Body

National Institutes of Health researchers have identified a naturally occurring lipid--a waxy, fatty acid--used by a disease-causing bacterium to impair the host immune response and increase the chance of infection. Inadvertently, they also may have found a potent inflammation therapy against bacterial and viral diseases.

Lipids are known to help Francisella tularensis bacteria, the cause of tularemia, to suppress host inflammation when infecting mouse and human cells. In a new study published in the Journal of Innate Immunity, researchers from NIH's National Institute of Allergy and Infectious Diseases found a form of the lipid phosphatidylethanoloamine, or PE, present in the bacterium. The composition of PE found in F. tularensis differs from PE found in other bacteria. In cell-culture experiments, the researchers discovered that the natural and a synthetic form of PE reduced inflammation caused by both tularemia bacteria and dengue fever virus.

Tularemia is a life-threatening disease spread to humans via contact with an infected animal or through the bite of a mosquito, tick or deer fly. Although tularemia can be successfully treated with antibiotics, it is difficult to diagnose, mainly because F. tularensis bacteria can suppress the human immune response. Dengue fever, primarily spread by Aedes aegypti mosquitoes, is rarely fatal but usually leads to a high fever, severe headache and pain throughout the body. There is no specific treatment for dengue fever.

After identifying PE as the lipid that impaired the immune response, the scientists began to consider its potential therapeutic value. Because natural F. tularensis is highly infectious and therefore challenging to work with, the group developed synthetic lipids--PE2410 and PEPC2410--that would be much easier to study and produce. They then verified that both synthetic lipids also suppressed the immune response during infection of mouse and human cells in the laboratory.

Because several types of viral infections involve an unconstrained inflammatory response, the group tested natural and their synthetic PE in the laboratory against dengue fever virus-infected human cells. Both versions inhibited the immune response compared to the immune response seen in infected but untreated cells.

The group plans to continue exploring how F. tularensis impairs the immune response. They hope their findings will eventually lead to the development of a potent, broad-spectrum anti-inflammatory therapeutic.

SAN DIEGO, CA - Female athletes are two to eight more times likely to injure their ACL than males, however utilizing one graft repair treatment method in females may be more beneficial than another, according to researchers presenting their work today at the American Orthopaedic Society for Sports Medicine's (AOSSM) Annual Meeting in San Diego.

Young females have been shown in previous literature to have a higher risk for graft failure with very little known about why this occurs. "Our study compared clinical outcomes in young females who had ACL reconstruction using bone-patellar tendon-bone (BTB) and quadrupled hamstring (HS) autografts. Higher rates of re-tears in our patients were seen in our youngest patients using HS autografts," said senior author, Kevin B. Freedman, MD from the Rothman Institute in Philadelphia, PA.

Freedman and his colleagues reviewed 256 female patients between the ages of 15-25 who underwent primary ACL reconstruction using either the BTB or HS autograft between January 2012 and May 2015. Patients with a prior history of ACL injury to either knee were excluded. The results illustrated that graft re-tear occurred in 6.9% of BTB patients and 13.6% of HS patients. Contralateral ACL tear occurred in 7.4% of BTB patients and 6.2% of HS patients. When researchers broke down the graft tears by age, those in the 15-20-year-old group had a significantly lower rate of re-tear with 6.4% in the BTB compared to 17.5% in the HS group. This same difference was not observed in older females in the 20-25 age group

"More research needs to be performed to better understand female ACL injury and what the best methods for repair are in our youngest patients who are at highest risk of re-injury. We hope that our research will add to the literature and treatment prospects for this complex problem," said Freedman.

New Haven, Conn. -- Yale health experts warn that current efforts to confront the growth of opioid addiction and overdose deaths must better incorporate an understanding of how women fit into this epidemic.

In a commentary published in The Lancet, Women's Health Research at Yale Director Carolyn M. Mazure, and Yale Program in Addiction Medicine Director David A. Fiellin, M.D., called for researchers, clinicians, and policymakers to account for the different ways in which women encounter opioid addiction and treatment.

"As we tackle this epidemic, we must be sure that action plans fully understand and include the influence of gender differences on pain, opioid use, and addiction," Fiellin said. "Women and men are not identical, and we must treat all people with attention to their specific risks and clinical needs."

For example, as outlined in the commentary, women have a greater sensitivity to pain than men and are more likely than men to begin their misuse of opioids through medical treatment. Women are more likely to be prescribed opioids with other medications that increase the likelihood of an overdose. Between 1999 and 2016, overdose deaths from opioid prescriptions increased by 404% for men and 583% for women.

