Body

PHOENIX, Ariz. -- March 1, 2018 -- An anti-cancer drug used to fight leukemia shows promise against a rare and aggressive type of ovarian cancer -- small cell carcinoma of the ovary hypercalcemic type (SCCOHT) -- which strikes young women and girls, according to a study led by the Translational Genomics Research Institute (TGen).

Ponatinib was found in TGen-led drug screens and preclinical studies to significantly delay tumor growth and reduce tumor volume in SCCOHT, according to the study published online in the scientific journal Clinical Cancer Research. The findings suggest that ponatinib should be tested for use in SCCOHT patients in clinical trials.

The statistics for SCCOHT are bleak. This rare and aggressive form of ovarian cancer has been diagnosed in women as old as 47, and as young as 14 months, with a median diagnosis of only 24 years of age. It has a dismal two-year survival rate of less than 35 percent.

"Current treatment for this devastating cancer has such poor response rates and extreme toxicity that we must find better therapeutics," said Dr. Jeffrey Trent, TGen President and Research Director, and the senior author of the study. "Our work identifies a new treatment strategy that could provide these young women with improved patient benefit."

An international research team led by TGen, an affiliate of City of Hope, first discovered that a mutation in the gene SMARCA4 was the genetic cause of SCCOHT, according to a 2014 study published in Nature Genetics. The SMARCA4 gene -- previously associated with lung, brain and pancreatic cancer -- was the only recurrently mutated gene in the study's samples.

In the most recent study, TGen laboratory researchers found that SCCOHT tumors, driven by the inactivation of the SMARCA4 gene, are reliant on receptor tyrosine kinase (RTK) cellular pathways. Researchers identified these pathways from screens of drugs already approved by the FDA that might be effective against this cancer.

"We identified ponatinib as the most effective clinically approved RTK inhibitor," said Dr. Jessica Lang, a TGen post-doctoral fellow and co-lead author of the study. "It holds the potential for rapidly improving outcomes for these young patients."

In laboratory models, ponatinib delayed tumor-doubling time by four-fold, while reducing tumor volumes in models by as much as 58.6 percent, the study said.

"Evaluation of a panel of selective RTK inhibitors highlighted ponatinib as the most potent tested agent in SCCOHT cell lines," said Dr. William Hendricks, Assistant Professor in TGen's Integrated Cancer Genomics Division, and the other co-lead author of the study. "Clinical investigation of this FDA-approved oncology drug is warranted in SCCOHT."

Much of the work in this study was inspired by the memory of Taryn Ritchey, a 22-year-old TGen patient who in 2007 lost her battle with ovarian cancer. More than 14,000 patients in the U.S. will die this year from ovarian cancer, making it the 5th leading cause of cancer death among American women.

A completely new classification of diabetes which also predicts the risk of serious complications and provides treatment suggestions. We are now seeing the first results of ANDIS - a study covering all newly diagnosed diabetics in southern Sweden -- published in The Lancet Diabetes & Endocrinology.

The major difference from today's classification is that type 2 diabetes actually consists of several subgroups, the results indicate.

"This is the first step towards personalised treatment of diabetes", says Leif Groop, physician and professor of diabetes and endocrinology at Lund University in Sweden.

Today, about 425 million people around the world have diabetes. By 2045, the number is expected to have increased to 629 million*. Secondary diseases in the form of kidney failure, retinopathy (eye damage), amputations and cardiovascular diseases result in huge costs to society and major individual suffering. Thus, the need for new and better treatment options is great.

"Current diagnostics and classification of diabetes are insufficient and unable to predict future complications or choice of treatment", explains Professor Leif Groop, who initiated the study.

He believes that the results represent a paradigm shift in how to view the disease in the future.

"Today, diagnoses are performed by measuring blood sugar. A more accurate diagnosis can be made by also considering the factors accounted for in ANDIS (All New Diabetics In Skåne)."

Since 2008, the researchers have monitored 13 720 newly diagnosed patients between the ages 18 and 97. By combining measurements of, for example, insulin resistance, insulin secretion, blood sugar levels (BMI, HbA1c, GADA, HOMA-B and HOMA-IR) and age at onset of illness, the researchers were able to distinguish five distinct clusters that differ from today's classification (see diagram).

In addition to a more refined classification, the researchers also discovered that the different groups are more or less at risk of developing various secondary diseases.

"This will enable earlier treatment to prevent complications in patients who are most at risk of being affected", says Emma Ahlqvist, associate professor and lead author of the publication.

Diabetes is currently divided into: type 1 diabetes (approx. 10 per cent), type 2 diabetes (85-90 per cent) and a number of less common diseases such as LADA, MODY and secondary diabetes.

However, the researchers suggest a new set of subgroups:

Group 1, SAID (severe autoimmune diabetes): essentially corresponds to type 1 diabetes and LADA (latent autoimmune diabetes in adults), and is characterised by onset at young age, poor metabolic control, impaired insulin production and the presence of GADA antibodies.

Group 2, SIDD (severe insulin-deficient diabetes): includes individuals with high HbA1C, impaired insulin secretion and moderate insulin resistance. Group 2 had the highest incidence of retinopathy.

Group 3, SIRD (severe insulin-resistant diabetes): is characterised by obesity and severe insulin resistance. Group 3 had the highest incidence of kidney damage - the secondary disease producing the highest costs to society.

