Body

AUGUSTA, Ga. (June 11, 2018) - When trauma spills the contents of our cell powerhouses, it can evoke a potentially deadly immune response much like a severe bacterial infection.

A drug that cleaves escaped proteins called N-formyl peptides appears to reduce resulting dangerous leakage from blood vessels and improve survival, report researchers at the Medical College of Georgia at Augusta University.

The research drug deformylase, or something similar, may one day be a novel treatment for patients with systemic inflammatory response syndrome, or SIRS, a body-wide inflammatory reaction to trauma or infection, as well as sepsis, a systemic infection when the cause of the infection, like a bacteria, is known.

"We are hoping our work will improve the care of trauma and other critically ill patients," says Dr. Patricia Martinez Quinones, general surgery resident at MCG and AU Health.

Martinez Quinones is presenting the work in both animal models and human cells during the Oral Presentations by Young Investigators session on the final day of the Shock Society's 41st Annual Conference June 9-12 in Scottsdale, Arizona.

"Once mitochondria (cell powerhouses) are damaged, they just break apart and their contents spill into the circulation," says Martinez Quinones.

Michondria use N-formyl peptides to make energy for our cells but significant volumes outside the powerhouse can quickly become a detriment. Deformylase appears to neutralize them by removing their formyl group - a combination of carbon and oxygen atoms with hydrogen.

This formyl group is part of every bacterial protein as well as all 13 proteins made by mitochondria, says Dr. Camilla Ferreira Wenceslau, research scientist in the MCG Department of Physiology and senior author of the ongoing studies.

"That is what triggers the immune system to trigger an inflammatory cascade," says Dr. Keith O'Malley, interim chief of MCG's Division of Trauma/Surgical Critical Care and a co-investigator on the ongoing studies.

In fact, the mitochondria themselves can similarly neuter the proteins and those benign versions are normally the only ones it releases, until there is an injury.

"The entire hypothesis behind this - and it's called the danger theory - is that our mitochondria used to be bacteria so when their contents are released our body treats them like an infection," Martinez Quinones says.

The results can be pretty much the same as if external bacteria entered our bodies: rapid heart rate, fever, precipitous drop in blood pressure and swelling.

"Trauma releases fragments of mitochondria that still carry the signature from bacteria," says Wenceslau.

If outside bacteria are the source of the immune reaction, an antibiotic should quell the resulting cascade of damage, O'Malley notes. But despite the similarities, there are no known antibiotics that target spilled mitochondrial contents, Martinez Quinones adds.

Deformylase, or something like it, on the other hand may one day be useful at both infective sepsis from an invader and this "sterile" sepsis from our own mitochondria, she notes.

In the lab of MCG physiology chair Dr. R. Clinton Webb, the investigators have looked at a mouse model of sepsis. They've also incubated human endothelial cells that line the aorta with N-formyl-rich plasma taken from patients with severe trauma.

Deformylase improved sepsis survival in their animal model by 28 percent and prevented separation of the tightly knit human endothelial cells that keep blood vessel content contained.

"What we saw is that there was a marked improvement in the vascular function of the animals that were treated with deformylase meaning that the vessels that were leaky and couldn't contract now could," Martinez Quinones says. "Also, once we treated the plasma with deformylase, the endothelial cell disruption went away."

Their findings to date have them theorizing that circulating levels of mitochondrial DNA and N-formyl peptides might one day be good biomarkers that could change both how patients are monitored and treated, Martinez Quinones says.

Five years ago, the researchers showed that N-formyl peptides have a powerful relaxant effect in rat arteries that carry blood from the aorta to the gastrointestinal tract. They surmised that when high levels are present, following trauma and other disease, it exacerbates dilation of the arteries and low blood pressure as well as inflammation.

In a study, published last year in the Journal of Trauma and Acute Care Surgery, they looked daily at levels of mitochondrial DNA and N-formyl peptides in the fluid of patients with an open abdominal wound following a significant injury. They found that a routine flushing of the area significantly reduced levels of N-formyl peptides. They hypothesized then and are now studying whether more frequent flushing can help those patients keep levels low and reduce their risk of SIRS and sepsis.

Current studies have them looking in the peritoneal fluid, blood and urine at levels of these peptides in patients who are getting the standard irrigation of the area every 48 hours versus every 24 hours, Martinez Quinones says. If they find more frequent flushes control the levels, that could be sufficient for patients like these with access.

However O'Malley notes that many trauma patients as well as patients with other tissue-damaging disease like cancer and pneumonia do not have ready access at the injury site.

The current version of deformylase they are using has an extremely short half-life so their many pursuits include a more stable version that could be used clinically for those patients, Martinez Quinones says.

The single layer of endothelial cells lining blood vessel walls, which ensure that contents stay inside, are a major target when the body perceives a major infection like sepsis. Patients can experience what's termed vascular collapse, so they lose tone and the body gets less blood. The typically tight juncture of endothelial cells get lost so blood vessels become leaky and fluid seeps into nearby tissue prompting dangerous swelling in organs like the kidneys and brain. In a sort of vicious cycle, this worsening scenario prompts production of things like oxidative stress and nitric oxide, which exacerbate problems like inflammation and low blood pressure.