A 2016 study found that emergency medical services were three times less likely to administer the life-saving drug naloxone to women experiencing an opioid overdose that ultimately killed them.

Pregnant women and their newborns are at special risk for health complications, as 28% of pregnant women entering addiction treatment reported misusing prescription opioids in 2012, up from 2% two decades earlier.

In addition, women exposed to an addictive substance develop a drug use disorder more rapidly than men. Women seeking treatment for opioid addiction also suffer increased limitations in their social and work lives, reducing their ability to maintain employment and housing. This compounds negative effects for children and families because women are most often the primary caregivers.

Because many substance use interventions have been developed around treating men, women are less likely to enter traditional treatment programs. Women-only programs show better involvement and often better results.

The authors recommended that insurance coverage to manage pain should be increased for non-opioid therapies, that medical practitioners take care to address the specific needs of women with opioid use disorder, and that women with children and women who are pregnant are protected so they can seek treatment without worrying they might lose custody.

"Both women and men are suffering from addiction to opioids across the United States, across Canada, and increasingly internationally," Mazure said. "But women and men experience different paths to addiction and possess different treatment needs. It is imperative that we understand these differences if we are to help people and save lives."

SAN DIEGO, CA - Knee pain in active patients over 40 is often difficult to treat but according to researchers presenting their work today at the American Orthopaedic Society for Sports Medicine's (AOSSM) Annual Meeting in San Diego utilizing a special kind of allograft may be a step in the right direction.

"Our findings note that patients older than 40 may benefit from using a fresh osteochondral allograft transplantation to treat focal cartilage defects, a common cause of knee pain in adults," said lead author, Dennis Crawford, MD, PhD from the Oregon Health and Science University in Portland, Oregon.

Crawford and his colleagues looked at a total of 80 patients broken into two groups. The study group consisted of 38 patients, 10 women and 28 men who were at least 40 years of age and a control group with 42 patients (27 men and 15 women) who were 39 years of age or younger. A statistically significant improvement for both groups was noted for the final follow-up for IKDC and all five KOOS sub-scores. Greatest changes were seen in the ability of patients to perform Sports and with improvement in healthful daily activity. Previous surgical treatment was performed on 31 of 38 knees in the study group and 37 of the 42 knees in the control group.

"This type of osteochondral allograft transplantation has traditionally been used in younger active patients with cartilage disorders. However, seeing this type of success allows sports medicine physicians another option in older patients and serves as a predictable biologic joint preservation technique," said Crawford.

Pregnant women with type 1 diabetes run a higher risk of having babies with heart defects, especially women with high blood glucose levels during early pregnancy, a study from Karolinska Institutet and the Sahlgrenska Academy in Sweden published in The BMJ shows.

It has long been known that patients with type 1 diabetes are at increased risk of complications. A new study now shows that pregnant women with type 1 diabetes are at a higher risk of having babies with heart defects.

"This confirms previous findings that there is a higher risk of birth defects, primarily of the heart," says Professor Jonas F. Ludvigsson at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, and consultant at the Paediatric Clinic at Örebro University Hospital. "The risk of birth defects is especially sensitive to factors during early pregnancy, and here blood glucose plays a vital part."

The study demonstrates a clear correlation between elevated levels of blood glucose (HbA1c) in the mother and the risk of heart defects in her baby. However, even those women who followed the current guidelines had a higher, albeit still small, risk of heart defects. The results show that 3.3 per cent of pregnant women with type 1 diabetes and blood glucose levels within the recommended span gave birth to a baby with a heart defect. The corresponding figure for women without diabetes was 1.5 per cent.

Pregnant women with type 1 diabetes who had very high blood glucose levels (an HbA1c reading of 9.1 per cent or higher) were at much greater risk.

"Here, the risk of the baby having a heart defect was as much as 10.1 per cent - or one in every ten babies," says Professor Ludvigsson. "The reason why the risk of deformity can be linked to blood glucose levels in early pregnancy is that it is then that the fetus's organs develop. Also, many women aren't aware that they're pregnant during the first few months."

This, he stresses, is why women must know about the dangers before trying to have children.

