Body

A new study shows a drug developed in conjunction with investigators at Indiana University School of Medicine to alleviate symptoms of a rare musculoskeletal condition is significantly more effective than conventional therapies. The findings are published in Lancet.

X-linked hypophosphatemia, or XLH, is a phosphate-wasting disease that causes rickets and osteomalacia, or softening of the bones, and can cause short stature, bowed legs, dental abscesses and bone pain. This rare, genetic disease affects about 1 in every 20,000 people.

Researchers recruited 61 children between the ages of 1 and 12 at 16 centers around the world, including the U.S., Canada, the United Kingdom, Sweden, Australia, Japan and Korea. The children were randomly assigned to either receive Burosumab, a biweekly injection that was approved by the Food and Drug Administration in April 2018, or conventional therapies of taking oral phosphate and active vitamin D several times a day. The primary outcome was improvement in rickets on X-rays, as scored by radiologists that were unaware of which treatment group the participant was in.

The children were observed for 64 weeks, and by 40 weeks of treatment, researchers found 72 percent of the children who received Burosumab achieved substantial healing of rickets, while only 6 percent of those in the conventional therapy group saw substantial healing. Burosumab also led to greater improvements in leg deformities, growth, distance walked in a 6-minute test and serum phosphorus and active vitamin D levels.

"This is the first study comparing Burosumab head-to-head with conventional therapy," said lead investigator Erik Imel, MD, associate professor of medicine at IU School of Medicine. "We now know the magnitude of benefit from Burosumab over the prior approach with conventional therapy. This information is critical for doctors to make treatment decisions for patients with XLH."

Researchers plan to continue studying the long-term effects of Burosumab, including the effect treating children has on height outcomes as an adult and whether this treatment will decrease the need for surgeries to correct bowed legs.

Burosumab blocks a protein called fibroblast growth factor 23 that was originally discovered by investigators at Indiana University School of Medicine. Burosumab is marketed by Ultragenyx Pharmaceutical, Inc. in collaboration with Kyowa Hakko Kirin Co., Ltd. and its European subsidiary, Kyowa Kirin International PLC, under the brand name Crysvita.

Scientists from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and the Mannheim University Medical Center have now discovered that a certain group of cancer drugs (MEK Inhibitors) activates the cancer-promoting Wnt signalling pathway in colorectal cancer cells. This can lead to the accumulation of tumor cells with stem cell characteristics that are resistant to many therapies and can lead to relapses. The researchers thus provide a possible explanation for why these drugs are not effective in colorectal cancer.

Cells react to external influences via the biochemical reactions of the Wnt signalling pathway. Wnt signals coordinate the development of the early embryo, but also play a role in many pathological processes and in cancer. While researchers initially assumed that an excessively activated Wnt signalling pathway was primarily associated with the development of cancer, more recent results have shown that Wnt activity also affects cancer stem cells: "Wnt signals affect the balance between cells with stem cell characteristics and differentiated cells both in the healthy intestine and in colon cancer," explains Michael Boutros from the German Cancer Research Center (DKFZ) and the Mannheim Medical Faculty of the University of Heidelberg.

In colorectal cancer stem cells, the Wnt signalling pathway is particularly active and responsible for maintaining stem cell characteristics. Depending on the Wnt activity, the cancer cells can switch back and forth between the stem cell state and a differentiated state. This plays a decisive role in the success of treatment: Cancer stem cells are considered responsible for relapses after successful therapy. While the "normal" cancer cells are usually switched off by the drugs, the stem cells survive and represent a reservoir for later cancer relapses.

Due to the high relevance of Wnt activity for the course of the disease, the teams of Michael Boutros and Matthias Ebert from the Mannheim University Medical Centre were now investigating whether certain drugs used for the targeted treatment of colon cancer affect Wnt signals.

Many tumors are stimulated by mutations in the growth-promoting Ras signalling pathway. These overactive Ras signals can be attenuated by drugs called MEK inhibitors. However, these drugs have no effect in colorectal cancer, and the studies of the Heidelberg and Mannheim researchers now provide a possible explanation for this: The scientists showed that MEK inhibitors stimulate Wnt activity in both mice and organoids cultured from tumor cells of colorectal cancer patients.

