Body

Using human blood cells, Brazilian researchers have succeeded in obtaining hepatic organoids ("mini-livers") that perform all of the liver's typical functions, such as producing vital proteins, storing vitamins, and secreting bile, among many others. The innovation permits the production of hepatic tissue in the laboratory in only 90 days and may in the future become an alternative to organ transplantation.

The study was conducted at the Human Genome and Stem Cell Research Center (HUG-CELL). Hosted by the University of São Paulo (USP), HUG-CELL is one of the Research, Innovation and Dissemination Centers (RIDCs) funded by São Paulo Research Foundation - FAPESP.

This study combined bioengineering techniques, such as cell reprogramming and the cultivation of pluripotent stem cells, with 3D bioprinting. Thanks to this strategy, the tissue produced by the bioprinter maintained hepatic functions for longer than reported by other groups in previous studies.

"More stages have yet to be achieved until we obtain a complete organ, but we're on the right track to highly promising results. In the very near future, instead of waiting for an organ transplant, it may be possible to take cells from the patient and reprogram them to make a new liver in the laboratory. Another important advantage is zero probability of rejection, given that the cells come from the patient," said Mayana Zatz, director of HUG-CELL and last author of the article published in Biofabrication.

The innovative part of the study resided in how the cells were included in the bioink used to produce tissue in the 3D printer. "Instead of printing individualized cells, we developed a method of grouping them before printing. These 'clumps' of cells, or spheroids, are what constitute the tissue and maintain its functionality much longer," said Ernesto Goulart, a postdoctoral fellow in USP's Institute of Biosciences and first author of the article.

The researchers thereby avoided a problem faced by most human tissue bioprinting techniques, namely, the gradual loss of contact among cells and hence loss of tissue functionality.

Spheroid formation in this study already occurred in the differentiation process, when pluripotent cells were transformed into hepatic tissue cells (hepatocytes, vascular cells, and mesenchymal cells). "We started the differentiation process with the cells already grouped together. They were cultured in agitation, and groups formed spontaneously," Goulart told Agência FAPESP.

A liver in 90 days

According to the researchers, the complete process from collection of the patient's blood to functional tissue production takes approximately 90 days and can be divided into three stages: differentiation, printing, and maturation.

Initially, the blood cells are reprogrammed to regress to a stage of pluripotency characteristic of stem cells, becoming induced pluripotent stem cells (iPSCs). Japanese scientist Shinya Yamanaka was awarded the 2012 Nobel Prize for Medicine for developing this technique.

The next stage consists of inducing differentiation into liver cells. The spheroids are then mixed with bioink, a hydrogel-like fluid, and printed out. The resulting structures mature in culture for 18 days.

"The printing process entails the deposition of spheroids along three axes, which is necessary for the material to gain volume and give the tissue proper support," Goulart said. "The gel-like bioink is crosslinked to make the structures more rigid so that they can be manipulated and even sutured."

Most of the available methods for printing live tissue use immersion and cell dispersion in a hydrogel to recapitulate the microenvironment and ensure tissue functionality. However, experiments have shown that loss of cell contact and functionality tends to occur when dispersion is performed cell by cell.

"It's a somewhat traumatic process for the cells, which need time to get used to the environment and acquire functionality," Goulart said. "At this stage, they aren't tissue yet because they're dispersed, but as shown by our study, they already have the capacity to clear the blood of toxins and to produce and secrete albumin [a protein produced only by the liver], for example."

In this study, researchers developed mini-livers using blood cells from three volunteers as raw material and compared markers relating to functionality, such as the maintenance of cell contact and protein production and release. "Our spheroids worked much better than those obtained from single-cell dispersion. As expected, during maturation, the markers of hepatic function were not reduced," Goulart said.

Although the study was limited to producing miniature livers, the technique can be used in the future to produce complete organs suitable for transplantation, according to Goulart. "We did it on a small scale, but with investment and interest, it can easily be scaled up," he said.

How can the perspectives of patients with multiple sclerosis (MS) be given more consideration in clinical trials? This question was investigated and corresponding recommendations were developed by a working group of the Drug Commission of the German Medical Association (AkdÄ), the Charité University Hospital Berlin, and the Institute for Quality and Efficiency in Health Care (IQWiG). The analysis has now been published in the EPMA Journal*.

More than 200,000 people affected in Germany

Multiple sclerosis is the most common autoimmune disease of the central nervous system, affecting more than 200,000 people in Germany. They suffer from impaired vision and sensation as well as restrictions in coordination and even paralysis. The diagnosis is usually made between the ages of 20 and 40 - women are affected more frequently than men. The disease is chronic and inflammatory and so far there is no cure. In 85 to 90 percent of patients, the disease often starts with relapsing neurological deficits, which usually disappear completely or partially after weeks or months. After years or decades, a transition into a chronic progressive course often occurs: The patients' neurological state gradually worsens; in particular, their walking distance decreases.

Since the development of the first immunotherapy (interferon beta-1b) in 1995, numerous substances have been approved for the immunomodulatory treatment of MS, with the aim of reducing the number of relapses. Since then, the therapeutic landscape has expanded considerably. In parallel with the increasing number of available immunotherapies, treatment strategies have shifted from a pure "relapse prevention approach" to individualized medical care.

Working group systematically analysed 29 pivotal phase III trials

The working group of AkdÄ, Charité and IQWiG systematically analysed 29 drug approval ("pivotal") phase III trials on disease course-modifying / immunomodulating drugs for the treatment of MS. The analysis showed that the patient perspective and thus symptoms such as fatigue (i.e. tiredness and increased exhaustibility) or health-related quality of life were generally not taken into account. In contrast, biological indicators and endpoints of imaging procedures with unclear relevance for the severity of the disease were routinely investigated.

Friedemann Paul, Scientific Director of the Experimental and Clinical Research Center (ECRC), a joint establishment of the Charité and Max Delbrück Center for Molecular Medicine (MDC), notes: "If in future we design the studies in such a way that they are more closely orientated to the needs of patients, we will obtain study results that are more likely to enable us to provide patients with more targeted and individualized medical care."

Suggestions for improvement by the working group

All drugs available on the market were tested in mainly one- to two-year drug approval studies. Beyond this period, hardly any methodologically sound data on the benefits or side effects of these drugs are available. Wolf-Dieter Ludwig, Chairman of the AkdÄ explains: "Due to their duration and usually short follow-up, drug approval studies are not suitable for collecting data on the sometimes very serious side effects that only occur after long-term treatment." Due to these shortcomings in the design of clinical trials, the working group developed suggestions for improvement. Sinje Gehr, Project Head of the Charité MS Initiative states: "With our recommendations, we want to make a contribution to improving the care of patients with MS".