"There's an opportunity here for women to influence the risk of their baby developing a heart defect by keeping their blood glucose levels low. Yet we as doctors also know that many pregnant women struggle valiantly to keep their blood glucose down, as it is no easy task. The potential benefit of intensified insulin treatment to reduce the risk of heart defects should also be weighed against possible risks with hypoglycaemia in the mother and foetus," says Professor Ludvigsson.

The study was done by cross-referencing the National Diabetes Register with the National Patient Register and the Medical Birth Registry, and comparing 2,458 living newborns of mothers with type 1 diabetes with 1,159,865 babies of mothers without diabetes. Since this is an observational study no definitive conclusions can be drawn regarding causality. The researchers are now planning to make further investigations in the field.

The study was financed with grants from the Swedish Diabetes Association, the Strategic Research Area in Epidemiology (SfoEpi) at Karolinska Institutet, the Swedish Research Council and Stockholm County Council.

Children of mothers who follow a healthy lifestyle have a substantially lower risk of developing obesity than children of mothers who don't make healthy lifestyle choices, finds a study published in The BMJ.

The findings show that risk was lowest among children whose mothers maintained a healthy weight, exercised regularly, did not smoke, ate a healthy diet, and were light to moderate drinkers.

The researchers suggest that if both mothers and their children stuck to a healthy lifestyle this could result in an even further reduction in the risk of childhood obesity.

One in five American children and teenagers aged 6-19 years is obese. Obesity in childhood is associated with an increased risk of several disorders, including diabetes and cardiovascular disease, as well as premature death, in adulthood.

Identifying risk factors for the prevention of childhood obesity has become a public health priority. While the role of genetics in obesity is widely recognised, a rapid increase in obesity in recent years is more likely to be due to lifestyle changes.

Previous studies have shown that children's lifestyle choices are largely influenced by their mothers, however, it is unknown whether healthy lifestyle patterns in mothers during their offspring's childhood and adolescence influence the development of obesity.

So an international team based in Canada and the USA set out to investigate whether mother and child lifestyle factors have an effect on the risk of childhood obesity.

They examined medical history and lifestyle characteristics of 24,289 children aged 9-14 years who were born to 16,945 women in two US studies, the Nurses' Health Study II (NHSII) and Growing Up Today Study (GUTS).

Participants completed detailed questionnaires about their medical history and lifestyle, including body mass index (BMI), physical activity levels and diet. Mothers were also asked about their alcohol intake and smoking history.

Based on this information, the researchers calculated the risk of obesity for each child, using BMI measurements.

Generally, a BMI between 18.5 and 24.9 indicates a healthy weight. Below 18.5 is in the underweight range, between 25 and 29.9 is in the overweight range, and between 30 and 39.9 is in the obese range.

Women were on average 41 years old with a mean BMI of 25 and most (93%) were not current smokers. Their offspring were on average 12 years of age, and 46% were boys.

After taking account of potentially influential factors, such as age, ethnicity, history of chronic diseases, household income and education, the researchers found that the risk of obesity was 56% lower in children of women with a healthy body weight than children of mothers in other BMI categories.

Compared with offspring of women who were current smokers, children of non-smoking mothers had 31% lower risk of obesity.

Children of mothers who exercised for the recommended 150 minutes or more a week - and who were light to moderate drinkers (1-2 small glasses of wine or a pint of standard strength beer a day) - also had a lower risk of obesity compared with children of mothers who did not exercise and who did not drink alcohol.

Lastly, children of mothers who followed all five low risk lifestyle factors (a high quality diet, normal body weight, regular physical activities, light to moderate intake of alcohol, and non-smoking) had a 75% lower risk of developing obesity, compared with offspring of women who did not meet any of the low risk lifestyle factors.

This is an observational study, so no firm conclusions can be drawn about cause and effect, and the researchers outline some study limitations. For example, lifestyle characteristics, like weight, food intake and amount of physical activity of mothers and their children were exclusively based on self reports, which may have been subject to measurement errors.

Nevertheless, they say their study "shows that mothers' overall healthy lifestyle during the period of their offspring's childhood and adolescence is associated with a substantially lower risk of obesity in their children".

These findings highlight the potential benefits of implementing parent based interventions to curb the risk of childhood obesity, they say. "Prospective research examining the role of fathers in the development of obesity in offspring is needed" they add.

New drugs known as direct oral anticoagulants (DOACs) used to treat serious blood clots are associated with reduced risks of major bleeding compared with the older anti-clotting drug, warfarin, finds a study in The BMJ today.