At the same time, the gene activity of the cancer cells changed to a stem cell-typical pattern. MEK inhibitors reduce the division rate of intestinal tumors, but at the same time cancer stem cells accumulate in the intestinal cancer organoids. "This corresponds exactly to the picture of the "sleeping cancer stem cells" that have been described in many types of cancer for several years," explains Tianzuo Zhan, clinician scientist at both the DKFZ and the Mannheim University Medical Center "These cells survive the therapy and are subsequently responsible for the relapse.

Boutros and his colleagues are now hoping to find out whether the influence of MEK inhibitors on Wnt activity can be blocked with specific drugs.

The incidence of colon and rectal cancer in adults younger than 50 years has increased substantially over the latest available 10-year period in several high-income countries, going against a decline or stabilisation trend in the incidence of colorectal cancers within the overall populations of high-income countries.

This is according to an observational study published in The Lancet Gastroenterology & Hepatology journal, which looked at long-term data for colon and rectal cancer incidence in 21 population-based registries across Australia (1983-2012), Canada (1995-2014), Denmark (1978-2012), Ireland (1995-2013), New Zealand (1995-2014), Norway (1953-2014), and the UK (1995-2014).

During the most recent 10-year period up until 2014, the incidence of colon cancer in people aged 0-49 years increased significantly each year in Denmark (by 3.1%), New Zealand (2.9%), Australia (2.9%), and the UK (1.8%). Significant increases in the incidence of rectal cancer each year were also noted in this age group in Canada (by 3.4%), Australia (2.6%), and the UK (1.4%). Increases in the incidence among adults under 50 were most pronounced for rectal cancer, particularly in the 20-29 age group, where rectal cancer incidence increased annually by 18.1% in Denmark and 10.6% in Norway over the past decade.

Across the same time period, significant decreases in incidence of colon cancer per annum were observed in those aged over 50 in Australia (by 1.6%), Canada (1.9%), and New Zealand (3.4%) and of rectal cancer in Australia (2.4%), Canada (1.2%), and the UK (1.2%).

Colorectal cancer is the third most common cancer worldwide, with an estimated 1·8 million new cases diagnosed and 881 000 deaths associated with the disease in 2018.

This study is the first of its kind to comprehensively address and compare age-specific trends in the incidence of colorectal cancer, with its findings identifying divergent trends for different age groups.

"Although the incidence of colorectal cancer in adults younger than 50 years remains much lower compared with that in older age groups, our findings are of concern and highlight the need for action to counteract the rising burden of the disease in younger people. This rise in incidence among younger generations is likely to be driven in part by the changing prevalence of risk factors, such as obesity and poor diet. National programmes to promote healthy diets and physical activity might be the most efficient approach to ensure population-level changes," says the lead author of the study, Dr Marzieh Araghi from International Agency for Research on Cancer, Lyon. [1]

The authors of the study suggest that the decrease in incidence of colorectal cancer in people over 50 years old in most of the countries studied could be attributed to the introduction of routine screening programmes for premalignant polyps. In Australia, Canada, and the UK, where age-based screening began in 2006, overall decreases in incidence were more pronounced. In those countries where screening programmes began later, such as in Ireland (2012), Denmark (2014), Norway (2012, pilot programme only), and New Zealand (2017), overall rates have remained roughly stable.

Dr Araghi adds, "While population-based screening in people under 50 years old is not considered to be cost-effective due to relatively low incidence numbers, family history could help to identify younger people at high-risk of genetic susceptibility to colorectal cancer, for further assessment. However, future studies are needed to establish the root causes of this rising incidence to enable the development of effective preventive and early-detection strategies."

In terms of limitations, the researchers did not have access to individual-level data on risk factors and screening, so could not examine how changes to these factors interacted with trends in colorectal cancer over time. Furthermore, as noted in the linked commentary, there were only seven high-income countries included in this study; adding data from more countries could strengthen the conclusions on the changing epidemiology of colorectal cancer.