Certain symptoms and consequences of the disease are highly relevant for patients. It is therefore also important to collect data on the patient perspective in studies by means of patient-reported outcomes (PROs). Thomas Kaiser, Head of IQWiG's Drug Assessment Department explains: "If no data on symptoms and quality of life are collected in studies, then these studies do not provide a complete picture of the benefit of a drug." In general, patients are very focused on whether disabilities progress and whether symptoms such as fatigue, depression, cognitive impairment, pain, spasticity, sleep disorders or loss of vision increase. This was also evident in the MS Initiative discussion rounds. He adds: "Many of these symptoms could and should in the future be documented with the help of internationally established and validated patient questionnaires."

Future studies on MS should attribute greater importance to the immediate experience of patients with MS by focusing more on patient-reported outcomes. The individualized focus of medical treatment requires that studies consider not only clinical and radiological findings relevant for approval, but also the patient perspective. This applies in particular to very burdensome symptoms such as fatigue, pain, depression and cognitive impairment. Likewise, in view of the often-required long-term treatment with immunomodulating drugs, study participants should be observed for longer periods in order to gain more insight into significant complications and side effects.

San Antonio, Texas (December 17, 2019) - A major goal of tuberculosis (TB) research is to find a way to treat people with the latent (or inactive) form of the disease to keep them from developing symptomatic TB. A breakthrough study using a new animal model developed for this purpose showed a combination of two classes of antibiotics can wipe out this hidden threat. The study was published in the American Journal for Respiratory Clinical Care Medicine.

Deepak Kaushal, Ph.D., Director of the Southwest National Primate Research Center, and Jyothi Rengarajan, PhD, Associate Professor of Medicine at Emory University and the Yerkes National Primate Research Center, served as co-principal investigators of the 10-month study. Using rhesus macaques, the scientists were able to create a model of latent TB that resembles what occurs when a person is infected with Mycobacterium tuberculosis (Mtb), the bacteria that causes TB, but does not develop active disease. The bacteria are "hibernating" in the lungs, Dr. Kaushal explained.

"People with latent tuberculosis infection remain a source of disease because they can potentially reactivate at any point in time," Dr. Kaushal said. Complicating factors like an HIV infection, diabetes, aging or other diseases can trigger the latent bacteria to become symptomatic and infectious again. The current treatments for latent TB are lengthy. Many patients do not finish the course of therapy. Dr. Kaushal believes a shorter course of treatment would be beneficial.

Using low-dose infection through an aerosolization chamber, scientists gave the nonhuman primates enough TB to create a latent infection. The scientists then treated half of the animals with a once-weekly combination of antibiotics isoniazid and rifapentine for three months; the other half was untreated. This is likely the first report modeling LTBI treatment in nonhuman primates.

Afterward, the animals were infected with SIV (Simian immunodeficiency virus), which mimics HIV in humans, to test whether the drug treatment cleared bacteria from their lungs. Of the monkeys that had no treatment for latent TB, 70 percent developed active TB after SIV infection. None of the monkeys that had the three-month course of antibiotics developed active TB after SIV infection suggesting the treatment cleared the bacteria and prevented reactivation.

"The antibiotic treatment we used for this study is a new, shorter regimen the CDC recommends for treating humans with latent tuberculosis, but we did not have direct evidence for whether it completely clears latent infection" says Dr. Rengarajan. "Our experimental study in macaques showing almost complete sterilization of bacteria after treatment suggests this three-month regimen sterilizes humans as well."

This is the first time rhesus macaques were used as a model of latent TB treatment. Dr. Kaushal said the animal will be an important model for testing other TB treatment regimens going forward.

Around the world, TB claims more lives than any other infectious disease. In the U.S. alone, about 13 million people develop latent TB each year, and 15,000 to 20,000 people are diagnosed with active TB annually. Globally, close to one quarter of the population (1.8 billion) is infected with TB, according to the World Health Organization.

In an accompanying editorial published in the same journal, Dr. Andrew Vernon of the Division of TB Elimination at the Centers for Disease Control & Prevention and Dr. William Bishai of the Center for Tuberculosis Research at Johns Hopkins University write the application of this drug regimen "could presage a major step forward in TB prevention and control." They call the results of the study "dramatic."

The study was conducted at Tulane and Emory as part of a Tuberculosis Research Unit (TBRU) U19 award to Emory University (Program Directors: Henry Blumberg MD, Emory and Joel Ernst, MD, UCSF), and includes additional collaborators at Emory, UCSF and University of Florida from the TBRU-ASTRa study group.

The Tuberculosis Research Unit Network was established in 1994 to integrate scientist and clinician perspectives on the enormous health impact of the disease in TB endemic countries. Four multi-project awards empower researchers to study TB latency and persistence and their relation to active TB disease in humans.

AURORA, Colo. (Dec. 17, 2019) - Long-acting reversible contraceptives like intrauterine implants have greatly reduced unintended pregnancies and abortions, but government protections allowing religious hospitals to restrict care are limiting access to health care consumers, according to an expert at the University of Colorado Anschutz Medical Campus.

The commentary was published this month in the American Journal of Obstetrics & Gynecology.

"Long-acting reversible contraceptive (LARC) methods...are highly effective and result in a number of medical, social and economic benefits," said the commentary's author Maryam Guiahi, MD, associate professor of Obstetrics and Gynecology at the University of Colorado School of Medicine. "Previously, a major barrier to LARC access was financial, as many patients had inadequate insurance coverage or faced high upfront out-of-pocket costs."

But in 2012, the Affordable Care Act (ACA) required all insurance plans to provide contraceptives without high deductibles or copays. Costs dropped while there was an increase in the use of long-acting contraceptives.

Yet new barriers have surfaced, said Guiahi.

Many patients are treated at Catholic health care facilities which restrict access to contraceptives. Since 2016, 14.5% of U.S. hospitals have become Catholic-owned or affiliated, accounting for one in six beds. Those numbers will likely increase as Catholic facilities continue to expand and merge with other health care systems. Between 2001-2016, Catholic hospitals grew by 22%.

These hospitals are governed by the Ethical and Religious Directives for Catholic Health Care Services created by the U.S. Conference of Catholic Bishops. That means that most contraception is off-limits.

Guiahi said many physicians in these facilities have found workarounds allowing them to provide contraceptives to patients under the guise of reducing heavy menstrual bleeding or other medical problems.

In previous studies, the researcher found that many Catholic health care facilities lack transparency. One website review of all 646 U.S. Catholic hospitals found that 21% did not report their Catholic identity.

But so far there has been little research on the impact of restricting these long-acting contraceptives in Catholic hospital settings. Guiahi said her own efforts to research such outcomes "have been met with resistance and dismissal."

"This adds to my concerns over lack of transparency and frankly dishonesty from Catholic institutions," she said.

Guiahi, who once worked in a Catholic hospital, said most ob-gyns in these facilities understand the benefits of LARCs and what happens when they are restricted.