The findings provide initial reassurance about the safety of DOACs as an alternative to warfarin for all new patients.

For many years, warfarin has been the main treatment for potentially fatal blood clots, known as venous thromboembolism (VTE). But DOACs are increasingly being used as an alternative to warfarin because patients don't need regular tests to check if they have the right amount of drug in their bloodstream.

Clinical trials have shown a reduced or similar risk of major bleeding for DOACs compared with warfarin. But such trials involve only carefully selected patients, so bleeding rates often do not reflect those seen in everyday ("real world") clinical practice.

Furthermore, most observational studies have included only patients with irregular heartbeat (atrial fibrillation or AF), creating an information gap for patients without this condition.

So researchers at the University of Nottingham supported by National Institute of Health Research set out to investigate the risks and benefits associated with the three commonest types of DOACs (dabigatran, rivaroxaban, and apixaban) compared with warfarin in patients with and without AF.

Using data from two large UK primary care databases, they identified 196,061 patients who started or restarted anticoagulants (after more than a 12 month gap) between 2011 and 2016.

A total of 132,231 patients were taking warfarin, 7,744 dabigatran, 37,863 rivaroxaban, and 18,223 apixaban. Overall 53% (103,270) were diagnosed with AF and 47% (92,791) were prescribed anticoagulants for other conditions.

Patients were monitored for major bleeds leading to hospital admission or death, ischaemic stroke, VTE, and death from any cause ("all cause mortality").

After taking account of several known risk factors, the researchers found that apixaban was associated with a lower risk of major bleeding, particularly brain and gastric bleeds, in patients with and without AF, compared with warfarin.

They also found a lower risk of brain bleeds associated with use of dabigatran in patients with AF - and with use of rivaroxaban in patients without AF - compared with warfarin.

Rivaroxaban and low dose apixaban were, however, associated with increased risks of deaths from any cause in all patients when compared with warfarin, which may reflect closer monitoring of patients taking warfarin or may be related to other underlying conditions, suggest the researchers.

Overall, apixaban had the lowest numbers needed to treat over six months to avoid one extra major bleed (182 patients with AF and 138 without), compared with warfarin. In contrast, rivaroxaban had the lowest numbers needed to harm to observe one extra death (202 with AF and 61 without).

The researchers point out that this is an observational study, so no firm conclusions can be drawn about cause and effect, and they outline some limitations, such as possible misclassification due to patients not taking their medication.

Nevertheless, they say their study shows that "the risk of major bleeding is lower in apixaban users regardless of the reason for prescribing, appearing to show apixaban to be the safest drug."

"Our results give an initial, reassuring, indication of the risk patterns for all patients taking anticoagulants, in particular with respect to those prescribed apixaban," they conclude.

Expanding the availability of medication treatment for opioid use disorder in primary care settings would be a major step toward reducing overdose deaths, write two physicians specializing in addiction medicine and health care delivery in the July 5 issue of New England Journal of Medicine. In their Perspectives article entitled "Primary Care and the Opioid-Overdose Crisis - Buprenorphine Myths and Realities," Sarah Wakeman, MD, medical director of the Massachusetts General Hospital Substance Use Disorders Initiative and Michael Barnett, MD, of the Department of Health Policy and Management, Harvard T.H. Chan School of Public Health, describe current barriers to expanded delivery of buprenorphine treatment and outline possible solutions.

"One of the tragic ironies is that with well-established medical treatment, opioid use disorder can have an excellent prognosis," they write, noting that almost 80 percent of Americans with opioid use disorder are unable to receive treatment and that the growth in distribution of buprenorphine - one of three FDA-approved medications for the treatment of opioid use disorder - has been slowing rather than increasing in recent years. "To have any hope of stemming the overdose tide, we have to make it easier to obtain buprenorphine than to get heroin and fentanyl."

The authors describe 5 persistent but inaccurate myths that they believe prevent buprenorphine from being more widely adopted:

That is more dangerous that other common health care interventions,

That buprenorphine treatment is just replacing one addition for another,

That abstinence-based treatment - short-term detoxification and rehabilitation - is more effective than medication-based treatment,

That providing buprenorphine treatment is particularly onerous and time consuming for primary care physicians (PCPs),

That physicians should just reduce opioid prescriptions to address the overdose epidemic

Most outpatient buprenorphine treatment is already provided by PCPs, and expanding the availability of office-based buprenorphine treatment, as several other countries have done, presents a realistic solution to addressing the overdose crisis, the authors note. They write, "We are in the midst of a historic public health crisis that demands action from every physician. Without dramatic intervention, life expectancy in the United States will continue to decline. Mobilizing the PCP workforce to offer office-based buprenorphine treatment is a plausible, practical, and scalable intervention that could be implemented immediately."