Group 4, MOD (mild obesity-related diabetes): includes obese patients who fall ill at a relatively young age.

Group 5, MARD (mild age-related diabetes): is the largest group (about 40%) and consists of the most elderly patients.

"The most insulin resistant patients (Group 3) have the most to gain from the new diagnostics as they are the ones who are currently most incorrectly treated", says Professor Leif Groop.

The researchers subsequently repeated the analysis in a further three studies from Sweden and Finland.

"The outcome exceeded our expectations and highly corresponded with the analysis from ANDIS. The only difference was that Group 5 was larger in Finland than in Skåne. The disease progression was remarkably similar in both groups", says Leif Groop.

The recruitment of newly diagnosed diabetes patients continues and the researchers have several studies underway based on the data they have already acquired.

"The longer the study is running, the more and better data we'll get", says Emma Ahlqvist.

The researchers are also planning to launch similar studies in China and India with people of different ethnic backgrounds.

"This will give us even better opportunities to tailor the treatment to each individual", she concludes.

WASHINGTON -- A new report from the National Academies of Sciences, Engineering, and Medicine examines to what extent and in which ways health care utilization -- such as in-patient hospitalizations, emergency department use, and hospital readmission -- reflects disease severity, disability, and ability to perform gainful activity. The committee that conducted the study was unable to find an association between health care utilization and disease severity as it relates to the Social Security Administration's (SSA) determination of severe impairment -- an impairment or combination of impairments severe enough to prevent a person from performing any gainful activity regardless of age, education, or work experience.

Types of health care utilization vary with combinations of health conditions, and although there might be a connection between some types of utilization and impairment severity or disability, the committee could not make that specific connection on the basis of available data.

The SSA administers two programs that provide benefits based on disability. The Social Security Disability Insurance (SSDI) program provides disability benefits to people under the full retirement age who are no longer able to work because of a disabling medical condition or a terminal illness. The Supplemental Security Income (SSI) program is a means-tested income-assistance program for disabled, blind, and aged people who have limited income and resources regardless of their prior participation in the labor force.

The committee relied on hospitalization and other national data, given that annual data on hospitalizations has been collected in the U.S. since 1965, and it is easy to capture and more likely than data on other types of health care utilization to constitute a reliable measure of impairment severity associated with some diseases. However, care is given in many other settings, such as outpatient and urgent care centers, and this fragmented nature of the health care delivery system makes it difficult to account for all the types and locations of utilization for purposes of determining disease severity.

Many factors affect use of health care services, the report says, such as costs of care, availability of providers who accept the patient's insurance, and access to transportation options. Social determinants, such as race and ethnicity, language, income, and poverty, have a substantial effect on health care utilization and outcomes. In addition, different geographic regions experience varying degrees of availability of health care; urban regions have easier access than rural areas. People with disabilities face a number of barriers to accessing health care, including physical access -- lack of working elevators or ramps, automatic doors, hallways and doors wide enough to accommodate wheelchairs, and accessible parking -- and accommodation for barriers to communication, such as lack of staff willing to try to communicate with impaired patients during scheduling or other interactions.

Given appropriate data -- such as administrative records of past SSDI applications merged with data on health care utilization available at the time of determination and data on post-determination work outcomes -- there are models for quantifying the value of health care utilization for determining impairment severity, the report says. However, with the rapidly changing health care landscape, predictive models that are developed now might not have the same performance attributes later, and analyses will have to be repeated as changes occur.

The study was sponsored by the U.S. Social Security Administration. The National Academies of Sciences, Engineering, and Medicine are private, nonprofit institutions that provide independent, objective analysis and advice to the nation to solve complex problems and inform public policy decisions related to science, technology, and medicine. They operate under an 1863 congressional charter to the National Academy of Sciences, signed by President Lincoln. For more information, visit nationalacademies.org. A committee roster follows.

February 28, 2018 - In addition to restoring the pre-pregnancy shape of the abdomen, abdominoplasty ('tummy tuck') surgery with muscle repair can improve back pain and urinary incontinence after childbearing, reports a study in the March issue of Plastic and Reconstructive Surgery®, the official medical journal of the American Society of Plastic Surgeons (ASPS).

Although abdominoplasty is classified as a cosmetic procedure, it also improves two of the most common physical complaints experienced by women after labor and delivery. According to the new research "Abdominoplasty has a proven functional benefit as well as a cosmetic benefit," comments lead author D. Alastair Taylor, FRACS, of The CAPS Clinic in Deakin, Australia.

Abdominoplasty Improves Common Post-Childbearing Symptoms

The study included 214 women undergoing abdominoplasty with repair of the abdominal muscles at nine Australian plastic surgery centers. Many women seek tummy tuck surgery to restore the shape and appearance of the abdomen after childbearing. The women's average age was about 42 years, with an average of 2.5 deliveries.

Before and after surgery, the women completed questionnaires rating their disability from back pain and urinary incontinence: two very common problems after childbearing. In the preoperative questionnaires, about 51 percent of women had moderate to severe disability from back pain, while urinary incontinence was a "significant concern" for 42.5 percent.

On follow-up questionnaires at six weeks and six months, scores for both problems showed major improvement. At six months, only nine percent of patients still had moderate disability from back pain. Urinary incontinence remained a significant problem for less than two percent of women.