"When you are in shock, you only retain about a third of the fluid in your bloodstream," O'Malley says. "The rest of it seeps out." Blood pressure drops dramatically, and patients can end up in shock and nonresponsive, he says.

While the results are clear - and potentially deadly - the mechanism which results in the vascular dysfunction is not clear, the researchers say.

Sepsis is the second leading cause of death in non-coronary care ICUs in the United States, with a mortality rate of up to 45 percent, according to the Society of Critical Care Medicine.

A new study reveals that pediatric neuroblastoma patients are at elevated risk for long-term psychological impairment. In addition, those who experience such impairment as they get older tend to require special education services and to not go on to college. The findings are published early online in CANCER, a peer-reviewed journal of the American Cancer Society.

In the United States, neuroblastoma--a childhood cancer of nerve cells--is diagnosed at a median age of 17.3 months. Treatment advances in recent years have prolonged survival for many affected children, but their young age at diagnosis and the specific therapies they receive can make them vulnerable to health problems as their central nervous system develops.

To assess the long-term psychological effects of neuroblastoma and its treatment, Nina Kadan-Lottick, MD, MSPH, of Yale University School of Medicine and her colleagues studied 859 children who had been diagnosed with neuroblastoma at least five years earlier and were under 18 years old. Their median age at diagnosis was 0.8 years, and they were followed for a median of 13.3 years. These 859 neuroblastoma survivors were compared with 872 siblings of childhood cancer survivors.

Compared with siblings, neuroblastoma survivors had an increased prevalence of impairment in the domains of anxiety/depression (19 percent versus 14 percent), headstrong behavior (19 percent versus 13 percent), attention deficits (21 percent versus 13 percent), peer conflict/social withdrawal (26 percent versus 17 percent), and antisocial behavior (16 percent versus 12 percent).

Common treatments--vincristine, cisplatin, and retinoic acid--were not associated with impairment, but survivors who developed chronic health conditions as a result of their cancer treatment were at higher risk for developing worse outcomes. Specifically, developing pulmonary disease was linked with an increased risk of impairment in all five domains, and developing endocrine disease and peripheral neuropathy were each linked with impairment in three domains. In addition, survivors who experienced psychological impairment tended to require special education services and to not go on to college.

"These findings are novel because this is the first large study that could look at how neuroblastoma patients are doing in terms of psychological and educational outcomes. Before recent advances in treatment, this survivor population was much smaller and we were not able to analyze these sorts of long-term outcomes," said Dr. Kadan-Lottick. "The goal is not simply to get our patients to be cancer-free but also to optimize their mental, emotional, and social functioning as they move into adolescence and adulthood. Our hope is that these findings will help inform strategies for early screening and intervention to identify those survivors at highest risk for developing psychological and educational impairment later on in life."

June is National Cancer Survivors month.

June 10, 2018 - Atlanta, GA - A new study has found that half of influenza cases in patients admitted to the intensive care unit (ICU) received a false negative rapid influenza antigen test (RIAT). The false negative RIAT results could delay antiviral therapy for patients who were in the ICU with severe influenza. The research is presented at ASM Microbe, the American Society for Microbiology's annual meeting, held from June 7th through 11th in Atlanta, Georgia.

The researchers, led by Po-Yen Huang, MD, Chang-Gung Memoria Hospital, Taoyuan,Taiwan, performed a retrospective analysis of 307 patients with influenza requiring ICU admission at Chang-Gung Memorial Hospital, a tertiary medical center in Taiwan, from August 2009 to July 2017. Of these 307 cases of confirmed influenza, RIAT was performed on 259 with 126 (49%) testing negative. Among the 307 cases, 45 (15%) either tested negative on all upper respiratory tract (URT) samples or did not have URT samples tested. The diagnosis of these 45 cases instead relied on the tests from lower respiratory tract (LRT) samples.

RIAT is a popular at point-of-care settings since it provides physicians readily available results. A positive test result with its high specificity confirms the diagnosis of influenza. However, a negative test result and its low sensitivity often misleads physicians to exclude the influenza diagnosis. About half of the cases in the study had negative RIAT results. A substantial portion (15%) of the patients were ultimately diagnosed solely by testing lower respiratory tract (LRT) samples. Influenza diagnoses could not be based on the results of RIAT.

"As physicians specialized in infectious disease, we advocate that testing of the LRT samples are crucial for diagnosis of severe influenza with critical illness," said Dr. Huang.

Compared to the RIAT positive cases, the RIAT negative patients shared similar clinical characteristics except they required longer ICU stays (median 12 vs. 9 days) and longer ventilator days (median 12 vs. 6 days). Furthermore, antiviral treatment was significantly delayed in the RIAT negative patients (median 1 vs. 0 days).

"Negative RIAT results delayed treatment with antiviral medication," said Dr. Huang, MD. "Decision-making for antiviral medication based on RIAT results should be discouraged. Prompt empiric antiviral medication should be provided to all critically ill patients with severe respiratory infection."