Wakeman is an assistant professor of Medicine at Harvard Medical School (HMS) and a physician at Massachusetts General Hospital; Barnett is an assistant professor of Health Policy and Management at the Harvard Chan School, an instructor in Medicine at HMS and a Brigham and Women's Hospital physician. Their article is one of three addressing improvements in medication treatment for opioid use disorder in the same NEJM issue.

Sepsis is an infection that kills as many Americans each year as stroke and Alzheimer's combined-about 250,000-but very little has changed in the treatment of this age-old scourge.

Now researchers at Columbia University Irving Medical Center have found a clue in understanding how an infection can spiral into sepsis by blunting the body's immune response. This research may also help doctors identify the patients who may need immediate intensive treatment to save their lives.

From Infection to Organ Failure

Sepsis can start with a simple infected cut. When the immune system fails to fight off the infection, sepsis occurs when inflammation spreads throughout the body, leaving patients vulnerable to organ damage, severe secondary infections, and death. While time is of the essence, doctors lack quick, efficient ways to diagnose this deadly condition.

"The best treatment for sepsis starts with rapid detection. Our results suggest that specific molecules called microRNAs may be potential biomarkers of poor prognosis, indicating the need for more aggressive treatment options," explains the study's senior leader Sankar Ghosh, PhD, the Silverstein and Hutt Family Professor of Microbiology & Immunology and chair of the Department of Microbiology & Immunology at Columbia University Vagelos College of Physicians and Surgeons (VP&S).

The immune system initially launches a vigorous attack against sepsis, but then the innate immune response shuts down. In a search to understand the underlying mechanism, Ghosh's team identified two microRNAs (miR-221 and miR-222) that are produced in immune cells during prolonged inflammation. These microRNAs silence inflammatory gene expression and in a mouse model of sepsis suppress the immune system at a time when the body desperately needs a full immune response.

Identifying Patients in Danger of Sepsis

Patients with suspected sepsis had a similar reaction. Among 30 hospitalized patients, those with evidence of organ failure exhibit higher levels of miR-221 and miR-222 in their blood samples. In septic patients, those with elevated miR-221 and miR-222 also exhibited evidence of immunosuppression.

The two microRNAs could be the basis of a test to help physicians classify patients into those with organ failure who are at high risk of sepsis and death and those patients with milder infections. With faster diagnosis, doctors could start antibiotics and fluids to control the infection more quickly before patients succumb to organ failure and secondary infections.

"When doctors face sepsis in the hospital, it is usually a mystery as to what is causing the infection, but they must act quickly. They can choose to use the broadest spectrum of antibiotics for an aggressive approach to cover every bacterial cause of infection, but this may later cause antibiotic resistance, a growing problem," says study co-author Daniel Freedberg, MD, assistant professor of medicine at CUIMC. "Any test that can identify the cause of sepsis to guide treatment options is invaluable."

Clinical trials will be needed to validate the usefulness of testing patients for these microRNAs as a quick guide to prognosis and treatment. The research comes at a time when the number of sepsis cases per year has been on the rise in the United States, according to the National Institutes of Health. Creating better diagnostics may be able to help reverse this trend and save lives.

Anticonvulsant drugs are increasingly being used to treat low back pain, but a new study in CMAJ (Canadian Medical Association Journal) finds they are ineffective and can have adverse effects.

"Clinically, the prescription of anticonvulsants for back and neck pain, including radicular pain in primary care, has increased by 535% in the last 10 years," writes Dr. Oliver Enke, University of Sydney, Sydney Medical School Nepean, Kingswood, Australia, with coauthors, citing data from a recent study on prescribing trends for back pain.

Low back pain affects millions of people and is the number one cause of disability. Clinical practice guidelines usually recommend nonpharmacologic treatments and nonopioid pain relievers rather than stronger analgesics such as anticonvulsants.

The study findings are based on high and moderate-quality evidence from 9 placebo-controlled randomized trials that found a lack of evidence of benefit from anticonvulsants and more adverse events from some of these drugs.

"We have shown, with mostly high- and moderate-quality evidence, that common anticonvulsants are ineffective for chronic low back pain and lumbar radicular pain, and are accompanied by increased risk of adverse events," write the authors.