"Yet many feel overwhelmed by the influence of the Catholic church and the government, despite being the very experts on contraceptive care," she said.

She urged action by physicians and others to ensure that research and health care access are not being sacrificed in the name of religion.

"We must demand that research efforts within Catholic institutions be ethical and expanded in order to understand the ways in which restrictions impact patients, the extent to which workarounds compensate and whether certain populations are at greater risk of adverse outcomes compared to others," Guiahi said. "By providing evidence of the real-life implications of institutional restrictions to LARC in Catholic settings, we can then inform advocacy efforts to ensure equitable access to effective health care."

Nasal saline and corticosteroid sprays are pretty standard treatment for individuals battling chronic rhinosinusitis (CRS). They thin out thick mucus buildup and help ease the swelling in the nasal cavity that are the bane of anyone who has battled what physicians often refer to as the asthma of the sinuses.

If used consistently and appropriately, these nasal sprays can lessen the need for antibiotics and oral steroids that are needed when symptom severities flare, according to a recent study from Dr. Ahmad Sedaghat, an ear, nose and throat specialist at the University of Cincinnati College of Medicine.

Sedaghat and a team of researchers looked at 150 patients at Massachusetts Eye and Ear undergoing medical management for CRS and found that CRS-related usage of oral steroids and antibiotics dropped by 0.2 courses per three-month period on average. That's about one fewer courses of antibiotics and oral steroids in a year to deal with severe symptoms of CRS.

Those results were reported in the scholarly journal Laryngoscope and, according to researchers, are statistically significant.

When researchers focused on individuals in this study needing oral steroids (roughly 40 patients) and those needing antibiotics (33 patients), the use of antibiotics for CRS dropped by 40% while the use of oral steroids associated with CRS decreased by 67%, said Sedaghat.

"We found that the use of the sprays or irrigations improved antibiotics and oral steroids usage by closer to three-to-four courses per year, on average, which is a huge effect," said Sedaghat, also a UC Health physician. "Medication usage was reduced by one course every three-to-four months. The medical therapy we provided in the form of intranasal saline and intranasal steroids dramatically cut down on the usage of systemic antibiotics and steroids."

Antibiotics have gastric and intestinal side effects and lead to body resistance, while long-term use of steroids can cause mood disturbance, insomnia, weight gain, diabetes, cataracts and other problems. "We really want to minimize the use of these medications," said Sedaghat.

"If you simply treat patients regularly and consistently with what we call appropriate medical management, and that means staying on top of them and making sure these patients are using their sprays every single day, these patients will have dramatically fewer problems," said Sedaghat.

CRS is similar to asthma, but it occurs in the sinusitis instead of the lungs.

"Most people know someone who has asthma," he said. "In those individuals, the body produces inflammation in the lining of the lungs, and that leads to wheezing and chest tightening and shortness of breath. In some people, the body produces inflammation in the lining of the sinuses. It's not fatal like asthma, but chronic rhinosinusitis leads to a dramatic decrease in the quality of life. They are miserable."

There are four main symptoms of CRS -- nasal obstruction, nasal drainage, facial pain or pressure and decreased sense of smell. Patients need to have two out of four of these symptoms for at least 12 weeks to be diagnosed with CRS.

"The hope is with the consistent use of these nasal irrigations and corticosteroid sprays, we can keep symptoms at an acceptable level and so symptoms don't affect patients' quality of life," said Sedaghat.

Sedaghat said researchers initially believed that individuals who came into the study with more severe CRS symptoms would need more antibiotics or steroids. "What we found is that is not the case," he said. "What we found is the usage of antibiotics and steroids and the acute exacerbations is independent of baseline symptomlogy."

"How bad you are on a day-to-day basis, that behavior of the disease, is very different than the frequency of you getting exacerbations in symptoms. These spikes in symptoms are coming from somewhere else," said Sedaghat. "If physicians are not savvy to this, you may see someone with low-level symptoms and think the patient will be fine and believe treatment shouldn't be as rigorous. In those patients, we found exacerbations of symptoms."

"The frequency you needed antibiotics before the study is predictive of the frequency you need antibiotics at the end of the study," said Sedaghat. "If you needed more antibiotics when you first started, then you will need antibiotics during the study period even if the frequency of exacerbations decreased."

Four months after treating them, Yasuhiro Shiga, MD, PhD, checked on his rats. Walking into the lab, he carried minimal expectations. Treating spinal cord injuries with stem cells had been tried by many people, many times before, with modest success at best. The endpoint he was specifically there to measure -- pain levels -- hadn't seemed to budge in past efforts.

"Well, it doesn't seem to be working. I don't see any real change in pain behavior in any of the groups," said Shiga, a visiting scholar at University of California San Diego School of Medicine, apologetically, as he walked into the office of his supervisor, Wendy Campana, PhD, professor in the Department of Anesthesiology and Program in Neuroscience.

But, to Campana's surprise, he continued, almost as an after-thought.

"Although ... some rats are actually really moving."

The difference for those rats was this: Before delivering them into the spinal cord injury site, Shiga and Campana had conditioned stem cells with a modified form of tissue-type plasminogen activator (tPA), a drug commonly used to treat non-hemorrhagic stroke.

Their findings are published December 17, 2019 in Scientific Reports.

tPA is used to break up blood clots, allowing blood to more freely flow back into the brain following a stroke. But tPA is also a naturally occurring enzyme known to boost neuron growth and dampen inflammation. So the researchers used an enzymatically inactive form of tPA, still anti-inflammatory and pro-neuron growth but without effect on blood clotting, which could be a dangerous side effect in a person not having a stroke.

In a laboratory dish, the researchers added the modified tPA to neural progenitor cells -- the precursors to neurons. They had generated these pre-neurons from induced pluripotent stem cells, a special kind of stem cell that can be derived from a person's skin cells. After 15 minutes, the researchers transferred either tPA-conditioned or unconditioned neural progenitor cells to the injury site in a rat model of severe spinal cord injury.

Two months after treatment, the researchers found 2.5-fold more tPA-conditioned neural progenitor cells than unconditioned cells still present in the rats. What's more, the tPA-conditioned cells had begun specializing into full-fledged neurons, with axons (branches) emerging from the site of transplantation and extending as far as four vertebrae away. According to Campana, that's unusual.

"It was striking to see at two and four months the tremendous improvements in the ability of those progenitor cells to survive in the injury cavity," she said. "Just keeping these cells alive has been very difficult in past studies."

Even more surprisingly, it turned out that what Shiga had observed in the rats with modified tPA was a three-fold increase in motor activity after four months, as measured using a well-established scoring system that quantifies a combination of rat joint and limb movements, trunk stability, paw and tail positioning, stepping and coordination.

Pain is a special focus of Campana's lab and the team was initially most interested in that aspect of spinal cord injury treatment. They measure pain in rat models based on how they lift their front paws in response to added weights.