Scores for back pain continued to improve from six weeks to six months after abdominoplasty, while urinary incontinence improved no further after six weeks. The women underwent several different types of abdominoplasty surgery; the improvements in back pain and incontinence were similar regardless of the technique used.

Nearly 128,000 abdominoplasty procedures were performed in the United States in 2016, according to ASPS statistics. Tummy tuck is sometimes performed as part of "mommy makeovers" to restore the shape and appearance of a woman's body after childbearing.

The new findings--including before-and-after measurements in a large group of plastic surgery patients--are consistent with previous case reports of improvement in back pain and urinary incontinence after abdominoplasty. These functional improvements may result from restoring strength and stability in the abdominal and pelvic region as the operation incorporates repair of the abdominal muscle separation (rectus diastasis) that can occur after pregnancy.

"By reducing the problems of back pain and incontinence, abdominoplasty with rectus repair leads to a better life for women after childbearing," Dr. Taylor comments. He believes that health insurance plans should recognize that abdominoplasty has functional benefits, beyond the cosmetic improvement offered.

"The results demonstrate that tummy tucks do have functional benefits, as well as cosmetic ones, particularly in the postpartum population," comments Editor-in-Chief Rod J. Rohrich, MD, in a featured video on the Plastic and Reconstructive Surgery website. "If you are done having children, and still suffering from back pain or incontinence, you may consider an abdominoplasty as a surgical solution."

February 28, 2018 - Children and adolescents undergoing surgery can be swept up in the ongoing opioid epidemic, according to a review and update in the Journal of Pediatric Orthopaedics, official journal of the Pediatric Orthopaedic Society of North America (POSNA). The journal is published by Wolters Kluwer.

"The magnitude of the problem of prescription opioid use by children and teenagers is overwhelming," according to the article by Ellen Raney, MD, of Shriners Hospitals for Children, Portland, Ore., and colleagues. They present finding from a POSNA survey of opioid prescribing by pediatric orthopaedic surgeons, along with recommended strategies to reduce opioid prescribing and potential misuse among children and adolescents.

Specialists Urged to Respond to High Rates of Opioid Use by Children and Teens

Dr. Raney and coauthors trace the roots of the opioid epidemic to policies of the 1980s and 1990s advocating opioid treatment of pain as a "moral imperative." Dependence or addiction to opioid medications may occur as quickly as two months in about one-third of people. According to one estimate, 16 percent of the US population has an opioid addiction--outnumbering those with heart disease, diabetes, and cancer.

"Though it receives less attention, the dilemma in the pediatric and teenage population is no less dire," Dr. Raney comments. "Like most doctors who work to provide the best care for all patients, we were stunned by the extent and origin of the problem as research became available."

In one study, nearly 13 percent of high school seniors reported nonmedical use of prescription opioids. Most of these initially had a legitimate prescription, but used their leftover medications recreationally. Overall, nearly one-fourth of US high school seniors had some exposure to prescription opioids. A study of seventh- and eighth-graders found a five percent prevalence of nonmedical prescription opioid use.

The National Poison Data System reported that 60 percent of pediatric exposures to prescription opioids, reported as poisonings, were in children up to five years old, and 30 percent in teenagers. Most teenage opioid deaths were from intentional opioid use, whereas children under six were exposed unintentionally to medications around the home.

Dr. Raney and colleagues report findings from a 2016 survey of POSNA member surgeons regarding opioid prescribing. Three-fourths of responding surgeons said they made pain management decisions for their patients, rather than involving a pain specialist. Medication decisions were based mainly on "anecdotal experience," rather than on the limited evidence or guidelines currently available.

The survey findings raise concern that decisions about opioid prescribing may be made without research or understanding of the best management strategies. Some of the prescribing practices could lead to surplus of medications that could be diverted to nonmedical or recreational use.

Dr. Raney and colleagues outline strategies that pediatric orthopaedic surgeons can follow to minimize the impact of the opioid epidemic in children and teens undergoing surgery. First steps include education and standardized prescribing practices, including appropriate plans for disposal of unused pills.

Other strategies include changing patient expectations for postoperative pain control, along with legislation and other initiatives to shift prescribing practices. The authors outline specific strategies before, during, and after surgery to reduce opioid prescribing and nonmedical use. They write, "The need to manage our patients' pain appropriately should be safely balanced against the potential harm of drug diversion to both the individual and society at large."

Dr. Raney and colleagues conclude, "We as pediatric orthopaedists can make a difference by educating ourselves and our trainees, improving our prescribing patterns, and encouraging patients to utilize nonopioid and nonpharmacologic modalities to decrease pain." This year's POSNA Annual Meeting, to be held May 9-12 in Austin, Texas, will include a special symposium on the opioid epidemic and strategies for pediatric orthopaedic patients.

DALLAS, Feb. 28, 2018 - Higher waist and hip size are more strongly associated with heart attack risk than overall obesity, especially among women, according to research in Journal of the American Heart Association, the Open Access Journal of the American Heart Association/American Stroke Association.

In a study of nearly 500,000 adults (aged 40-69) from the United Kingdom, researchers found that while general obesity and obesity specifically around the abdomen each have profound harmful effects on heart attack risk in both sexes, women were more negatively impacted by higher waist circumference and waist-to-hip ratio than men.