Guidelines recommend breastfeeding as the best source of nutrition for most babies. The Nutrition 2018 meeting will feature new research findings on the nature of breast milk and how breastfeeding may affect the health of both moms and babies.

Nutrition 2018 is the inaugural flagship meeting of the American Society for Nutrition held June 9-12, 2018 at the Hynes Convention Center in Boston. Contact the media team for abstracts, images and interviews, or to obtain a free press pass to attend the meeting.

Findings point to short and long-term benefits for mother and baby

Breastfeeding may help reduce mom's risk of type 2 diabetes after gestational diabetes
A study of 4,400 women followed for more than 20 years suggests breastfeeding for a longer period of time could help women diagnosed with gestational diabetes during pregnancy lower their risk of developing type 2 diabetes later in life. Women with gestational diabetes who lactated for more than one year total (for all children combined) reduced their risk of type 2 diabetes by about 30 percent compared to those who did not breastfeed at all. The research suggests the long-term beneficial impact of lactation may persist across the lifespan of aging women. Sylvia Ley, Brigham and Women's Hospital and Harvard T.H. Chan School of Public Health, will present this research on Tuesday, June 12, from 9:15-9:30 a.m. in the Hynes Convention Center, Room 210 (abstract).

Breastfeeding appears protective against metabolic syndrome in teen years
Metabolic syndrome is a cluster of conditions that raise the risk of heart disease and diabetes. A study of overweight and obese Hispanic teens with a family history of type 2 diabetes found that those who were breastfed for at least one month as babies were substantially less likely to have metabolic syndrome in their teen years compared to those who were not breastfed. This protective benefit of breastfeeding was seen among those born to mothers with and without gestational diabetes during pregnancy. Sarvenaz Vandyousefi, University of Texas at Austin, will present this research on Tuesday, June 12, from 9:30-9:45 a.m. in the Hynes Convention Center, Room 210 (abstract).

Breastfeeding appears protective against overweight in babies who gain weight rapidly
Gaining weight rapidly during early life puts infants at increased risk for obesity later on. In a new study, babies who gained weight rapidly in the first four months of life were significantly more likely to be classified as overweight by one year of age if they were exclusively formula fed rather than breastfed for 11 months or longer. Jillian Trabulsi, University of Delaware, will present this research on Tuesday, June 12, from 9:45-10:00 a.m. in the Hynes Convention Center, Room 210 (abstract).

B. infantis probiotic boosts benefits of breastfeeding in developed countries
Although breastfeeding is known to support a healthy gut microbiome in infants, babies in developed countries do not reap the same benefits as those in developing countries. A new study conducted in collaboration by the University of California, Davis and Evolve BioSystems finds supplementing breastfed infants in developed countries with the probiotic B. infantis ECV001 improves their gut microbiome health, as long as they continue to breastfeed. Bethany Henrick, University of California, Davis, will present this research on Saturday, June 9, from 1-1:15 p.m. in the Hynes Convention Center, Room 311 (abstract).

New insights into the composition of breast milk

Evidence that a woman's weight influences what's in her breastmilk
Preliminary findings from a new study reveal that breast milk of obese women has higher levels of total fat, the inflammatory marker C-reactive protein, and hormones including leptin and insulin compared to breast milk of normal-weight women during the first six months postpartum. The implications of these differences for infant growth and development are yet unknown. Clark Sims, Arkansas Children's Nutrition Center/University of Arkansas for Medical Sciences, will present this research on Sunday, June 10, from 8 a.m.-6 p.m. in the Hynes Convention Center, Exhibit Hall D (poster 377) (abstract).

A breastfeeding mom's diet may influence her baby's intestinal microbiome
The fat, carbohydrate, protein and calorie contents of a breastfeeding mom's diet have been found to be associated with the kinds of bacteria found in her baby's stool. This study, the first of its kind relating a mother's diet to her infant's microbiome, sheds new light on how the intestinal microbiome is shaped during the first months of life. Janet E. Williams, University of Idaho, will present this research on Monday, June 11, from 8 a.m.-3 p.m. in the Hynes Convention Center Auditorium (poster 250) (abstract).

Drinking sweetened beverages causes fructose spike in breastmilk
Researchers report the concentration of fructose in breastmilk rose and remained high for up to 5 hours after lactating women consumed a 20-ounce bottle of soda containing 65 grams of sugar (in the form of high-fructose corn syrup). Fructose levels in breastmilk were unaffected by drinking an artificially-sweetened beverage containing zero grams of sugar. Paige K. Berger, University of Southern California, will present this research on Tuesday, June 12, from 9-9:15 a.m. in the Hynes Convention Center, Room 210 (abstract).

Please note that abstracts presented at Nutrition 2018 were selected by a committee of experts but have not generally undergone a rigorous peer review process such as that required for publication in a scientific journal. As such, the findings presented should be considered preliminary until a peer-reviewed publication is available.

CORVALLIS, Ore. - Web page articles and other written materials designed to encourage physical activity are often too difficult to be easily read and understood by most U.S. adults, limiting their effectiveness, new research from Oregon State University shows.