Writing in a linked commentary, Professor Giulia Martina Cavestro from Vita-Salute San Raffaele University, Milan says, "Araghi and colleagues address the debate about lowering the age of screening. In 2018, the American Cancer Society recommended that screening for colorectal cancer should start at age 45 years for all adults. Such an approach is needed, but other initiatives should be endorsed alongside this decision. Furthermore, public awareness campaigns are essential to increase adherence to screening, and more gastroenterology units are likely to be needed. The lower age for screening should not be one-size-fits-all--personal and family history should be taken into account. Among the many risk factors, the importance of taking an accurate family history during a risk assessment cannot be overstated."

A team led by Johns Hopkins Medicine researchers says it has identified two protein biomarkers in urine that may one day be used to better diagnose acute interstitial nephritis (AIN), an underdiagnosed but treatable kidney disorder that impairs renal function in the short term and can lead to chronic kidney disease, permanent damage or renal failure if left unchecked.

The finding is reported in the May 16, 2019, issue of the Journal of Clinical Investigation Insight.

Acute interstitial nephritis is a condition marked by inflammation and swelling of the renal tubules, the tiny portals in the kidneys where blood is filtered. As a result, the tubules cannot properly reabsorb water and useful organic substances, such as glucose and amino acids, or secrete waste products such as urea and creatinine into urine. AIN is commonly the result of autoimmune diseases or allergic reactions to more than 100 medications, including antibiotics, pain relievers and antacids. The disease is estimated to cause 15 to 20% of all hospitalizations for acute kidney injury.

Currently, the only method of diagnosing AIN is by examining renal tissue obtained with a biopsy, putting patients at some risk from complications. Additionally, samples can sometimes be misinterpreted or yield inconclusive results.

"What has been needed is a biological diagnostic tool that is safe, easy to get and measure, simple to interpret, consistent across patient populations and most importantly, extremely accurate at identifying AIN." says Chirag Parikh, Ph.D., director of the Division of Nephrology at Johns Hopkins University School of Medicine and senior author of the new paper.

To find such a biomarker, Parikh and his colleagues looked for a substance linked to AIN's most distinct characteristic, inflammation of the renal tubules, formally known as tubulitis.

Knowing that cytokines -- proteins secreted by immune cells known as CD4+ T lymphocytes -- are the agents causing inflammation of the tubules, the researchers measured the amounts of 12 urine and 10 blood plasma proteins in samples from 79 adult, biopsy-confirmed AIN patients, and compared them to the amounts in 186 adult kidney biopsy patients without an AIN diagnosis.

The results, reviewed independently by three pathologists, showed that none of the plasma biomarkers were associated with AIN, but that two proteins -- tumor necrosis factor-alpha (TNF-α) and interluken-9 (IL-9) -- were consistently seen in the urine of AIN patients. Neither cytokine was present in the control samples, either in plasma or urine.

"Because both cytokines are seen in allergic diseases such as atopic dermatitis and food allergies, and AIN most often is the result of an allergic response, it makes sense to consider using them as diagnostic tools," Parikh says.

"Additionally, we knew that IL-9 leads to the accumulation of mast cells that release histamine and other chemicals that induce allergic responses, and kidney biopsies from AIN patients frequently reveal the presence of mast cells," he adds. "This suggests that IL-9 may be the stronger link to AIN, and perhaps, the better candidate as a future predictive biomarker."

To test the sensitivity of using IL-9 in this manner, the researchers compared its AIN-detecting ability in patients whose disease was confirmed by pathologists who evaluated biopsied material or was symptomatically diagnosed by clinicians prior to the biopsies.

"If biopsy diagnoses are considered 100% accurate, then IL-9 had a very comparable ranking of 84%, and this was significantly better than the 62 to 69% achieved by clinicians without biopsies," Parikh says.

The next step for the research team, Parikh says, will be to verify the findings of this study in a larger group of patients and get support for the development of TNF-α and IL-9 as tools to complement AIN diagnosis by biopsy. He says the hope is that later, biomarkers can replace kidney biopsies altogether.

"Biopsy is currently the 'gold standard' for AIN diagnosis, but we believe that biomarkers will one day be a more robust, more accurate, more cost effective and more patient-friendly method," Parikh says.

Stigma is the main reason why elite athletes with mental health issues don't seek the help they need, finds a summary of the available evidence, published in a special issue of the British Journal of Sports Medicine devoted to the topic.

But a poor understanding of mental illness, busy schedules, and gender stereotyping also play their part, the findings suggest.