This study suggests that the differences in the quantity and distribution of fat tissue not only results in differences in body shape between women and men, but may also have differential implications for the risk of heart attack in later life, researchers noted.

"Our findings support the notion that having proportionally more fat around the abdomen (a characteristic of the apple shape) appears to be more hazardous than more visceral fat which is generally stored around the hips (i.e., the pear shape)," said lead author Sanne Peters, Ph.D., Research Fellow in Epidemiology at the George Institute for Global Health at the University of Oxford in the United Kingdom.

Additional research on sex differences in obesity may yield insights into the biological mechanisms and could inform sex-specific interventions to treat and halt the obesity epidemic.

According to statistics in the AHA's 2018 Statistical Update, 40 percent of American women age 20 and older and 35 percent of men were considered obese in 2013-14 national surveys. Being obese puts you at a higher risk for health problems such as heart disease, stroke, high blood pressure, diabetes and certain cancers.

Technology users should be offered more detailed support and guidance when creating account passwords in order to make them more secure and harder to crack, a study suggests.

Research led by the University of Plymouth found those who receive basic guidance including password meters were up to 40 per cent more likely to make their choices secure.

However, those given feedback such as how likely it was that hackers could guess their passwords - and therefore access private information held in their accounts - were up to 10 times more likely to change their original choice to something more secure.

The research was conducted by the University Centre for Security, Communications and Network Research (CSCAN), in conjunction the Desautels Faculty of Management at McGill University and the Department of Computer Sciences at Purdue University.

Published in Computers & Security, it comes at a time when the global cyber security threat is continuing to rise with accounts held by individuals and organisations constantly at risk of attack.

Steve Furnell, Professor of Information Security and the Director of CSCAN, said: "Over the past few years, numerous cyberattacks and security incidents have demonstrated that protecting personal and professional assets is no longer an optional duty. Yet many still occur out of unintentional mistakes such as negligence, carelessness, and human errors. Despite the advance in security technology, the weakest link in the information security realm still lies in end-users so it is essential that more support is offered to try and overcome this in the future."

The research focused on two experiments designed to investigate how variations in password meter usage and feedback can positively affect resulting password choices.

In one experiment, 300 users creating an internet account were offered either none or a range of advice including a standard password meter, emojis or an emotive feedback message. The results showed the number of choices rated 'weak' falling from 75 per cent, where users received no guidance, to around a third when they were shown more emotive messages.

For the second, 500 participants in the United States were presented with more specific security-related advice, including suggestions of how long it would take a hacker to crack their password. Those users had a significantly greater understanding of the risks, and created passwords that were longer and up to 10 times stronger as a result.

As part of the study, researchers also demonstrated that several leading sites - including Facebook, Twitter and Amazon - continue to permit weak passwords practice, allowing combinations of the user's first name and surname, a string of numbers such as "1234567890" and the word "password" respectively.

Professor Furnell added: "If this lack of provision is apparent with market-leading sites, it is unlikely that users are being better served in other contexts, and it potentially goes some way to explaining why bad practices persist. A common weakness in the provision of security is that while relevant features are present and available to be employed, users are often expected to use them with little upfront guidance, or ongoing support. It is therefore hardly surprising to find that users' resulting behaviours are often explicitly insecure.

"These findings provide a lesson not only for passwords, but for end-user security in general, as the combination of effective guidance and enforcement gives users the chance to understand and buy into security right from the start."

Mutations in known breast cancer genes such as BRCA1 and BRCA2 are identified in only approximately 20 per cent of women who are offered genetic testing for familial breast cancer.

Researchers at the University of Melbourne, led by Professor Melissa Southey, looked at 210 people from 25 multiple-case breast cancer families. They identified 24 previously unknown epigenetic changes that alter a woman's risk of breast cancer and can be passed down through generations without involving changes in the DNA sequence of genes.

"For the majority of women who undergo genetic testing, there is no explanation for their breast cancer predisposition," said Professor Southey, from the Department of Clinical Pathology at the University of Melbourne and Chair of Precision Medicine at Monash University.

"This ground-breaking work is not only helpful for women from families with many cases of breast cancer, it will improve breast cancer risk prediction for all women, and pave the way for the development of epigenetic therapeutics for breast cancer."

The study, published in Nature Communications, looks at epigenetic changes called DNA methylation, where methyl group chemicals modify DNA without changing its sequence. DNA methylation can mimic genetic variation, predisposing a family to breast cancer. The study is one of the first to systematically scan the genome for places where DNA methylation is heritable, and is the first to apply this to familial breast cancer.

University of Melbourne statistician Dr James Dowty said: "Our methods were very successful when applied to breast cancer, and the exciting thing is that they can be applied to many other hereditary diseases. This work was the result of a very fruitful collaboration between molecular biologists and statisticians, like a lot of work in modern medical research."

University of Melbourne and Monash University research fellow Dr Eric Joo said: "Some individuals know they come from a family with a lot of breast cancer but do not have a mutation in a known breast cancer gene. This study should help answer why some of those families have a lot of cancer. It's very exciting to be unlocking part of a big puzzle."

Dr Joo hopes more work will be done to develop tests to screen for the methylation markers associated with breast cancer.

Leukemia can be a terrifying diagnosis for the more than 60,000 U.S. patients who are told they have this blood cancer every year. But the treatment for this disease can be just as frightening. For patients with certain forms of leukemia, the only chance they have for a cure is to receive a massive dose of radiation and chemotherapy that kills their hematopoietic stem cells (HSCs), the cells responsible for making new blood, and then receive new HSCs from a healthy donor.