Written resources can enhance and support health behavior changes and are considered a fundamental component of health promotion efforts. If they are not easy to read, they are less useful and access inequities will continue to persist, said Brad Cardinal, a kinesiology professor in the College of Public Health and Human Sciences at OSU.

"If we think it's an important message, we should make it as broadly accessible as possible," he said.

Easily-read resources using plain, simple language are more likely to have a positive impact. They also are more likely to promote health literacy, or the knowledge, motivation, confidence and skill to obtain and apply accurate health information. Those with higher health literacy are more likely to engage in preventive health behaviors, including regular physical activity, said Cardinal, a national expert on the benefits of physical activity.

"When people access the web and try to read something about exercise or health that is above their comfort level, they can easily become confused. Taken to extremes, misunderstandings could result in unnecessary pain or injury," he said. "But someone with stronger reading skills and higher health literacy could read the same thing and use the information to be successful."

Cardinal and OSU doctoral candidate Jafrā D. Thomas recently published two papers on the topic. The first paper, a readability review of more than 150 written resources, was published in the Sociology of Sport Journal.

The second, an analysis of 14 past studies of readability of physical activity resources, was just published in the journal Quest. Thomas is lead author of both papers; Brian Flay, professor emeritus in OSU's College of Public Health and Human Sciences, is also a co-author on the second paper.

In the first paper, Thomas and Cardinal reviewed 163 articles and downloadable documents on popular health promotion websites such as WebMD.com, Heart.org and CDC.gov. They grouped the articles based on their sources: government, professional association, voluntary health agency or commercial, and used several readability formulas to measure the reading grade level of each resource.

They found that more than 50 percent of the materials, which included a range of topics such as physical activity and exercise ideas, technical instruction and management of specific health conditions, were written above an eighth-grade reading level, the maximum recommended for accessibility. Only 2.5 percent were written for optimal reading levels, which is fifth-grade or lower.

In the second paper, Thomas, Flay and Cardinal examined 14 studies published between 1992 and the present, which when combined, had reviewed more than 800 written health educational resources on topics such as physical activity, physical fitness or sports medicine.

The average reading level across the studies was greater than 10th-grade, more than two full levels above the maximum recommended eighth-grade reading level. There was no difference in the reading level of resources produced by the government and those by non-government agencies.

The findings suggest that despite the efforts underway by public health officials and policymakers to improve the readability of health resources, through efforts such as the 2010 Plain Writing Act, the problem continues to persist, Cardinal said.

"The goal of such resources, regardless of who produced or disseminated them, should be to assure they are readable," he said. "This is the minimum way of trying to assure they are accessible for the widest possible audience."

The findings in both papers underscore the important role readability plays in reaching target audiences, and in particular underrepresented audiences such as those for whom English is a second language or those with less formal education, said Thomas.

"People with more education tend to participate more in physical activities, in part because they have more access to resources," he said. "When resources aren't readable, they are likely to favor people with more education and could contribute to disparities in physical activity rates."

Public health officials and policymakers can do their part by creating and following readability policies; checking readability of materials using tools already embedded in word-processing programs or that are free online; and running materials past focus groups to check for readability and comprehension, Thomas said.

"Approach the work with an inclusive mindset," he said. "Strive to keep things plain and simple and don't be afraid to give people options and ask them what they prefer."

Hip replacements relieve pain and restore mobility for hundreds of thousands of patients in the United States each year, but about 40,000 of the more than 280,000 of these procedures performed annually in the U.S. are to replace failed previous hip replacements, at a direct cost of more than $1 billion. One main cause of the need to perform a second hip replacement surgery (known as a revision surgery) is the destruction of bone tissue around the replacement joint, a condition called osteolysis, which may cause the joint to loosen.

Now a research team at Rush University Medical Center has identified a pair of biomarkers that indicate which patients are likely to develop osteolysis. Biomarkers are detectable molecules in body fluid or tissue that are a sign of a health condition.

The team published their findings today in the Journal of Orthopaedic Research. The discovery could lead to tests that would enable surgeons to identify those patients in advance and adjust post-operative monitoring routines for them. It even might lead to treatments to prevent osteolysis in these patients.

"We are hopeful that early biomarkers for implant loosening will alert surgeons to be especially vigilant in their follow-up of at-risk patients and may eventually lead to treatments delaying or avoiding the need for revision surgery," said the paper's senior author D. Rick Sumner, PhD, chairperson of the Department of Cell & Molecular Medicine in Rush Medical College and the Mary Lou Bell McGrew Presidential Professor for Medical Research.

With the U.S. population aging, many individuals remaining very active late in life and others becoming heavier, hip replacements are projected to increase by 174 percent by 2030, with a projected 137 percent increase in the number of hip revision surgeries over the same time period.

"We need to find effective strategies to handle this demand. These joints need to last, if possible, for the rest of a patient's life," said Joshua Jacobs, MD, a co-investigator on the study. Jacobs is Rush University's vice provost for research and the William A. Hark, MD/Susanne G. Swift Professor and chairperson of the Rush Department of Orthopedic Surgery.

Choosing candidates for closer scrutiny

Bone tissue in the body continuously is in a cycle of resorption (removal) and formation. Osteolysis occurs when the amount of bone resorption is greater than the amount of bone formation, resulting in weakened bones.