Coaches and sports governing bodies have a crucial role in helping to de-stigmatise mental ill health and promote a culture of mental wellbeing, say the researchers.

Mental illness affects up one in three elite athletes every year. The elite sports culture, with its heavy training demands and constant drive to improve performance, only serve to heighten the risk, the evidence suggests.

In a bid to quantify the barriers to accessing treatment and the cultural factors influencing mental health, the researchers trawled research databases, looking for relevant studies involving elite athletes--defined as those competing at professional, Olympic, or collegiate/university levels--and published up to November 2018.

Several key themes emerged from among the 52 studies included in their review, which covered more than 13,000 elite athletes from 71 sports.

Stigma was the most commonly reported factor preventing elite athletes with mental health issues from seeking help, in the belief that mental ill health is a sign of weakness rather than the hallmark of a 'winner' and would be seen as such by peers, managers, and the public.

"Athletes fear, possibly rightly so, that disclosing mental health symptoms or disorders would reduce their chances of maintaining or signing a professional team contract or an advertising campaign," note the researchers.

Other key factors included low levels of mental health literacy--knowledge and beliefs about mental health disorders that aid their recognition, management and prevention; previous negative experiences of seeking help; and busy schedules.

Further barriers identified in the studies included gender stereotyping, particularly what it means to be a man; younger age; US as opposed to European nationality; and certain personality traits such as conscientiousness and lack of openness.

The factors influencing mental health included difficulties accepting women as athletes in some cultures because of societal expectations of the female role; black and minority ethnicity; financial considerations; and keeping quiet about religious beliefs.

The review studies varied widely in content and design, added to which many elite athletes come from countries where there are few, if any, mental health services, caution the researchers.

But they nevertheless suggest, that, on the basis of their findings, greater efforts are needed to overcome stigma and boost mental health literacy among elite athletes.

"Coaches could be important agents for supporting positive mental health attitudes within the elite athlete environment, including fostering an environment of mental health treatment-seeking," they conclude.

Their study is one of 20 systematic reviews informing the first ever consensus on the diagnosis and treatment of mental ill health in elite athletes--also published in the special issue of the journal--by the International Olympic Committee (IOC).

The consensus, which also emphasises the role coaches and sporting bodies can have in de-stigmatising mental health, was drawn up by a panel of 23 experts from 13 nations.

It includes psychiatrists, psychologists, exercise scientists, neurologists, and sports medicine doctors, among other professionals.

The consensus aims to provide a standardised, evidence-based approach to the particular mental health issues found among elite athletes. These range from sleep disorders, depression and anxiety, through the impact of injuries and concussion, to eating disorders, substance misuse, gambling and other addictions.

The consensus makes a raft of recommendations on how best to minimise the negative impact of competitive sport on each of these disorders.

It also looks at major stressors, such as harassment and abuse, the barriers to seeking help, the end of an elite sports career; and future directions for research and clinical practice.

"The IOC hopes that all involved in sport will increasingly recognise that mental health symptoms and disorders should be viewed in a similar light as other medical or surgical illnesses or injuries; all can be severe and disabling, and nearly all can be managed properly by well informed medical providers, coaches and other stakeholders," says the consensus.

A linked editorial, which explains the impetus for the development of the consensus statement, expresses the hope that it will help to break a taboo, and act as a catalyst for organisations, coaches and sport governing bodies to create an environment that is conducive to mental wellbeing.

"Sport should be a public good. The healthy athlete provides a symbol of an ideal society--a society where personal wellbeing is promoted and those who seek treatment for mental health concerns are not stigmatised," it concludes.

Less chemotherapy is as effective at controlling disease for elderly or frail patients with advanced cancer of the stomach or oesophagus (food pipe), and leads to fewer side effects such as diarrhoea and lethargy. These are the results of a Cancer Research UK funded study, presented prior to the ASCO conference today (Wednesday).

Results from the GO2 trial could change the standard of care for patients who can't have full dose chemotherapy due to their age, frailty or medical fitness.

The study, which ran at hospitals all over the UK, coordinated from the University of Leeds, involved 514 people with stomach or oesophageal cancer. Their average age was 76 and the oldest was 96 years old. All were either frail, elderly or medically unfit, and for those reasons would be unlikely to tolerate full-strength treatment, which involves three chemotherapy drugs.