While patients are waiting for these new cells to go to the bone marrow factory and begin churning out new blood cells, patients are left without an immune system. Devoid of working HSCs for two to four weeks--or longer, if a first transplant doesn't take--patients are vulnerable to infections that can be just as deadly as their original cancer diagnosis.

As they wait in the protected confines of a hospital, patients who undergo HSC transplants receive blood tests every day to gauge successful engraftment, searching for the presence of immune cells called neutrophils, explains Kirsten M. Williams, M.D., blood and bone marrow transplant specialist at Children's National Health System.

"As you head into week three post-transplant and a patient's cell counts remain at zero, everyone starts to get nervous," Dr. Williams says. The longer a patient goes without an immune system, the higher the chance that they'll develop a life-threatening infection. Until recently, Dr. Williams says, there has been no way beyond those daily blood tests to assess whether the newly infused cells have survived and started to grow early healthy cells in the bone marrow, a process called engraftment.

A new study could change that paradigm. Research published online Dec. 13, 2017, by The Lancet Haematology and co-led by Dr. Williams suggests that a new imaging agent can safely show engraftment as early as days after transplant--giving a helpful and hopeful preview to patients and their doctors.

The study evaluated an investigational imaging test called 18F-fluorothymidine (18F-FLT). It's a radio-labeled analogue of thymidine, a natural component of DNA. Studies have shown that this compound is incorporated into just three white blood cell types, including HSCs. Because it's radioactive, it can be seen on various types of common clinical imaging exams, such as positron emission tomography (PET) and computed tomography (CT) scans. Thus, after infusion, the newly infused developing immune system and marrow is readily visible.

To see whether this compound can readily and safely visualize transplanted HSCs, Dr. Williams and colleagues tested it on 23 patients with various forms of high-risk leukemia.

After these patients received total-body irradiation to destroy their own HSCs, they received donor HSCs from relatives or strangers. One day before they were infused with these donor cells, and then at five or nine days, 28 days, and one year after transplantation, the patients underwent imaging with the novel PET/and CT scan imaging platform.

Each of these patients had successful engraftment, reflected in blood tests two to four weeks after their HSC transplants. However, the results of the imaging exams revealed a far more complicated and robust story.

With 18F-FLT clearly visible in the scans, the researchers saw that the cells took a complex journey as they engrafted. First, they migrated to the patients' livers and spleens. Next, they went to the thoracic spine, the axial spine, the sternum, and the arms and legs. By one year, most of the new HSCs were concentrated in the bones that make up the trunk of the body, including the hip, where most biopsies to assess marrow function take place.

Interestingly, notes Dr. Williams, this pathway is the same one that HSCs take in the fetus when they first form. Although experimental model research had previously suggested that transplanted HSCs travel the same route, little was known about whether HSCs in human patients followed suit.

The study also demonstrated that the radiation in 18F-FLT did not adversely affect engraftment. Additionally, images could identify success of their engraftments potentially weeks faster than they would have through traditional blood tests--a definite advantage to this technique.

"Through the images we took, these patients could see the new cells growing in their bodies," Dr. Williams says. "They loved that."

Besides providing an early heads up about engraftment status, she adds, this technique also could help patients avoid painful bone marrow biopsies to make sure donor cells have taken residence in the bones or at the very least help target those biopsies. It also could be helpful for taking stock of HSCs in other conditions, such as aplastic anemia, in which the body's own HSCs fade away. And importantly, if the new healthy cells don't grow, this test could signal this failure to doctors, enabling rapid mobilization of new cells to avert life-threatening infections and help us save lives after transplants at high risk of graft failure.

"What happens with HSCs always has been a mystery," Dr. Williams says. "Now we can start to open that black box."

Research published by Public Health England (PHE) estimates that at least 20% of all antibiotic prescriptions written in primary care in England are inappropriate. This implies that antibiotic prescribing nationally should be reduced by 10% by 2020, in accordance with the national ambition to cut levels of inappropriate prescribing in half. These data are published in five articles in a supplement to the Journal of Antimicrobial Chemotherapy.

Professor Paul Cosford, Public Health England Medical Director said: "Antibiotics are critical to modern medicine, saving millions of lives since the 1940s when they were first introduced. Using antibiotics when you don't need them threatens their long term effectiveness and we all have a part to play to ensure they continue to help us, our families and communities in the future. This publication highlights the role GPs can play and I urge all practices to look at ways they can reduce their inappropriate prescribing levels to help make sure the antibiotics that save lives today can save lives tomorrow."

Health Secretary, Jeremy Hunt said: "Drug-resistant infections are one of the biggest threats to modern medicine and inappropriate prescribing of antibiotics is only exacerbating this problem. "We are leading the world in our response--since 2012, antibiotics prescribing in England is down by 5% and we've invested more than £615 million at home and abroad in research, development and surveillance. But we need to go further and faster otherwise we risk a world where superbugs kill more people a year than cancer and routine operations become too dangerous." Antibiotics are important for treating serious bacterial infections, but their effectiveness is threatened by antibacterial resistance. Antibiotics are unique among drugs as the more they are used, the less effective they become and over time resistance develops. In response to this, the UK government set an ambition to reduce inappropriate antibiotic prescribing by 50% by 2020. This work seeks to quantify the amount of current antibiotic prescribing that is inappropriate.