These findings support recent guidelines from the United States and the United Kingdom that do not recommend the use of anticonvulsants.

"Anticonvulsants in the treatment of low back pain and lumbar radicular pain: a systematic review and meta-analysis" is published July 3, 2018.

Charlottesville, VA (July 3, 2018). Researchers from the University of Michigan found that serum levels of two biomarkers of traumatic brain injury, tau and ubiquitin C-terminal hydrolase L1, are elevated following high-acceleration head impacts, even when there is no clinical diagnosis of concussion. Their complete findings are reported today in the Journal of Neurosurgery, in the article "Elevated markers of brain injury as a result of clinically asymptomatic high-acceleration head impacts in high-school football athletes" by Jacob R. Joseph, M.D., and colleagues.

In American football, athletes are regularly subjected to head impacts of varying intensities--hits that may or may not produce the clinical signs and symptoms of a concussion. Sometimes it is difficult to tell whether all of these hits result in brain injury and to what extent. Current neuroimaging techniques often cannot detect brain injury induced by head impacts, and some athletes may not notice subtle symptoms or may be loath to report their symptoms lest they be removed from play.

In this paper, the authors used helmet-based accelerometers and measurements of serum biomarkers of traumatic brain injury (TBI) to examine the effects of high-acceleration head impacts (HHIs) and to specifically answer the following questions:
* Would HHIs result in high serum levels of biomarkers of TBI, even in the absence of clinical symptoms of concussion?
* What would be the longitudinal profile of TBI markers in athletes over the course of a high-school football season?

Sixteen high-school varsity football players wore helmet-based accelerators that measured and recorded all head impact data during practices and games throughout the 2016 football season. An HHI was defined as a hit to the head involving both linear acceleration greater than 95g and rotational acceleration greater than 3760 rad/second2. During the entire football season a total of 7,756 head impacts were recorded, of which only 11 (0.001%) met the criteria of an HHI. Six athletes experienced one or more HHIs at some point during the season; five other athletes who did not experience an HHI served as controls.

Blood samples were collected from players at the beginning of the season (16 players), at the end of a game in which an HHI occurred (6 players), following the final game (5 players used as controls for the 6 players with HHI), and after the end of the season (12 players in whom there was no diagnosis of concussion and no discrepancy in biomarker analyses). The athletes' blood samples were tested for serum levels of the following TBI markers: tau, ubiquitin C-terminal hydrolase L1 (UCH-L1), neurofilament light protein, glial fibrillary acidic protein, and spectrin breakdown products.

The authors' review of TBI biomarker levels showed statistically significant increases in serum levels of both tau and UCH-L1 after an athlete sustained a single HHI, compared with levels in athletes who did not experience an HHI. When the authors examined TBI biomarker levels over the course of the season, they also found statistically significant increases in post-season levels of both tau and UCH-L1, compared to pre-season levels, in athletes with no diagnosis of concussion. There were no significant increases in the serum levels of the other TBI biomarkers that were tested.

UCH-L1 is a biomarker of neuronal body injury and tau is a biomarker of axonal injury. In their prospective, observational cohort study, Joseph and colleagues identified an association between increased biomarkers of neuronal and axonal head injury and HHI in high-school varsity football players. In addition, the authors showed an association between increased biomarkers of neuronal and axonal head injury, and athletes who played throughout the course of an entire football season, even those athletes in whom no HHI exposure occurred.

The authors acknowledge the small sample size, the lack of non-collision sport controls, and other limitations of the study. They indicate difficulty in trying to interpret the present findings, because the football players did not exhibit the clinical signs and symptoms of concussion. They also raise several questions that can only be answered by future studies.

When asked about the importance of this pilot study, Dr. Joseph responded, "This study suggests asymptomatic high acceleration head impacts, which represent only 0.001% of all impacts, may be on the same spectrum as concussion. Whether these elevations in blood biomarkers of traumatic brain injury are clinically significant is yet to be known. However, we are excited as this potentially provides a new avenue to reduce the risk to young athletes. Specifically, we believe that technological improvements and refinements of game rules may be able to reduce the incidence of HHI."

WHAT:
Fetal death in utero occurred in more than one-fourth of monkeys infected in the laboratory with Zika virus in early pregnancy, according to new research published in Nature Medicine. The finding raises the concern that Zika virus-associated pregnancy loss in humans may be more common than currently thought, according to the study authors.