"The addition of tPA-treated neural precursors didn't reduce pain in this model," Campana said. "But we also didn't exacerbate it -- and to not see increased pain is important safety information for clinical translation to improve motor outcomes. We also don't want worsen the pain burden of patients living with spinal cord injuries."

One limitation of this spinal cord injury model is that the rats don't live long enough to truly recapitulate what for humans is a long-term condition, or long enough to measure potential changes in gene expression over time. But it is currently the best available non-human primate model for the human situation, Campana said.

While Campana's work may be many years away from testing in patients, her approach has two potential advantages compared to other studies: 1) the use of induced pluripotent stem cells means a patient's own cells would be the source of treatment, rather than a transplant of donated cells from another person, and 2) tPA is already approved by the U.S. Food and Drug Administration (FDA) for use in humans.

The team next plans to dive into what, exactly, modified tPA does to neural progenitor cells on a molecular level that stimulates their growth and allows them to help repair spinal cord injuries.

Meanwhile, other UC San Diego School of Medicine researchers are testing other approaches to treating spinal cord injuries with stem cells in clinical trials. For example, in June 2018, a team reported https://health.ucsd.edu/news/releases/Pages/2018-06-01-stem-cell-based-phase-I-trial-to-repair-spinal-cord-injuries-produces-encouraging-results.aspx that a first-in-human phase I clinical trial in which neural stem cells were transplanted into participants with chronic spinal cord injuries produced measurable improvement in three of four subjects, with no serious adverse effects.

There are currently an estimated 291,000 people living with a spinal cord injury in the U.S. and approximately 17,730 new cases each year, according to 2019 statistics provided by the National Spinal Cord Injury Statistic Center at the University of Alabama at Birmingham. There is no way to reverse damage to the spinal cord. There are no FDA-approved stem cell-based therapies available for spinal cord injuries. Depending on the type and severity of the injury, spinal cord injuries are currently managed -- and further injury prevented -- with a combination of surgery, medications to manage pain, rehabilitation and assistive devices.

The number of teens taking and overdosing from benzodiazepines, commonly prescribed anxiety medications, has risen dramatically over the past decade, according to a national study coauthored by Rutgers researchers.

The study, published in the journal Clinical Toxicology, found a 54 percent increase in cases involving children ages 12 to 18 that were reported to U.S. Poison Control Centers from 2000 to 2015.

The researchers, from several institutions including MedStar Health, analyzed 296,838 benzodiazepine exposure cases involving children under the age of 18 obtained from the National Poison Data System. While the rate of exposure in children under the age of 6 decreased, the rate for adolescents rose from 17.7 exposures per 100,000 children in 2000 to 27.3 exposures per 100,000 children in 2015. The study also found a rise in intentional abuse, with nearly half of all reported exposures in 2015 documented as intentional abuse, misuse or attempted suicide.

"While benzodiazepine overdose by itself is typically not life-threatening, the findings of this study show an increase in teens taking one or more additional substances, which increases the severity of the effects, including death or life-threatening symptoms that can affect future health," said Diane Calello, executive and medical director of the New Jersey Poison Control Center at Rutgers New Jersey Medical School's Department of Emergency Medicine, one of the authors.

Approximately 70,000 children receive care in an emergency department annually due to medication overdoses, with nearly 12 percent of these visits resulting in hospitalization. Calello said the increased availability of prescription medications is a likely cause of both adult and pediatric poisonings.

"Our study group found that the increasing rate of reported benzodiazepine exposures appear to reflect the increasing rate of benzodiazepine prescriptions that have been reported across the United States over the past decade," she said. "Medical providers should be aware of the increased prevalence of benzodiazepine exposures to help limit unnecessary prescribing. Parents and caregivers must be counseled on the proper use, storage and disposal of these high-risk medications."

A drug that once helped obese adults lose weight, but was withdrawn from the market due to heart risks, may be safe and effective for children with a life-threatening seizure disorder called Dravet syndrome, say researchers from UCSF Benioff Children's Hospitals and other major treatment centers.

The drug fenfluramine -- one half of the discontinued prescription weight-loss cocktail fen-phen -- was developed for pediatric use and found to decrease the number of seizures by more than half for many Dravet syndrome patients, according to their study, which publishes in The Lancet on Dec. 17, 2019.

The 119 study participants were between 2 and 18 years old, with an average age of 9 years, and were diagnosed with Dravet syndrome, a treatment-resistant form of epilepsy that develops in infancy and affects one in 15,700 babies born each year. The syndrome is characterized by prolonged and frequent seizures, developmental delays, speech impairments, sleep disturbances, and behavioral and health issues. Tragically, some 10 to 15 percent of Dravet patients die by age 25 from so-called sudden unexpected death, which may be due to seizure-triggered irregular heart rhythm or suffocation.

"If children with Dravet syndrome can be diagnosed and effectively treated when they are young, they may be spared further neurodevelopmental delays caused by repeated seizures," said co-first author Joseph Sullivan, MD, professor of neurology and pediatrics at UCSF Benioff Children's Hospitals, and director of the Pediatric Epilepsy Center of Exellence. "The results of this study may have significant quality-of-life implications for patients with Dravet syndrome and their families."

The participants, who had an average of 40 convulsive seizures in the month before the trial, despite their current medication regimen, were enrolled at hospitals in the United States, Canada, Australia and Europe. They were assigned to one of three groups in this phase 3 trial: 0.7mg/kg/day of fenfluramine, with a maximum daily dose of 26 mg per day; a lower dose of 0.2 mg/kg/day; or placebo, along with their current medications.

Higher Study Dose Means Fewer Seizures

The researchers found that patients who received the higher of the two study doses had 62 percent fewer convulsive seizures per month than those on placebo, and that those on the lower dose had 32 percent fewer convulsive seizures per month than the placebo participants. The average longest seizure-free interval was 25 days for the higher-dose group, 15 for the lower-dose group and nine days for those on placebo.

For parental assessment of improvements, 22 of 40 parents (55 percent) whose children participated in the higher-dose cohort said that their children were "much improved" or "very much improved," versus 16 of 39 parents (41 percent) in the lower-dose group and four of 40 parents (10 percent) whose children had taken placebo.

The researchers acknowledged that fenfluramine had been withdrawn from the market by the U.S. Food and Drug Administration in 1997, due to reports in some patients of damage to heart valves.

"This was a concern, but we knew the drug used in this study had undergone tests to enable pediatric use and that patients would be followed closely as part of the study," said Sullivan, who was the principal investigator in the North American study sites. "At the start of the study, when I asked parents what they would do if their child developed heart valve abnormalities, yet had significantly fewer seizures, they said they were willing to accept some risk. They knew that every seizures comes with the risk of sudden unexpected death."