The research found that the majority of antibiotic prescriptions in English primary care were for infections of the respiratory and urinary tracts. However, in almost a third of all prescriptions no clinical reason was documented. Antibiotic prescribing rates varied substantially between GP practices, nonetheless there is scope for all practices across the country to reduce their rates of prescribing.

For most conditions, substantially higher proportions of GP consultations resulted in an antibiotic prescription than is appropriate according to expert opinion. An antibiotic was prescribed in 41% of all uncomplicated acute cough consultations when experts advocated 10%; bronchitis (actual: 82% versus ideal: 13%), sore throat (actual: 59% versus ideal: 13%), rhinosinusitis (actual: 88% versus ideal: 11%), acute otitis media in 2-18yr olds (actual: 92% versus ideal: 17%).

This work demonstrates the existence of substantial inappropriate antibiotic prescribing and poor diagnostic coding in English primary care. Better diagnostic coding, more precise prescribing guidelines, and a deeper understanding of appropriate long-term uses of antibiotics would allow identification of further reduction potentials.

Researchers from the UK & Japan have identified how the brain's natural painkilling system could be used as a possible alternative to opioids for the effective relief of chronic pain, which affects as many as one in three people at some point in their lives.

The team, led by the University of Cambridge, have pinpointed an area of the brain that is important for endogenous analgesia - the brain's intrinsic pain relief system. Their results, published in the open access journal eLife, could lead to the development of pain treatments that activate the painkilling system by stimulating this area of the brain, but without the dangerous side-effects of opioids.

Opioid drugs such as oxycodone, hydrocodone and fentanyl hijack the endogenous analgesia system, which is what makes them such effective painkillers. However, they are also highly addictive, which has led to the opioid crisis in the United States, where drug overdose is now the leading cause of death for those under 50, with opioid overdoses representing two-thirds of those deaths.

"We're trying to understand exactly what the endogenous analgesia system is: why we have it, how it works and where it is controlled in the brain," said Dr Ben Seymour of Cambridge's Department of Engineering, who led the research. "If we can figure this out, it could lead to treatments that are much more selective in terms of how they treat pain."

Pain, while unpleasant, evolved to serve an important survival function. After an injury, for instance, the persistent pain we feel saps our motivation, and so forces us towards rest and recuperation which allows the body to use as much energy as possible for healing.

"Pain can actually help us recover by removing our drive to do unnecessary things - in a sense, this can be considered 'healthy pain'," said Seymour. "So why might the brain want to turn down the pain signal sometimes?"

Seymour and his colleagues thought that sometimes this 'healthy pain' could be a problem, especially if we could actively do something that might help - such as try and find a way to cool a burn.

In these situations, the brain might activate the pain-killing system to actively look for relief. To prove this, and to try and identify where in the brain this system was activated, the team designed a pair of experiments using brain scanning technology.

In the first experiment, the researchers attached a metal probe to the arm of a series of healthy volunteers - and heated it up to a level that was painful, but not enough to physically burn them. The volunteers then played a type of gambling game where they had to find which button on a small keypad cooled down the probe. The level of difficulty was varied over the course of the experiments - sometimes it was easy to turn the probe off, and sometimes it was difficult. Throughout the task the volunteers frequently rated their pain, and the researchers constantly monitored their brain activity.

The results found that the level of pain the volunteers experienced was related to how much information there was to learn in the task. When the subjects were actively trying to work out which button they should press, pain was reduced. But when the subjects knew which button to press, it wasn't. The researchers found that the brain was actually computing the benefits of actively looking for and remembering how they got relief, and using this to control the level of pain.

Knowing what this signal should look like, the researchers then searched the brain to see where it was being used. The second experiment identified the signal in a single region of the prefrontal cortex, called the pregenual cingulate cortex.

"These results build a picture of why and how the brain decides to turn off pain in certain circumstances, and identify the pregenual cingulate cortex as a critical 'decision centre' controlling pain in the brain," said Seymour.

This decision centre is a key place to focus future research efforts. In particular, the researchers are now trying to understand what the inputs are to this brain region, if it is stimulated by opioid drugs, what other chemical messenger systems it uses, and how it could be turned on as a treatment for patients with chronic pain.

MINNEAPOLIS - People who are frequently exposed to diesel exhaust while on the job may have a higher risk of amyotrophic lateral sclerosis (ALS), and that risk may increase with greater exposure, according to a preliminary study released today that will be presented at the American Academy of Neurology's 70th Annual Meeting in Los Angeles, April 21 to 27, 2018.

"There is some suggestion from previous studies of occupation that workers in jobs with higher exposure to diesel exhaust may have a higher risk of ALS. However, no studies have directly looked at the relation between diesel exhaust exposure during different time points in life and ALS," said study author Aisha Dickerson, PhD, of Harvard T.H. Chan School of Public Health in Boston, Mass. "The overall risk of developing ALS is low, but our findings suggest that the greater the exposure to diesel exhaust, the greater the risk of developing ALS."

ALS is a rare neurologic disease that mainly affects the nerve cells responsible for controlling voluntary muscle movement such as walking or talking. ALS is a disease that gets worse over time and eventually leads to death, most often from respiratory failure. There is currently no cure for ALS.