"The bone weakens, and eventually the implant can loosen. Sometimes, the weakened bone can break," Sumner said.

"It's one of the major causes of a patient needing to have a revision (a surgery to fix or replace the failed implant). If we could prevent it, we would go a long way to increasing the lifespan of joint replacement."

Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at the National Institutes of Health, the study analysed annual urine samples and medical data collected from 26 hip replacement patients between 1989 and 1997. The late Jorge Galante, MD, the first chairperson of orthopaedic surgery at Rush, initiated the collection to study the effectiveness of an artificial hip joint he had developed and used for some of these patients. Jacobs continued the study in 1995, and the specimens have remained in frozen storage ever since.

For their study, Sumner and his colleagues took what he calls "a candidate protein approach." They drew on a previous review of medical literature they had conducted, which identified 40 possible biomarkers of future osteolysis development.

They divided the markers into four groups based on their likelihood to predict osteolysis and focused on the two groups that were most likely. The researchers winnowed the field of candidate proteins by eliminating markers found in blood rather than urine and those for which tests weren't readily available.

Two combined biomarkers provided strongest indication of risk

Ultimately they tested for the presence of seven biomarkers and compared findings to the medical history of the patients - 16 of whom eventually had developed osteolysis. A biostatisican on the team then conducted an analysis to determine which combinations of the biomarkers correlated most with the osteolysis development.

"We looked at each marker independently, but none of them worked that well by themselves. Then he looked at panels of markers," Sumner explained.
"When we did that, we found we got a much better discrimination between patients that developed osteolysis and those that did not."

The analysis found that a higher than normal levels of the connective tissue protein alpha CTX (a marker for bone resorption) and the immune response protein interleukin 6 (a marker of inflammation) were highly accurate in identifying patients at risk for osteolyosis. The combination was detectable in patients up to six years before they were diagnosed with osteolysis.

"Just a panel (combination) of these two worked as well as a panel of seven," Sumner said. "If that gets confirmed, it's important, because it makes tests much simpler. You only have to look for two markers.

"Another interesting finding in our study was that the pre-operative levels of our two-biomarker panel were just as predictive of subsequent osteolysis as any of the post-operative levels, noted Ryan Ross, PhD, an assistant professor of cell and molecular medicine at Rush. "This follows some exciting genetic work by other researchers that tends to suggest that there may be a subset of patients that are just more prone to implant failure due to their underlying skeletal metabolism."

To confirm the findings, researchers will need to analyze a larger cohort of hip replacement patients for whom similar specimen samples and medical information is available.

Sumner expects that if the findings are confirmed and tests for the biomarkers are developed for hip replacement patients, "it would alert a surgeon that this is patient at higher risk and is a patient that probably would need to be followed more carefully."

Sumner's research also might yield a possible treatment for those patients. He currently is conducting another study funded by NIH looking at the feasibility of using osteoporosis medication to slow or reverse osteolysis.

Preliminary results of a recent study show that teen girls reported a higher degree of interference of daytime sleepiness on multiple aspects of their school and personal activities than boys.

The study examined whether teen boys and girls report similar negative impact of sleep disturbances on their daytime functioning.

"What was most surprising is the fact that teenage girls reported a higher degree of interference of daytime sleepiness than teenage boys on multiple aspects of their school and personal activities," said co-author Pascale Gaudreault, who is completing her doctoral degree in clinical neuropsychology under the supervision of principal investigator Dr. Geneviève Forest at the Université du Québec en Outaouais in Gatineau, Québec, Canada. "For example, teenage girls have reported missing school significantly more often than teenage boys due to tiredness, as well as reported having lower motivation in school due to a poor sleep quality."

731 adolescents (311 boys; 420 girls; ages 13 to 17.5 years; grades 9-11) completed a questionnaire about sleep and daytime functioning. Questions were answered on a seven-point Likert scale (1=never; 7=often). Gender differences were assessed using t-tests.

Study results show that teenage girls reported more difficulties staying awake during class in the morning, during class in the afternoon, and during homework hours than boys. They also reported feeling too tired to do activities with their friends, missing school because of being too tired, feeling less motivated in school because of their poor sleep, and taking naps during weekends more often than boys. However, there was no gender difference when it came to using coffee or energy drinks to compensate for daytime sleepiness or for falling asleep in class.

"These results suggest that teenage girls may be more vulnerable than teenage boys when it comes to the negative impacts of adolescence's sleep changes," said Gaudreault.

The research abstract was published recently in an online supplement of the journal Sleep and will be presented Tuesday, June 5, in Baltimore at SLEEP 2018, the 32nd annual meeting of the Associated Professional Sleep Societies LLC (APSS), which is a joint venture of the American Academy of Sleep Medicine and the Sleep Research Society.

Two drugs that are commonly used off-label in the treatment of male infertility are clomiphene citrate (CC) and anastrozole (AZ); however, data are lacking on the use of combination CC+AZ therapy. A new BJU International study found that combination CC+AZ therapy is safe and effective for patients with elevated estradiol or a low testosterone/estradiol ratio.