To minimize risk, the children were exempted from the trial if heart valve irregularities were spotted via electrocardiogram at the screening visit, even though these findings are considered by most cardiologists to be normal. Additionally, the maximum daily dose in the study was capped at 26 mg, versus doses of 52-to-104 mg or more for the adults who took fenfluramine as part of the weight loss combination prescription fen-phen.

No cases of heart valve damage or pulmonary hypertension were identified during the 14-week trial, nor in the ongoing open-label extension trial with many patients taking the study drug for more than one year.

Weight Loss, Lethargy, Sleepiness are Side Effects

Most side effects were mild-to-moderate and were evenly distributed among the higher-dose, lower-dose and placebo groups. However, weight loss was evident in the fenfluramine groups: eight of 40 patients (20 percent) in the higher-dose group lost weight, ranging from 7.2 percent to 11.4 percent of their body weight, compared with five of 39 patients (13 percent) in the lower-dose group. Those children's weight loss ranged from 8.4 percent to 21.9 percent of their body weight. The authors note that in this latter case, the patient had been "actively managed for obesity by a nutritionist."

Cases of diarrhea, lethargy and sleepiness were also higher in the two fenfluramine groups than in the placebo patients.

Sullivan said a reduction in the number of seizures was "tremendously encouraging for patients and families." This was reinforced by the experience of Dravet patients in Belgium, where fenfluramine was approved for compassionate use in 2002. "Some of these patients have been taking fenfluramine for up to 30 years, with sustained, clinically meaningful reductions in seizure activity without evidence of cardiopulmonary disease," he said.

14-week randomised controlled trial of 119 children aged between 2-18 years finds evidence for the benefit of fenfluramine in Dravet syndrome when given in addition to existing anti-epilepsy drugs.

Fenfluramine was previously used for weight loss in obese adults and withdrawn in the 1990s after concerns about heart-related side effects when given in high doses to that population: however, in the new study, low doses were given and none of these side effects were observed, though more safety data is needed.

Children with Dravet Syndrome given fenfluramine experienced a greater reduction in convulsive seizures, compared to patients given a placebo for a 14-week treatment period, according to a randomised controlled trial published in The Lancet.

Dravet syndrome is a rare, treatment-resistant epileptic disorder. It is one of a group of severe epileptic disorders that affect around one in 15,700-22,000 babies born each year. Dravet syndrome is responsible for about 10% of childhood onset epilepsy cases, where patients have frequent, debilitating seizures, neurodevelopmental, motor and behavioural problems and high mortality due to sudden unexpected death in epilepsy (SUDEP). Patients with Dravet syndrome have a substantially higher rate of SUDEP compared with the general population of patients with epilepsy. Current therapies are inadequate for most patients, and approximately 45% of patients have more than three convulsive seizures per month despite multiple antiepileptic drugs.

Fenfluramine was marketed for weight loss in obese adults, most often in combination with another weight loss drug called phentermine, but voluntarily withdrawn from the market in 1997 because of high rates of heart problems in some individuals given high doses of up to 220mg per day. Evidence of its antiepileptic effects was reported in small case studies and observational studies, in particular in a compassionate use program in Belgium in which Dravet syndrome patients have been treated daily with fenfluramine for up to 30 years with sustained, clinically significant reductions in seizure frequency, without evidence of heart valve disease.

The drug tested in the study is a low dose fenfluramine oral solution. It had been reported to have antiepileptic activity in small case studies and observational studies and in Belgium, child neurologists obtained a Royal Decree to permit ongoing testing in patients with Dravet syndrome. The daily doses used were comparable to those in the Phase 3 study ranging from 0.13 mg/kg per day to 0.69 mg/kg per day.

In the study, two identical 14-week-long phase 3 randomised controlled clinical trials designed to assess the effectiveness and safety of fenfluramine, compared to placebo - one trial in the USA and Canada, and the other in western Europe and Australia. The results of the two trials were merged and analysed together. They included 119 participants with Dravet Syndrome aged between two and 18 years old (the average age was 9 years old). The authors note that patients included in the trial had a high seizure burden, with an average of about 1.5 convulsive seizures per day (around 40 seizures within a 28-day period).

Participants were divided into three groups, receiving either placebo (40 participants), a low dose of fenfluramine (0.2mg per kg per day - 39 participants), or a higher dose (0.7mg per kg per day - 40 participants). The drug was given orally by parents and caregivers.

Nine patients withdrew before the end of the trial, including three in the placebo group (one for lack of effectiveness, and two for patient or guardian decision) and six in the higher dose group (five for side effects, and one for patient or guardian decision). Additionally, six of the patients in the higher dose group did not tolerate the maximum dose due to side effects and either had the dose reduced (3 patients) or discontinued treatment (3 patients). These patients were included in the higher dose group for the analysis.

Comparing patients given the higher dose of fenfluramine (0.7mg per kg per day) with those given placebo, the authors estimated a 62% reduction in the mean number of convulsive seizures.

Comparing the patients' level of seizures before and while they were given treatment, the study found that patients given the higher dose had an average 75% reduction in frequency of convulsive seizures per 28 days (from 21 before treatment per 28 days to five during treatment). Patients given the lower dose had an average 42% reduction (from 18 seizures per 28 days before treatment to 13 during treatment) and the placebo group had an average 19% reduction per 28 days (from 27 before treatment per 28 days to 22 during the trial).

Looking at the side effects of the drug, the authors found that 21-38% of patients in the active treatment groups had decreases in appetite and weight loss above the 7% threshold was observed in 13% of patients in the fenfluramine 0.2 mg/kg per day group, and in 20% of patients in the fenfluramine 0.7 mg/kg per day group. Other common adverse events seen were diarrhoea, fatigue, lethargy and sleepiness (somnolence).

Scans of the heart during the study revealed no heart valve problems in all patients and no signs were observed of high blood pressure in the arteries of the lungs during the entire trial. The authors noted that cardiac safety of fenfluramine in the current study was limited by the short treatment and observation period of 14 weeks in this trial, and longer term research will still be needed. However, these findings are consistent with those reported with long-term use of fenfluramine in Dravet syndrome in Belgium, where no cases of heart problems have been reported with up to 30 years of fenfluramine treatment.

Study author, Dr J. Helen Cross, UCL Great Ormond Street NIHR BRC Institute of Child Health, UK, says: "The frequent seizures suffered in Dravet syndrome impact on the lives of patients and their families. The patients in this study had a high baseline seizure burden with an average of approximately 40 seizures per month across all treatment groups. In our clinical trial we saw impressive reductions in seizures in the patients who received fenfluramine compared with those on the placebo, and although further study will need to assess the long-term safety, I am optimistic about what we have seen so far." [1]

Study author, Arnold Gammaitoni, Zogenix, USA, says: "We believe fenfluramine, if approved by regulatory authorities, could be an important new treatment option for patients with Dravet syndrome, a condition marked by debilitating seizures, extremely poor neurodevelopmental outcomes, and a significant rate of SUDEP. Since the trial finished, most of the patients from this study have continued treatment in an ongoing, long-term open label extension study, where we have continued to see clinically meaningful reduction of convulsive seizures with no signs of heart valve problems." [1]

The authors note a limitation of their study is that the occurrence of side effects of fenfluramine could have meant patients and their families could guess that they were on the drug, which may have led to bias in the reporting of seizures (ie, it may have been clear from a child's reduced appetite that they were on fenfluramine).