For this study, researchers identified 1,639 people with an average age of 56 from the Danish National Patient Registry who were diagnosed with ALS between 1982 to 2013. Each person with ALS was then matched with 100 people of the same age and sex who did not have ALS. The researchers then gathered the employment history for each person and calculated their estimated diesel exhaust exposure before each person was diagnosed with ALS or the same time period in the healthy participants. The estimated exposure was based on potential hazards for specific jobs, including service station attendants, bus drivers and construction workers. The study authors determined the cumulative amount of exposure to diesel exhaust participants had. They calculated exposure for both up to five and 10 years before the diagnosis time period, allowing for the time it may take for diesel exhaust to have an effect on the body.

The participants were divided into four groups based on amount of exposure to diesel exhaust. Men with any exposure to diesel exhaust at jobs held at least 10 years prior to their date of inclusion in the study were 20 percent more likely to have ALS than men with no exposure to the exhaust during the same time period. For men who had a greater than 50 percent likelihood of being exposed to exhaust based on their occupation, the link was stronger. That group was 45 percent more likely to develop ALS than those with no exhaust exposure at both five and 10 years prior to study inclusion. No associations were seen among women, although the types of jobs and even tasks performed in the same job can differ substantially for men and women.

The results were adjusted for other factors that could affect risk of ALS including socioeconomic status and the region of Denmark where a participant lived.

Dickerson said, "This type of exposure deserves more attention and study as we work to develop a better understanding of what causes ALS. Importantly, the general population can be exposed to diesel exhaust from traffic pollution. Understanding whether that exposure increases ALS risk is also an important question to pursue."

The study was supported by the National Institute of Environmental Health Sciences and the National Institutes of Health.

The study does not show that diesel exhaust causes ALS; it only shows an association.

A limitation of this study was that it used a job exposure matrix to estimate occupational diesel exhaust levels and could not directly measure personal exposures. However, the authors note that any potential misclassification caused by this would likely have diminished the observed associations.

Metal detection has helped mining companies strike gold and airport security identify passengers who are a potential threat. Now USC scientists have pushed its use into another realm: studying cancer.

By imaging metal-tagged antibodies on biopsies from a patient with metastatic prostate cancer, Bridge Institute researchers at the USC Michelson Center for Convergent Bioscience have created highly detailed, digital facsimiles of cancer cells that can travel through the body. The metal tags enable scientists to identify and characterize the cancer cells in a blood sample after it is placed on a slide.

"That is exactly what is happening when the TSA swipes your hands," said Peter Kuhn, a Dean's Professor of Biological Sciences at the Bridge Institute at the USC Michelson Center. "They are looking for metals, which are really easy to identify."

The USC-led study, published in January by Convergent Science Physical Oncology, established the proof of concept for the metal-detection technique, which allows scientists to see circulating and disseminated tumor cells at a molecular level in a way not possible before. Creating such highly detailed copies of tumors may help researchers develop more precise treatment plans for individual patients.

"We are trying to understand how cancer actually moves from the initial location to other places in the body and can settle there," Kuhn said.

Through his work, Kuhn aims to shed new light on how cancer spreads through the body and evolves over time. Such discoveries have already led to better personalized care for patients, which tailors the treatment to the individuals as much as to their specific form of cancer.

Because Kuhn's research bridges multiple fields, he holds professorships at the USC Dornsife College of Letters, Arts and Sciences, the USC Viterbi School of Engineering and the Keck School of Medicine at USC - all of which are tied to the USC Michelson Center, a hub for convergent bioscience at the university.

Image: iStock

Mapping cancer for precision medicine

The study examined whether scientists could achieve a better blueprint for the spread of the tumor, which is the most difficult phase of cancer. Cancer spreads via rare circulating and disseminated tumor cells that break away from their original source, such as tumors in the breast or the prostate, and travel through the body. These rogue tumor cells spread into organs, such as the liver or lungs, or into the bones, where they metastasize undetected, making effective treatment very challenging.

Until now, researchers have relied on fluorescence microscopy, staining cells with a fluorescent labeled antibody and then examining them with microscopes. Fluorescence microscopy is useful, but its routine use is limited in the number of colors available in a single experiment.

With the Fluidigm Hyperion Imaging System to monitor the biology of the cancer cells and understand how the cancer changes, scientists could see protein biomarkers that may determine how a tumor cell would respond to a drug therapy or why it would fail to respond, how it could spread and how it might affect the patient's immune system response.

The new approach of using metal-tagged antibodies and a laser ablation system, coupled with a mass spectrometer, gives scientists the ability to track 35 different metal labels simultaneously.

As a result, it provides 35 distinct views of the cancer cell's biology, Kuhn said.

"Oftentimes, we sequence the cancer's genetic code, and that's great because the only way to build something like a building or a machine is with a blueprint. But not every blueprint ends up being built to specification or even perform as expected," Kuhn said. "For a closer perspective and for purposes of improving the precision of medical treatment, you have to move in, from genome to proteome to cell."

Zooming in - and out - on cancer

Looking at cancer is like seeing a painting at different distances. From afar, it is one of Monet's water lily paintings. But up close, nearly touching the canvas, one can see the individual points of paint in varying colors and shapes that comprise every object within the painting.

