and department chair. The paper is published in the inaugural issue of the IEEE Engineering in Medicine & Biology Society's Open Journal of Engineering in Medicine and Biology.

The ability to quickly assess the effectiveness of a cancer drug would be a notable improvement over typical cancer protocols in which chemotherapy drugs are given, then tested for several months, and a patient switched to another drug if the first is ineffective. The new device can determine the optimal drug combination in as little as two weeks. "When we can tell the doctor that the patient needs a combination of drugs and the exact proportion of each, this is precision medicine."

Akay's team takes a piece of a tumor biopsy, cultures it and puts it in the chip. Then they add chemotherapy drugs to the chip's microvalves to determine the best drug combination, and the specific proportion, that kills the most tumor cells.

The team cultured 3D tumor spheroids, or clusters, from GBM cell lines as well as patient-derived GBM cells in vitro and investigated the effect of the combination of Temozolomide and a nuclear factor-κB inhibitor on tumor growth.

"Our study revealed that these drugs have synergistic effects in inhibiting spheroid formation when used in combination, and suggests that this brain cancer chip enables large-scale, inexpensive and sample-effective drug screening to 3D cancer tumors in vitro. Further, this platform could be applied to related tissue engineering drug screening studies," said assistant professor Yasmine Akay. She is joined on the team by research assistant professor Naze Gul Avci and post-doctoral fellow Hui Xia. The tissue samples were provided by project collaborator Jay-Jiguang Zhu, MD, director, Neuro Oncology, McGovern Medical School at UT Health.

To minimize any sample loss in vitro, the team improved their existing brain cancer chip system by adding an additional laminar ?ow distribution layer, which reduces sample loss during cell seeding and prevents spheroids from escaping. This allows the spheroids to form uniformly throughout the chip for consistent drug testing between each spheroid.

BUFFALO, N.Y. -- Research by University at Buffalo biologists is providing new insights into alpha-synuclein, a small acidic protein associated with Parkinson's disease.

Alpha-synuclein is known to form abnormal clumps in the brains of patients with Parkinson's, but scientists are still trying to understand how and why this happens.

The new study explores alpha-synuclein's basic properties, with a focus on a section of the protein known as the non-amyloidal component (NAC). The research was done on fruit fly larvae that were genetically engineered to produce both normal and mutated forms of human alpha-synuclein.

The study, led by University at Buffalo biologist Shermali Gunawardena, was published on Jan. 10 in the journal Frontiers in Cellular Neuroscience.

Some key findings:

The NAC region appears to aid alpha-synuclein in moving through pathways called axons that run from one area of a neuron to another. When the NAC region was missing, alpha-synuclein did not move within axons.

Alpha-synuclein that's missing the NAC region may help to prevent unwanted aggregates of the protein. In experiments, Gunawardena's team showed that it's possible -- at least in fruit flies -- to prevent some key problems that occur when too much alpha-synuclein is produced: clumping of the protein; abnormalities in the structure of synapses, which form connections between neurons; and a decrease in the speed at which larvae crawl. The scientists found that when the larvae are engineered to produce both excess alpha-synuclein and a version of alpha-synuclein with the NAC region missing, the larvae crawl normally, the protein doesn't aggregate, and the synapses are normal.

"We show that in fruit fly larvae, we're able to prevent some problems mimicking symptoms of Parkinson's disease, such as accumulation of alpha-synuclein in neurons," says Gunawardena, PhD, associate professor of biological sciences in the UB College of Arts and Sciences.

"Our work highlights a potential early treatment strategy for Parkinson's disease that would leverage the use of deletion of the NAC region," Gunawardena adds. "One reason this study is important is because it shows rescue of alpha-synuclein aggregates, synaptic morphological defects and locomotion defects seen in Parkinson's disease in the context of a whole organism."