In the study of 51 men, AZ provided an effective means for lowering estradiol levels and increasing the testosterone/estradiol ratio following the initiation of CC therapy. CC is a selective estrogen receptor modulator that increases gonadotropin production and indirectly stimulates androgen synthesis, but it is associated with increased estradiol levels. AZ is an aromatase inhibitor that decreases conversion of testosterone to estradiol.

Autologous fat transfer, also known as "lipofilling", is a minimally invasive procedure in which the plastic surgeon uses the patient's own fat obtained by liposuction to perform breast reconstruction. For more than a decade, experts have questioned the oncological safety of this technique when applied to the former breast cancer patient, because autologous fat transfer stimulates the formation of blood vessels and tissue regeneration; however, a recent BJS (British Journal of Surgery) meta-analysis of published studies found that the technique does not result in an increased rate of cancer recurrence.

The findings indicate that autologous fat transfer can be performed safely in breast reconstruction after breast cancer.

"Lipofilling need not be feared of causing cancer relapse in the former breast cancer patient," said lead author Dr. Todor Krastev of Maastricht University Medical Centre in the Netherlands.

Buprenorphine (BUP) is approved for the treatment of opioid addiction. The current dosing regimen of BUP in pregnant women is based on recommendations designed for non-pregnant adults, but physiological changes during pregnancy may alter BUP exposure and efficacy. As described in a British Journal of Clinical Pharmacology study, researchers have developed a physiologically based pharmacokinetic model that predicts changes in BUP exposure at different stages of pregnancy. The model predicted a decrease in BUP exposure during pregnancy and demonstrated the need for an increase in dose or dosing frequency to maintain efficacy throughout pregnancy. This must be followed by a reduction in dose of buprenorphine after delivery.

"Modeling can help make predictions when it is difficult to get actual data in a patient population such as pregnant women with opiate addiction. Our predictions in fact agree with our clinical observations in a small number of patients published earlier. Lack of recognition of the impact of pregnancy on how the body handles drugs can cause therapeutic failure and may explain the high withdrawal rate of subjects on methadone / buprenorphine maintenance therapy for opioid addiction," said senior author Dr. Raman Venkataramanan, of the University of Pittsburgh School of Pharmacy.

Drugs used to treat rheumatoid arthritis may impact mental health by improving pain and stiffness and by targeting inflammatory processes common to arthritis and depression; however, a recent review of published studies demonstrates that relying on rheumatoid arthritis therapies alone may not meaningfully improve patients' mental health.

The findings, which are published in Arthritis & Rheumatology, indicate that providing dedicated mental health care is essential to help arthritis patients with depression and other mental conditions.

"This review summarises the findings from over 70 clinical trials to examine the association between different rheumatoid arthritis treatments and mental health outcomes," said lead author Dr. Faith Matcham, from the Institute of Psychiatry, Psychology and Neuroscience, King's College London.

"Our findings suggest that otherwise effective pharmacotherapy alone is unlikely to have an impact on mental health outcomes for the majority of rheumatoid arthritis patients. Optimal mental health outcomes may be achieved through providing integrated psychological support alongside routine care."

Exposure to tobacco smoke prenatally and postnatally was associated with hearing impairment in a Paediatric and Perinatal Epidemiology study of young children in Japan.

In the study of 50,734 children aged 3 years who were born between 2004 and 2010, 3.8% were exposed to smoking only during pregnancy; 15.2% were exposed in utero to only maternal past smoking; 3.9% were exposed only to second-hand smoke at 4 months; and 0.9% were exposed to tobacco smoke during pregnancy and at 4 months.

The prevalence of hearing impairment at age 3 years was 4.6%. Compared with children not exposed to tobacco smoke prenatally and at 4 months, children exposed to only maternal past smoking during pregnancy had a 26% increased relative risk of hearing impairment, children exposed to only second-hand smoke at 4 months had a 30% increased relative risk, those exposed to only smoking during pregnancy had a 68% increased relative risk, and those exposed to smoking during pregnancy and second-hand smoke at 4 months had a 2.4-times increased relative risk.

"Although public health guidelines already discourage smoking during pregnancy and in front of children, some women still smoke during pregnancy and many young children are exposed to second-hand smoke," said senior author Dr. Koji Kawakami, Kyoto University, in Japan. "This study clearly shows that preventing exposure to tobacco smoke during pregnancy and postnatally may reduce the risk of hearing problems in children. The findings remind us of the need to continue strengthening interventions to prevent smoking before and during pregnancy and exposure to second-hand smoke in children."

The modelled data on overall survival of the statistical evaluation of the impact of crossover on the ADMYRE study were presented.

Of the 84 patients treated in the comparator arm (dexamethasone as a single agent), 44% received the combination with plitidepsin after progression.

After analyzing the impact of crossover, the registered overall survival with plitidepsin was 11.6 months against the 6.4 months of dexamethasone alone.

Madrid, 5th June, 2018. - PharmaMar (MSE:PHM) has presented today how crossover has had an influence on the overall survival of the ADMYRE trial. The impact on overall survival of those patients that relapsed after receiving dexamethasone as a single agent and who were subsequently treated with plitidepsin in combination with dexamethasone was analyzed. Of the 84 patients treated from the comparator arm -dexamethasone as a single agent- 44%, 37 patients were treated with the combination with plitidepsin thereafter.