In a linked Comment, Professor Samuel F Berkovic of the Epilepsy Research Centre at the University of Melbourne, Australia, says: "Until recently, infants with severe epilepsy and intellectual disability often received a diagnosis of not much more than that--the cause was usually unknown, treatment was supportive, and families often felt disempowered due to lack of information about the condition."

He continues: "Although these diagnostic and therapeutic advances are welcome, strategies need to improve the overall neurological outcome are needed. A number of therapies are currently under investigation for Dravet syndrome and other epileptic encephalopathies... The transformation of this field from one of hopelessness, if not disinterest, to exciting cutting-edge science with definite therapeutic advances and hope for a major breakthrough is remarkable."

A new peer-reviewed commentary published in the January issue of the American Journal of Public Health argues for new metrics to evaluate the public health response to HIV in the United States. The U.S. Department of Health and Human Services (HHS) has announced plans to reduce the number of new HIV infections by 75 percent in the next five years and 90 percent in the next 10 years. "Ending the HIV Epidemic" (EtHE) efforts will focus initially on 48 high burden counties; Washington, DC; San Juan, Puerto Rico; and seven states with substantial rural HIV burdens, before moving on to all U.S. counties.

Dr. Denis Nash, Distinguished Professor of Epidemiology at the CUNY Graduate School of Public Health and Executive Director of the CUNY Institute for Implementation Science in Population Health, notes that because ending the public health threat of HIV requires intensification and more focused targeting of implementation, there is a need for new metrics to inform and evaluate EtHE initiatives. Nash argues that newer metrics should complement the current metrics that focus on new HIV infections, individuals successfully being treated for HIV, and coverage of pre-Exposure Prophylaxis (PrEP), a drug which can prevent HIV infection.

The HHS plan should develop metrics that track the deployment and uptake of specific intervention delivery strategies, which would provide data regarding plan goals. Nash contends that HIV-related health disparities in both implementation outcomes and health outcomes require special attention.

"Given the major disparities in HIV incidence and the potential for these disparities to be further exacerbated through differential access to HIV testing, PrEP, HIV treatment, and treatment adherence support, special attention must be paid to the use of metrics and targets capable of informing action and course corrections aimed at mitigating disparities," Nash says.

Finally, Nash underscores the need for HHS to develop a public facing web-based dashboard system that more rapidly disseminates actionable information based on the new metrics needed to inform the implementation of the HHS plan.

"We have made substantial strides in getting useful data into the hands of those that are in a position to act in support of New York's Ending the Epidemic initiative," he said, referring to New York's Ending the Epidemic Dashboard system. "The national EtHE Plan needs a timely dissemination system like the one we have here in New York in order to accelerate impact and share lessons learned within and across those jurisdictions aiming to end HIV as a local public health threat."

Low educational levels predict an increased risk of developing or dying from heart disease and stroke according to the first nationwide study of the link between education and risk of cardiovascular disease.

The study, which is published in the European Heart Journal [1] today (Tuesday), is also the first nationwide study to look at the extent to which low income and work stress plays a role in the association between education and cardiovascular disease. It found that low income and work stress could explain between 21-54% of the increased risk of developing or dying from cardiovascular disease among people with and without cardiovascular or metabolic diseases at the start of the study.

Researchers led by Dr Elisabeth Framke at the National Research Centre for the Working Environment in Copenhagen, Denmark, analysed data from 1,638,270 Danish residents aged 30 to 59 in 2000 who did not have cardiovascular disease or diabetes at the start of the study. In addition, they looked at 41,944 people who had been diagnosed already with cardiometabolic disease, which includes heart disease and metabolic conditions such as diabetes. They followed them all until the end of 2014 to see who developed or died from these medical conditions.

Dr Framke said: "We found that among healthy individuals, those with a low educational level have a higher risk of developing cardiovascular disease than those with a high educational level. Among 10,000 men with low education, 61 would develop a cardiovascular disease within 12 months, whereas among 10,000 men with high education, only 34 would develop the disease within this time-frame. After taking some variables into account that could affect the results, such as age and migration background, this corresponds to a 1.62-fold higher risk among those with low education.

"Among women, the picture is similar, although working-age women have a much lower risk of cardiovascular disease than men. Among 10,000 women with low education, 32 would develop a cardiovascular disease within 12 months, whereas among 10,000 women with high education, only 16 would develop the disease within this time-frame. This corresponds to a 1.66-fold higher risk."

The researchers also gathered information on annual disposable household incomes and "job strain", which is a combination of the psychological demands of a job and the amount of control a person has over their work. A job with high job strain would be one where there are high psychological demands, but little control.

"When we took household income level and level of work stress, measured by the combination of high job demands and low job control, into consideration, the increased risk among those with low educational level lessened somewhat. We found a 1.46-fold higher risk among men and 1.53-fold higher risk among women," said Dr Framke.

This means that adjusting for income and job strain reduced the risk by 25% for men and by 21% for women.

The researchers found a similar pattern when they looked at people who had cardiovascular disease or diabetes when the study started. Men and women with a low educational level had a 1.52-fold and 2.18-fold higher risk of dying of cardiovascular disease respectively than men and women with a high educational level. After adjusting for income and job strain, the risk was reduced to a 1.24-fold and 1.79-fold increased risk in men and women respectively - a reduction in risk of 54% in men and 33% in women.

"Our interpretation of these findings is that low income and high job strain may play a role in how low educational level affects the risk of developing or dying from cardiovascular disease, but that also a considerable part of this association is independent of income and job strain," said Dr Framke.

"If low income and high job strain play a role in how educational level affects risk of cardiovascular disease, then improvement of disposable income and reduction of job strain may help to reduce the increased risk of developing or dying from cardiovascular disease among people with low educational attainment.

"Furthermore, ensuring equal treatment regardless of educational level is important, both in terms of preventing the development of cardiovascular disease amongst healthy people and of preventing death from cardiovascular disease amongst people who already have heart disease, diabetes or have suffered a stroke."

A major strength of the study is its size: it included all employees in Denmark aged 30-59. Fourteen years of follow-up, with annual updates of information such as education, income, job strain, development of diseases and causes of death, taken from population and nationwide registers meant that the data were accurate and comprehensive.

The study can only show that there is an association between factors such as education, low income and job strain and cardiovascular disease, not that they cause the disease. Other limitations include the fact that the findings cannot necessarily be generalised beyond the age group examined or to other countries. The data lacked information on biological and behavioural factors that can affect the risk of cardiovascular disease, such as blood pressure, cholesterol levels, smoking and diet.