A large team of experts aggregated data on Zika-infected macaques from six National Primate Research Centers (NPRCs) in the United States for the new analysis. The study was funded in part by the National Institute of Allergy and Infectious Diseases (NIAID) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), both components of the National Institutes of Health.

Zika virus is most often transmitted to humans via the bite of an infected Aedes aegypti mosquito. It also is transmitted sexually. Many people infected with Zika virus will not have symptoms; others may have fever, rash, headache, joint pain, red eyes, and muscle pain. Zika virus can be passed from an infected pregnant woman to her fetus and cause a range of birth defects collectively known as congenital Zika syndrome. Although Zika virus was first discovered in 1947, Zika-related birth defects were not reported until 2015 during a large outbreak of Zika in the Americas. No licensed treatments or vaccines for Zika virus are currently available, but many are in various stages of development. For example, NIAID is leading an international Phase 2 trial of an experimental Zika vaccine.

Research recently published in the New England Journal of Medicine showed a 5.8 percent miscarriage rate and a 1.8 percent stillbirth rate in a cohort of pregnant women with symptomatic Zika virus infection in French Guiana, Guadalupe or Martinique. Authors of the new nonhuman primate analysis note that the rates from the NEJM study could be an underestimate--the study included only symptomatic pregnant women, whereas many people with Zika infection are asymptomatic.

For the new analysis, experts combined published and unpublished data from various studies of pregnant macaques infected with Zika virus. Fetal death (miscarriage or stillbirth) occurred in 13 of 50 (26 percent) of the animals studied. Macaques infected early in pregnancy had significantly higher rates of fetal death than those infected after gestation day 55. The results track with human data showing more severe fetal outcomes in women infected with Zika in their first trimester compared to those infected later in pregnancy. The rates of fetal death in macaques underscore the need for careful monitoring of fetal loss and stillbirth in Zika-affected human pregnancies, the authors write.

New methods of studying the evolution of treatment resistance in head and neck cancer are being developed by researchers at the Johns Hopkins Kimmel Cancer Center.

The scientists wanted to examine how cancers acquire resistance to treatment over time and whether those changes could be modeled computationally to determine patient-specific timelines of resistance.

The research was published by Genome Medicine on May 23, 2018.

The Coordinate Gene Activity in Pattern Sets algorithm (CoGAPS) was used to determine the molecular changes associated with resistance during the course of the development of the resistance. It required developing new methods of collecting data from in vitro cell models and developing a computational analysis approach to measure these observations that has not previously been done for cancer.

"The biggest novelty in this paper is considering time as a variable. We have to prove that it matters before putting that burden on patients," said senior author Elana Fertig, Ph.D. "But we think it will result in better treatment."

The study examined cetuximab treatment effects on cancer cells from head and neck squamous cell carcinoma over 11 weeks. During that time, they used the same pool of cells to see what happened during the time period, attempting to avoid any outside variables from using different batches of cells.

CoGAPS was used to quantify the evolving changes during treatment. The resulting data showed how the changes occurred over time and when those changes resulted in immediate therapeutic response or resistance. Having that information could lead to combined or alternative therapies to combat the resistance.

Most model systems were developed to sync to existing data, comparing pre- and post-treatment," said co-lead author Genevieve Stein-O'Brien, Ph.D. "To take this algorithm and find out how the resistance was acquired, we needed to know what was going on in between (the pre- and post-treatment) during the full time course."

Although a wide variety of molecular alterations conferring resistance to the treatment have been discovered, the mechanisms and timing of their evolution are still poorly understood. With the CoGAPS algorithm combining experimental biology and computer programming, the scientists hope to give doctors and patients better information about how the disease is progressing during treatment.

Co-lead author Luciane Kagohara, Ph.D., said CoGAPS is a departure from standard approaches but allows them to go deeper and study therapeutic resistance and the fundamental pathways in an individual.

"If we can map that, it will really pave the way to predict when resistance is going to occur and what drugs can be used to combat that resistance," she said.

The scientists believe the computational approach to studying cancer cells over time with targeted therapies could be used for other types of cancers and other drug therapies.

A multidisciplinary team from the University of Granada has developed software that can make it easier to identify potential pancreatic cancer biomarkers and thereby achieve earlier diagnosis of the disease. Pancreatic cancer can be diagnosed using biomarkers which, in this case, are differentially expressed genes indicative of this illness.