This data has been presented as a poster discussion session during the American Society of Clinical Oncology (ASCO) that is being held from the 1st to the 5th of June in Chicago (USA).

The ADMYRE study is a pivotal, randomized, open label, international, multicenter, phase III study, which included 255 multiple myeloma patients who had relapsed after having previously received at least 3, but no more than 6 prior lines and that compared both the safety and efficacy of plitidepsin plus dexamethasone against dexamethasone alone.

The primary endpoint of this study was Progression Free Survival -which resulted to be positive- was to demonstrate a statistically significant reduction in the risk of disease progression or death of 35% against the comparator.

During the presentation, the 2 statistical models used (RPSFT and the two stage method) to correct and measure the impact of crossover on overall survival were discussed, emphasizing the two stage model (Latimer et al.), that was considered the most adequate in the context of the Admyre study.

Accordingly, and taking into account the effect of crossover using the two stage method, a statistically significant increase in overall survival in the plitidepsin plus dexamethasone arm (11.6 months) against the comparator (6.4 months) was observed.

The studies presented at this meeting are available at http://abstracts.asco.org

Washington, DC - June 5, 2018 - Dogs are a potential reservoir for a future influenza pandemic, according to a study published in the journal mBio. The study demonstrated that influenza virus can jump from pigs into canines and that influenza is becoming increasingly diverse in canines.

"The majority of pandemics have been associated with pigs as an intermediate host between avian viruses and human hosts. In this study, we identified influenza viruses jumping from pigs into dogs," said study investigator Adolfo García-Sastre, PhD, director of the Global Health and Emerging Pathogens Institute and principal investigator, Center for Research on Influenza Pathogenesis (CRIP), Icahn School of Medicine at Mt. Sinai, New York City.

Influenza can jump among animal reservoirs where many different strains are located; these reservoirs serve as mixing bowls for the genetic diversity of strains. Pandemic influenza occurs when viruses jump from animal reservoirs to humans; with no prior exposure to the virus, most people do not have immunity to these viruses. The main animal hosts for influenza are wild birds, poultry and other domestic birds in a species pack; swine; and horses. Some of the viral genes from the 2009 pandemic H1N1 virus originated in birds, from an avian virus that jumped to pigs, exchanged some of its genes with previously circulating swine viruses and then jumped from pigs into humans. Birds and swine are major reservoirs of viral genetic diversity, whereas equines and canines have historically been restricted to one or two stable influenza A viruses lineages with no or very limited transmission to humans.

Fifteen years ago, researchers documented an influenza virus in a horse jumping into a dog, and this created the first circulating canine influenza viruses. Five years ago, researchers identified an avian-origin H3N2 canine influenza virus circulating in farmed dogs in Guangdong, China.

"In our study, what we have found is another set of viruses that come from swine that are originally avian in origin, and now they are jumping into dogs and have been reassorted with other viruses in dogs. We now have H1N1, H3N2, and H3N8 in dogs. They are starting to interact with each other. This is very reminiscent of what happened in swine ten years before the H1N1 pandemic."

Specifically, in the new study, the researchers sequenced the complete genomes of 16 influenza viruses obtained from canines in Southern China (Guangxi autonomous region) during 2013-2015. Other key study collaborators included Martha Nelson, PhD, a specialist in phylogenetic analysis and transmission reconstruction at CRIP, and Ying Chen, PhD, an influenza surveillance specialist who brought the samples from China. The researchers found that the genomes contained segments from three lineages that circulate in swine in China: North American triple reassortant H3N2, Eurasian avian-like H1N1, and pandemic H1N1. In addition, the swine-origin H1N1 viruses were transmitted onward in canines and reassorted with the CIV-H3N2 viruses that circulate endemically in Asian dogs, producing three novel reassortant CIV genotypes (H1N1r, /H1N2r, and H3N2r).

The viruses in the study were collected primarily from pet dogs presenting with respiratory symptoms at veterinary clinics. Dogs in certain regions of China, including Guangxi, are also raised for meat and street dogs roam freely, creating a more complex ecosystem for canine influenza virus transmission. "The new virus we have identified in our study is H1N1, but it comes from swine and is of avian origin, so it is different antigenically from the new H1N1s that were seen in the pandemic and a different origin as the previous H1N1 seen in humans," said Dr. García-Sastre.

Future studies will focus on characterizing the virus further and assessing, using human sera, whether humans have existing immunity against canine H1N1 or not. "If there is a lot of immunity against these viruses, they will represent less of a risk, but we now have one more host in which influenza virus is starting to have a diverse genotypic and phenotypic characteristics, creating diversity in a host which is in very close contact to humans," said Dr. García-Sastre. "The diversity in dogs has increased so much now that the type of combinations of viruses that can be created in dogs represent potential risk for a virus to jump to a dog into a human."