PHILADELPHIA - An experimental, off-the-shelf immunotherapy that combines a targeted antibody and chemotherapy can lead to potentially durable responses in multiple myeloma patients whose disease has relapsed or is resistant to other standard therapies. A multi-center, international trial evaluated the drug, belantamab mafodotin, and found almost a third of patients whose disease had returned after other therapies achieved a partial response or better when treated with this therapy, which targets the B-cell maturation antigen (BCMA). Data from 196 patients on the trial, called DREAMM-2, have been submitted to the U.S. Food and Drug Administration for consideration for approval. The findings were published in Lancet Oncology today.

"Our data show this therapy can make a difference for patients with multiple myeloma who have exhausted all other options, including other antibody therapies," said the study's senior author Adam D. Cohen, MD, an assistant professor of Hematology-Oncology in the Perelman School of Medicine at the University of Pennsylvania and a member of Penn's Abramson Cancer Center. The study's first author is Sagar Lonial MD, FACP, chief medical officer of the Winship Cancer Institute of Emory University.

Multiple myeloma is a cancer of plasma cells, which build up in the bone marrow and crowd out healthy blood cells. It can also cause painful bone lesions, kidney damage, and recurrent infections. The American Cancer Society projects there were about 32,000 new cases in the United States in 2019, and the prognosis for patients whose disease has relapsed or is refractory (r/r) is poor. Patients enrolled in this trial were required to have disease that had relapsed or was refractory to a proteasome inhibitor, immunomodulatory drug (IMiD), and anti-CD38 antibody, a particularly difficult group to treat.

BCMA is a receptor on the surface of multiple myeloma cells that helps the cancer grow and survive. It is rarely expressed on healthy B cells, making it a promising target for therapy. Belantamab mafodotin is an experimental antibody-drug conjugate that consists of an antibody to target BCMA that is linked to a potent chemotherapy drug called MMAF. After binding to BCMA, belantamab mafadotin is internalized into the myeloma cell and then releases the MMAF, leading to highly targeted killing of the myeloma within the bone marrow while limiting systemic chemotherapy side effects. Belantamab mafadotin can also attract surrounding immune cells to attack the myeloma cells through a mechanism called antibody-dependent cellular cytotoxicity (ADCC). Patients receive an outpatient infusion every three weeks.

This phase two trial involved 58 centers in eight countries. Between June 2018 and January 2019, 196 patients were treated with either a low dose or high dose of the drug. In the low dose treatment group, 31 percent of patients (30 out of 97) achieved an overall response - meaning the treatment lowered the amount of cancer in their bodies. Of that group, 60 percent (18 patients) had a very good partial response or better - meaning the myeloma levels were reduced by 90 percent or more compared to before starting treatment. For the higher dose group, 34 percent (34 out of 99) achieved an overall response, with 59 percent of those (20 patients) achieving a very good partial response or better. Responses were achieved quickly, after a median of 1.4 months of treatment. With a follow up of 6.3 months for the low dose cohort and 6.9 months for the high dose cohort, the duration of response was not reached in either group. The median progression-free survival was 2.9 months and 4.9 months respectively, though it was not reached in patients who responded.

"These data build off the phase one trial that showed patient responses improved over time and contributed to prolonged progression free survival," Cohen said. "Since this study did not reach the median duration of response, we anticipate that further follow-up on these patients will confirm these responses can be durable."

Eight percent (8 out of 97) and 10 percent (10 out of 99) of patients in the low and high dose cohorts, respectively, had to stop treatment due to side effects. The most common patient-reported side effects included nausea (in 24 percent of low-dose and 32 percent of high-dose patients), fatigue (16 percent and 26 percent, respectively), blurred vision (22 percent and 30 percent, respectively), and dry eye (14 percent and 23 percent, respectively), with the majority of side effects being mild to moderate in severity. Microscopic changes to the lining of the cornea (the outer clear covering over the eye) were noted on eye examination in 71 percent of low dose and 75 percent of high dose patients, and were an expected side effect of the drug. While the effects are reversible, Cohen said patients on this trial needed to be co-managed with eye specialists so they could receive frequent eye exams and symptom management. Other side effects included thrombocytopenia, or low platelet count in the blood, which was reported in 35 percent of low dose patients and 59 percent of high dose patients.

"Overall, the side effects are manageable with appropriate supportive care, and the fact that this treatment can be given once every three weeks as an outpatient infusion means this could be a convenient and beneficial therapy for multiple myeloma patients," Cohen said. He notes that additional research is already underway to evaluate belantamab mafodotin in combination with other treatments.

DENVER/December 16, 2019 – Latex exposure could be detrimental to a horse’s respiratory health. That’s the surprising discovery from Morris Animal Foundation-funded research at the Royal Agricultural University and University of Nottingham. While further investigation is needed, researchers say latex could be among the allergens responsible for causing severe equine asthma (sEA), a serious horse ailment with limited treatment options. The team published their findings in the Nature journal Scientific Reports.

The finding came from a larger study that applied a new, more-comprehensive microarray platform to determine the precise allergens within horses’ stable dust that elicit sEA. Researchers tested nearly 400 extracts and proteins associated with the equine environment on blood samples from 138 horses from Switzerland, France, the United States and Canada.

The study revealed several previously suspected allergens, such as pollen, mold and insect proteins, are likely involved in sEA, but the most surprising finding was the implication that natural rubber latex might also play a role. In fact, four of the five most significant allergens associated with sEA were latex proteins. The fifth was a protein from Aspergillus fumigatus, a common fungus previously linked with sEA. Until now, latex had not been tested due to limitations associated with classical allergen assessment methods.

“Research to date has generally implicated fungi and bacteria as the predominant allergens associated with sEA, so this was a little unexpected,” said Dr. Samuel White, Senior Lecturer at Nottingham Trent University, and the lead author of the paper. “We would need to learn more about how these allergens affect actual predisposed horses, but avoidance of latex allergens may still be beneficial.”

Horses primarily come into contact with natural rubber latex on artificial riding surfaces, like arenas and racetracks. Urbanized environments, which also have higher levels of breathable latex from car tires, have been identified as a risk factor in sEA, as well.

The high level of breathable dust associated with training on artificial surfaces has already been linked with chronic bronchitis, inflammation and oxidative stress in riding instructors, and latex has long been associated with a variety of respiratory conditions in humans.

Severe equine asthma, which closely resembles human asthma, is a debilitating and chronic allergic respiratory condition. Diagnosed in all breeds, it affects 14% of horses in the Northern Hemisphere. When exposed to allergens, these horses can experience inflammation and constriction of the airways, as well as excessive mucus production. sEA also is known as heaves, recurrent airway obstruction and chronic obstructive pulmonary disease.