Patients went through a careful medical assessment, then went onto chemotherapy with just two drugs* and were allocated at random to receive them at either full-strength, medium-dose or low-dose. They were then carefully monitored to see how well the cancer was controlled, whether they had symptoms and side-effects, whether they felt their treatment was worthwhile, and what overall effect it had on their quality of life.

The researchers reported that the medium and lower doses of chemotherapy were as effective as the full-strength dose for controlling the cancer. But when the researchers looked at the overall effect of treatment, including quality of life, they reported that it was the lowest dose treatment that came out best.**

Around 15,800 people in the UK are diagnosed with stomach and oesophageal cancers every year***. Almost half (45%) of these people are 75 and over****. By 2035, this proportion is projected to rise to 55%*****, because of the UK's ageing population. This study, is one of few phase III trials in the country that seek to address how to best care for and treat this increasing population of elderly or frail cancer patients.

These findings also open up the possibility of more older and frail patients being able to take part in clinical trials.

Professor Charles Swanton, Cancer Research UK's chief clinician, said: "These valuable results reduce fears that giving a lower dose chemotherapy regimen is inferior and could make a huge difference for patients with stomach or oesophageal cancer who can't tolerate intensive courses of treatment.

"Older or frail patients are often not considered for new drug trials or standard of care therapy as they're less able to tolerate combination chemotherapy. These trials are critical to provide much needed evidence on the effectiveness of new therapies and combination approaches, helping us develop new treatments for this growing group of patients."

The researchers also assessed whether there were differences for the patients in the study who were under 75, or less frail, who might be expected to benefit from stronger treatment; but will be reporting that the lowest dose treatment gave the best results for them as well.

Professor Matt Seymour, co-chief investigator at the University of Leeds and Leeds Teaching Hospitals NHS Trust said: "When we're treating people who are elderly or frail, we are especially conscious that treatment can have harmful as well as beneficial effects. Doctors often prescribe reduced doses of drugs, or sometimes no chemotherapy at all, based on their clinical experience, but until now there has been little hard evidence to help them in those decisions. Our results provide that evidence, so doctors can confidently give people a lower dose of chemotherapy, sparing them side effects without worrying that it's compromising their chance of survival.

"We hope this approach can be applied in other disease types so that more work can be done to improve both survival and quality of life for elderly and frail patients."

Liz Chipchase, from Cambridge, was diagnosed with oesophageal cancer in 2017 at 69 years old. She had two non-invasive surgeries under sedation to remove the cancerous cells and didn't require any additional treatment.

She said: "When I was diagnosed with oesophageal cancer, I was lucky that it was caught early enough that I didn't need chemotherapy. I was offered the choice between two different surgeries, giving me the opportunity to select the treatment I thought was best for me.

"Trials like this are important to empower people with choices that give them control over how they're treated - something I was fortunate to have. Any research that can help improve the quality of life for other patients is essential, so it's great to see results like these doing exactly that."

Dr Peter Hall, co-chief investigator from the Cancer Research UK Edinburgh Centre, said: "Increasingly we're realising it's not just age that affects how well someone can tolerate their treatment and we need to do more work to understand how other conditions or aspects of frailty might play a role.

"We should now look beyond chemotherapies, at some of the newer targeted therapies or immunotherapies to understand how we can tailor different treatments to patients based on their individual circumstance."

Current efforts to tackle antibiotic resistance are "not nearly radical enough", a leading scientist says.

Dr Ben Raymond, of the University of Exeter, says relying too heavily on reducing antibiotic use and discovering new drugs could lead to "disaster".

In a new study, he proposes five rules for "sustainable use". These include acting to protect new drugs before resistance becomes a problem, using more diverse antimicrobials to reduce long-term use of single drugs, and using data to design management plans for particular superbugs.

The World Health Organisation says antibiotic resistance is rising to dangerous levels worldwide, and warns of "a post-antibiotic era in which common infections and minor injuries can once again kill".

Dr Raymond, of the Centre for Ecology and Conversation on the University of Exeter's Penryn Campus in Cornwall, said: "People think the best way to tackle antibiotic resistance is to give out fewer antibiotics and find new drugs.