However, medical professionals currently face two problems when attempting to diagnose pancreatic cancer early and efficiently. Firstly, a patient's genetic expression data can be collected using several platforms such as Affymetrix or Illumina, but this heterogeneous data, despite possibly containing important information about potential cancer biomarkers, can be hard to analyse.

Secondly, 80 percent of patients already have locally advanced or metastatic disease at the time of diagnosis, due to the absence of reliable biomarkers which could help to detect the illness at an earlier stage. The UGR researchers behind the study, which set out to address these problems, therefore explain that: "All improvements aimed at identifying new biomarkers of this illness are essential if we are to diagnose cancer earlier and improve the prognosis of patients."

The study, led by UGR scientists Ignacio Rojas Ruiz, Octavio Caba Pérez and José Carlos Prados Salazar and published in the journal PLOS ONE, is indeed a step towards solving these issues. The new software developed as part of the study integrates patients' genetic data from different microarray platforms and sorts through them to identify pancreatic cancer biomarkers, especially those which are new, sensitive and specific.

How the software works

The sensitivity and specificity of a biomarker refers to the level of accuracy with which it indicates pancreatic cancer; the more sensitive and specific a biomarker is, the more likely it is to indicate pancreatic cancer, as opposed to other illnesses. Several studies have already succeeded in establishing more specific and sensitive biomarkers, but the process of identifying them is made more complex than it could be.

The complications stem from the fact that there is currently an overwhelming number of sample preparation processes, labelling methods and different microarray platforms in use, which often leads to signal values that vary greatly. This variation in turn means that potentially life-saving information gets "lost in translation". Seeing as integrative systems--like the one developed by the UGR--help to remedy this problem, they could become fundamental tools for ensuring earlier, more efficient diagnosis of pancreatic cancer.

In fact, thanks to this new integrative software, the researchers have not only identified 5 commonly expressed potential biomarkers of the illness, but also 28 novel or "gained" genes which are only differentially expressed in the meta-analysis, but not in the individual studies. This is because these genes--currently under analysis--show consistent expression patterns indicative of pancreatic cancer only when several datasets are integrated. Using some of the new potential biomarkers would also be an improvement on the status quo, since the only biomarker currently in routine clinical use was recently found to be an unreliable diagnostic tool due to its limited sensitivity and specificity.

The researchers who conducted the study are from the Departments of Computer Architecture and Technology as well as Human Anatomy and Embryology, and collaborated with the Spanish Cooperative Group for Gastrointestinal Tumour Therapy (TTD) in order to carry out the project.

Australia's national science agency CSIRO has identified a new gene that plays a critical role in regulating the body's immune response to infection and disease.

The discovery could lead to the development of new treatments for influenza, arthritis and even cancer.

The gene, called C6orf106 or "C6", controls the production of proteins involved in infectious diseases, cancer and diabetes. The gene has existed for 500 million years, but its potential is only now understood.

"Our immune system produces proteins called cytokines that help fortify the immune system and work to prevent viruses and other pathogens from replicating and causing disease," CSIRO researcher Dr Cameron Stewart said.

"C6 regulates this process by switching off the production of certain cytokines to stop our immune response from spiralling out of control.

"The cytokines regulated by C6 are implicated in a variety of diseases including cancer, diabetes and inflammatory disorders such as rheumatoid arthritis."

The discovery helps improve our understanding of our immune system, and it is hoped that this understanding will enable scientists to develop new, more targeted therapies.

Dr Rebecca Ambrose was part of the CSIRO team that discovered the gene, and co-authored the recent paper announcing the discovery in the Journal of Biological Chemistry.

"Even though the human genome was first fully sequenced in 2003, there are still thousands of genes that we know very little about," Dr Rebecca Ambrose, a former CSIRO researcher, now based at the Hudson Institute of Medical Research said.

"It's exciting to consider that C6 has existed for more than 500 million years, preserved and passed down from simple organisms all the way to humans. But only now are we gaining insights into its importance."

Having discovered the function of C6, the researchers are awarded the privilege of naming it, and are enlisting the help of the community to do so.

"The current name, C6orf106, reflects the gene's location within the human genome, rather than relating to any particular function," Dr Stewart said.

"We think we can do better than that, and are inviting suggestions from the public."

A shortlist of names will be made available for final approval by a governing third party.

The breakthrough builds on decades of work in infectious diseases, by researchers from CSIRO, Australia's national science agency.