The researchers say it is time to think about ways to restrict the circulation of the influenza virus in dogs. The United States is free of avian influenza because every time avian influenza has been detected in poultry in this country, the chickens or turkeys are culled and eliminated from circulation," said Dr. García-Sastre. "There are attempts to restrict influenza virus in pigs through vaccination and one could consider vaccination for dogs."

MONTREAL, June 4, 2018 – Asthma and respiratory viruses don't go well together. Weakened by the common cold or the flu, a person suffering an asthma attack often responds poorly to emergency treatment; some must be hospitalized. This is especially true for preschoolers.

But what if there were a simple solution to help ward off the double whammy of an asthma attack and a respiratory virus? Well, there is one: to prevent getting sick, asthmatics can get an annual flu shot.

Unfortunately, however, only about 60 per cent do – but that might change.

In a new study in the journal Pediatrics, researchers at the Université de Montréal-affiliated CHU Sainte-Justine children's hospital and a master's student in epidemiology at McGill University make a strong case for vaccinating asthmatic kids against flu.

Just over one in 10 Canadian children have asthma, about 600,000 under the age of 12. The chronic disease often starts in early childhood, before six years of age, in the pre-school years.

"These kids should get their flu shot and they should get it systematically – it's worth it," said study co-author Francine Ducharme, a pediatrician and clinical epidemiologist at CHU Sainte-Justine who's a professor of pediatrics at UdeM.

40% risk of treatment failure if there's flu

"We now know that if these kids get the flu the risks are very high that emergency treatment for an asthma attack will fail," said Ducharme. "Instead of having an overall 17-per-cent risk of treatment failure, with flu their risk rises to almost 40 per cent."

The study is based on the national DOORWAY (Determinants Of Oral Corticosteroid Responsiveness in Wheezing Asthmatic Youth) study that Ducharme and colleagues conducted between 2011 and 2013 with funding from the Canadian Institutes of Health Research. That study looked at close to 1,000 children treated for moderate or severe asthma attacks in emergency rooms at Sainte-Justine, the Montreal Children's Hospital and three other Canadian hospitals. Nose swabs were taken and analyzed to see if the children also had the flu or other respiratory viruses when they came to the ER.

It turned out almost two-thirds did. Yet when the kids with respiratory viruses were given the standard treatments for their asthma attack – oral corticosteroids and inhaled bronchodilators – 20 per cent didn't respond and in most cases needed to be hospitalized. Those with influenza or parainfluenza turned out to have a 37-per-cent or more chance of not responding to treatment, compared to 13 per cent for children without a virus. Failure was also high in kids with respiratory syncytial virus (RSV).

By contrast, kids with strains of human rhinoviruses (HRVs) – the usual cause of the common cold – did respond well to treatment for their asthma. To the researchers, this was very reassuring, as HRVs are the most frequent trigger of asthma attacks necessitating a visit to the ER.

A simple solution...but with hurdles

"This is the first time we've been able to disentangle the risk of non-response to asthma treatment with the presence of specific viruses – specifically, influenza and rhinovirus," said co-author Caroline Quach, an associate professor of microbiology and infectious diseases at UdeM, chair of the Quebec Immunization Committee and chair of the National Advisory Committee on Immunization of the Public Health Agency of Canada. "The more than 20-per-cent higher absolute risk of treatment failure in flu cases is very significant."

There's also a simple solution – but with hurdles, she added.

"Influenza is the only respiratory virus that is vaccine-preventable. Granted, it's at best only 50-per-cent efficacious, but that's no reason for kids with asthma not to get vaccinated yearly, in the fall, before flu season starts. We can start as young as six months of age. Asthma is not usually diagnosed that early, but in Quebec every child who is diagnosed with asthma is eligible for influenza vaccination. The problem is that not many parents are prevailing themselves of the opportunity."

A major reason is access. Getting a flu shot often means an extra trip to a CLSC or public-health clinic, and not all parents can or want to take the time to get it done.

"It's an additional step, so what we're trying to promote is that kids get vaccinated where they get care – at Sainte-Justine, for example, where children can be vaccinated on site at our asthma, respiratory or general pediatric clinics. "

Easy access to vaccination

From 2012 to 2014, Quach and her student Joanna Merckx, then a McGill clinical fellow in pediatric infectious diseases, ran a free flu-vaccination clinic at the Montreal Children's Hospital, immunizing 2,640 kids who had high-risk conditions like asthma, and concluded the easy access worked.

"It was very well-accepted," Quach recalled. "It was easier to catch those children who were coming in anyway for their visits."

Despite the fact that, as the study said, "very little is known about the impact of consecutive and repeated use of LAIV (flu vaccine administered via nose spray) and IIV (via injection) in the population," the message she and her colleagues have for public-health policy makers is unequivocal: make it easy for parents to get their children vaccinated, and encourage them to do so.

"Everybody who has an asthmatic child should hear that influenza is bad news – the child might have an attack that needs hospitalization," Quach said. "They need to ask for the flu vaccine yearly."

About the study

"Respiratory viruses and treatment failure in children with asthma exacerbation," by Joanna Merckx, Francine M. Ducharme, Caroline Quach et al, was published June 4, 2018 in Pediatrics.

Journal

PEDIATRICS