When it comes to studying circulating and disseminated cancer cells, scientists need to see those points and be able to zoom in and out to fully grasp how they behave and spread. They especially want to capture this picture just as they are determining the course of treatment, which the metal-tracing technique enables them to do within a liquid biopsy.

Metal detectors for cancer

Researchers at the University of Zurich established the potential for using metals to characterize cancer in 2013.

"Bernd Bodenmiller did some elegant work on how to use metals attached to an antibody. We expanded on that by using his approach with the liquid biopsy that we had previously developed. We simply add the antibody cocktail, wait a while for binding and then wash off the excess and see what sticks - like tie dye," Kuhn explained. "Then, you use a laser to atomize the sample and a mass spectrometer to look for each of the metals."

Because of proof-of-concept studies like this, the technique is now an official product of Fluidigm and is available for researchers worldwide.

"This is really just the beginning," Kuhn said. "You'll see hundreds of studies now using this technique."

James Hicks, a research professor of biological sciences at Michelson Center and USC Dornsife, was also a study co-author.

USC Michelson Center

Hicks and Kuhn, whose work was highlighted as part of former Vice President Joe Biden's Cancer Moonshot initiative, are among an estimated 20 scientists and engineers at the Michelson Center from the USC Dornsife College of Letters, Arts and Sciences, the USC Viterbi School of Engineering and the Keck School of Medicine of USC. By collaborating across multiple disciplines, they are working to solve some of the greatest intractable problems of the 21st century in biomedical science, including cancer.

Working side by side, Michelson's researchers aim to hasten the development of new drug therapies, high-tech diagnostics and biomedical devices from the bench to the bedside.

A study at Children's Hospital Los Angeles is shedding new light on the best therapeutic approach for a rare and aggressive leukemia called mixed phenotype acute leukemia (MPAL).

The study--a quantitative synthesis of 20 years of scientific literature--found that starting MPAL treatment with a less-toxic regimen is associated with clear benefits for achieving remission and possibly for long-term survival. The findings were published online in the journal Leukemia on February 27, 2018.

MPAL accounts for 2 to 5 percent of leukemia cases and has been historically difficult to treat, with five-year survival rates of less than 50 percent. The disease affects both children and adults and contains characteristics of two more-common forms of leukemia: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).

Physicians must decide whether to treat patients with therapy for ALL or therapy for AML, or a hybrid of both approaches. The problem: There's no clear consensus on which approach is best.

"Because this disease is so rare, we haven't had clinical trials with thousands of patients to define the optimal therapy," says Etan Orgel, MD, MS, a specialist in MPAL and a physician in the Center for Cancer and Blood Diseases at Children's Hospital Los Angeles. "Instead, we have many small, isolated and often-conflicting case reports published in widely diffuse journals around the world. It's disjointed."

To make better sense of the available research and provide clearer treatment guidance for physicians, Orgel and a team of CHLA researchers embarked on the first-ever systematic review and meta-analysis of observational studies on MPAL. The team searched more than 17,000 published studies, eventually narrowing that list to 252 relevant papers from 33 countries covering 1,499 patients. Their review included studies using both the European Group and World Health Organization definitions of MPAL.

Their key finding: Patients initially treated with ALL therapy--a significantly less-toxic regimen--were three to five times more likely to achieve a complete remission than AML-treated patients.

Patients starting with ALL chemotherapy were also twice as likely to survive--but that benefit was only found in studies reporting patient results as a group. In studies reporting individual patient results, survival was similar in both the ALL and AML groups--a puzzling discrepancy researchers could not explain. Patients given hybrid therapy, though, fared the worst.

"This makes a really convincing case that starting with ALL therapy is beneficial on all fronts, from remission to overall survival--if not from increasing survival, then from decreasing side effects," says Maria Maruffi, MD, the first author on the study.

Researchers say the next step is a national clinical trial for this rare disease.

"This research provides key insights to help guide physicians treating patients walking in the door today," says Orgel, associate professor of Clinical Pediatrics at the Keck School of Medicine of the University of Southern California. "But it also highlights the critical need for a clinical trial to definitively determine the best therapy for MPAL and help move treatment for this rare disease forward."

New research from The Australian National University (ANU) has drilled down to the molecular level to find similarities across six pharmaceutical drugs used in pain relief, dentist anaesthetic, and treatment of epilepsy, in a bid to find a way to reduce unwanted side-effects.

One in five Australians experience chronic pain, and 250,000 Australians live with epilepsy, 40 per cent of which are children.

Until now, researchers have known that drugs which treat pain and epilepsy are effective, some of which have even been used clinically since the 1950s. But molecular details of how they work and why they cause side effects have not been studied until relatively recently, thanks to new technology.

Dr Amanda Buyan from the ANU Research School of Biology said thanks to the National Computational Infrastructure (NCI) super computing power at ANU, researchers are now able to run bigger and more complex simulations to get a better picture of what is going on.

"Understanding the molecular detail of how they work gives us clues to why these drugs might be effecting one part of the body that we want, but may also effect part of the body that we don't want to effect," she said.

"Understanding this can hopefully inform future scientists working on drug discovery that this is how we think these types of drugs work."

Dr Buyan hopes the research will better inform scientists about the possibility of changing the structure of existing drugs, or in designing a new drug to make sure that it does what is intended without the side effects.

"I hope that it leads to drugs being changed slightly to be more specific or lead to a different avenue that might be more fruitful."