“This new finding highlights the need to better understand the potential health effects of the environments we expose our horses to,” said Dr. Janet Patterson-Kane, Morris Animal Foundation Chief Scientific Officer. “It’s crucial that we identify which allergens might cause them distress so we know what to avoid as well as develop appropriate treatments.”

The team plans to conduct further research to establish exposure levels of latex in a horse’s daily environment and demonstrate the benefit of avoiding latex.

Morris Animal Foundation is funding other studies to address equine asthma. One is investigating if targeting a specific protein is a viable new therapeutic strategy to treat the condition. Another is examining differences in mast cell subtypes found in the airways of heathy and asthmatic horses to help identify better diagnostic and treatment strategies for equine asthma.

About Morris Animal Foundation

Morris Animal Foundation’s mission is to bridge science and resources to advance the health of animals. Founded by a veterinarian in 1948, we fund and conduct critical health studies for the benefit of all animals. Learn more at morrisanimalfoundation.org.

Horses
Allergy
Press Release
Respiratory Disease

Journal

Scientific Reports

DOI

10.1038/s41598-019-51820-7

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People were less likely to catch either influenza or a common cold-causing rhinovirus if they were already infected with the other virus, a new study by scientists from the Medical Research Council-University of Glasgow Centre for Virus Research has found.

Understanding how these distinct viruses inhibit each other could help public health planning to improve forecasting models that predict respiratory disease outbreaks and strategies for controlling disease spread, say the scientists.

It has been observed before that common cold infections appear to be less frequent in the influenza season and vice versa. The new study, published in the journal Proceedings of the National Academy of Sciences, is the first study with enough samples to provide strong evidence for this interaction at both the population and individual level.

Samples from 44,230 cases of acute respiratory illness, in 36,157 patients, were tested for 11 types of respiratory viruses over nine years in NHS Greater Glasgow and Clyde. Using this data, the researchers found that 35% tested positive for a virus and, of those, 8% were co-infected with more than one type of virus.

The most striking interaction they found was between influenza A viruses and rhinoviruses, a type of virus that can cause the common cold. Computer modelling of the data found that the inhibitory interactions between influenza and rhinoviruses appeared to occur within individual people as well as at a population level.

Patients with influenza A were approximately 70% less likely to also be infected with rhinovirus, than were patients infected with the other virus types.

Dr Sema Nickbakhsh, from the MRC-University of Glasgow Centre for Virus Research at the University of Glasgow, who was first author on the paper, said: "One really striking pattern in our data is the decline in cases of the respiratory virus rhinovirus, which is typically a mild common cold causing virus, occurring during winter, around the time that flu activity increases."

"In the same way as lions and spotted hyenas compete for food resources in the Masai Mara, we believe respiratory viruses may be competing for resources in the respiratory tract. There are various possibilities we're investigating, such as these viruses are competing for cells to infect in the body, or the immune response to one virus makes it harder for another unrelated virus to infect the same person."

Viruses from the same species - for example different strains of influenza - could be expected to compete or generate an overlapping immune response in the body, but the researchers say what makes these findings interesting is the interaction is between completely different types of viruses.

Dr Pablo Murcia, from the MRC-University of Glasgow Centre for Virus Research at the University of Glasgow, who led the research, said: "Traditionally people have studied viruses in isolation - you study only flu or rhinovirus - but we've shown here that we need to also be studying these viruses together like it's an ecosystem. My team are now doing experiments to try and understand how respiratory viruses, including influenza and rhinovirus, interact. If we understand how viruses interact and how certain viral infections may favour or inhibit each other, then maybe we can develop better ways to target viruses."

"Studying interactions between viruses could help to explain why different viruses circulate in different seasons or why they affect different age groups, and within the body why certain types of viruses infect different parts of the respiratory tract, like the nose or the lungs."

An example of how these viruses could also affect each other's spread at a population level, include that if a person is infected with one virus they're more likely to stay home and consequently not catch another virus.

Limitations of the study include that the correlations observed cannot show what is causing these interactions and that samples were only taken from people with symptoms of a respiratory infection, so it may not capture how the viruses behave in people who don't develop symptoms.

Dr Nickbakhsh added: "A key thing to note with this research is that we're looking at average risks over a very large number of patients who have sought healthcare - that's not to say that occasionally unlucky individuals can't be infected with influenza and a cold virus at the same time."

The study looked at how 11 viruses interacted. It did find relationships between some of the other virus pairs, but these were not consistent at both the individual host and population level, which the study did find for influenza A and rhinovirus.

Arlington, Va., December 16, 2019 - Hospitals reporting high levels of psychological safety are more likely to have comprehensive infection prevention and control (IPC) programs, according to the results of a survey appearing in the American Journal of Infection Control (AJIC), the journal of the Association for Professionals in Infection Control and Epidemiology (APIC), published by Elsevier.

Psychological safety refers to the shared belief that team members will not be reprimanded, punished, or embarrassed for speaking up, sharing ideas, posing questions, raising concerns, or making mistakes.

Healthcare-associated infections (HAI) result in tens of thousands of deaths, costing the US healthcare system billions of dollars each year. Despite the presence of evidence-based guidelines focused on HAI prevention and the proliferation of large-scale HAI implementation initiatives, variation in the use of recommended infection prevention practices across US hospitals remains an issue.

Researchers at University of Michigan Medical School and the VA Ann Arbor Healthcare System conducted a survey of infection preventionists in a random sample of nearly 900 US acute care hospitals in 2017 to identify hospital and IPC program characteristics, organizational factors, and the use of practices to prevent common HAIs. Hospitals were also ranked based on seven psychological safety questions. Their analysis showed a positive link between high psychological safety and the adoption of infection prevention practices that require staff to speak up and challenge deep-rooted customs. Only 38 percent of responding hospitals were deemed to have a high level of psychological safety.

"It is not surprising that high levels of psychological safety are associated with frequent use of socioadaptive safety interventions - those requiring personnel to speak up, ask for help, or provide feedback," stated the study authors. "Multiple studies have shown that organizational efforts to prevent HAIs require both technical and socioadaptive interventions. Ensuring that infection prevention programs are well supported may enhance safety climates and provide a platform for organizations to build a culture of psychological safety to improve patient safety."

Although the use of some practices to prevent device-related HAIs has increased in recent years, several socioadaptive prevention practices are still not used as frequently as they could be, according to the study authors, particularly for prevention of catheter-associated urinary tract infections and ventilator-associated pneumonia.

"With the increasing threat of antibiotic resistance, prevention of infection is more important than ever before," said 2019 APIC President, Karen Hoffmann, RN, MS, CIC, FSHEA, FAPIC. "In order to effectively prevent HAIs and protect patients, healthcare facilities must cultivate environments that are psychologically safe and fully supported by leadership, so that comprehensive IPC programs can be fully implemented."