"Those are important steps, but this approach alone is not nearly radical enough.
x

"Even if we can keep finding new drugs, disaster will follow if we use them in the same way as we use current ones.

"No drug yet discovered is evolution proof, and the typical practice of using single drugs at once, in unprotected 'monotherapies' is unsustainable.

"This 'business as usual' approach can be disastrous, as exemplified by the history of resistance in gonorrhoea and the emergence of untreatable infections.

"Resistance to new antibiotics can become widespread in two or three years, so new drugs must be partnered with more sustainable patterns of use."

The study's five rules are:

1. Prevention. "Resistance is easier to deal with before it becomes severe," Dr Raymond said. "Antibiotics can be protected by the way you use them, for example by avoiding heavy use of single drugs for extended periods of time, as using drugs in this manner creates more 'selection pressure' - the conditions microbes need to evolve resistance."

2. Don't rely on "fitness costs". Some plans depend on stopping use of a drug, in the hope that resistant bacteria suffer a "fitness cost" - dying out because they carry resistance genes that are no longer useful. This can work, but Dr Raymond warns that resistance to a drug does not necessarily go away just because use of that drug stops.

3. Limit supply of mutations. One way to do this is to use combinations of antibiotics, as microbes rarely develop resistance to multiple antibiotics at once. Dr Raymond also says it's "madness" from a resistance management perspective to build up a massive supply of resistance genes in the environment. Resistance in the environment can come from waste water and use of antibiotics in animals. "As an individual you are very unlikely to have acquired an antibiotic resistance microbe from an animal, but it's highly likely that environmental contamination has helped some of the microbes in your body acquire resistance," he said.

4. Low doses don't work, short courses might. A much greater pool of mutations can give microbes resistance to low doses of antibiotics, so such doses might help resistance evolve. Short, intensive courses of antibiotics might help patients without giving microbes the opportunity to evolve.

5. Information is power. "If you don't know what kind of resistance is around among patients or in your hospital, you could give people the wrong drug at the wrong time," said Dr Raymond. "The more data you have, the better you can design your resistance management programmes. Resistance management programmes should target specific microbes or groups of microbes, rather than resistance in general."

Dr Raymond warns that broader lessons of resistance management from other disciplines are "not widely appreciated" among microbiologists; while evolutionary biologists and clinicians need to talk to each other much more often.

The study, partly funded by the Medical Research Council, calls for a "new philosophy in which usage is tied to a long-term commitment to sustainability".

Dr Raymond added: "Some humility in the face of natural selection can ensure that human creativity keeps pace with evolutionary innovation."

Radiation therapy against cancer can increase the risk of cardiovascular disease much later in life, as the radiation causes chronic inflammation of the exposed blood vessels. In a new study published in the European Heart Journal, researchers from Karolinska Institutet in Sweden have shown that these inflammations can be treated with IL-1 inhibitors.

Damage to healthy tissue is one of the most important limiting factors when treating cancer with radiotherapy. Previous studies have shown that radiation changes the gene expression of blood vessels exposed to radiation, and leads to long-lasting inflammation. Now, researchers at Karolinska Institutet have shown that inhibitors of signalling substance Interlukin-1 (IL-1) can reduce the inflammation.

"We studied the deep blood vessels of patients who had previously been treated with radiation therapy, and we found chronic inflammation linked to IL-1 activity," explains Martin Halle, senior physician at Karolinska University Hospital and senior researcher at the Department of Molecular Medicine and Surgery, Karolinska Institutet, who led the study. "These findings were implemented into an animal model, where treatment with IL-1 inhibitors could reduce inflammation. The mice who had been treated with radiation therapy followed by two weeks of treatment with the IL-1 inhibitor anakinra displayed a reduced inflammation in the affected blood vessels."

However, the experimental studies are complicated as clinical symptoms do not present in patients until several years after the radiation therapy. In order to look at long term alterations, the researchers used the Biobank of Radiated Tissues at Karolinska (BiRKa) which contains both irradiated and non-irradiated blood vessels harvested from the same patient at the same occasion during reconstructive microsurgery following cancer.

Using microarray technology, a gene expression analysis of the samples from the biobank was conducted, suggesting potential treatment using IL-1 inhibitors. The trials were then conducted in mice with atherosclerosis whose heart and carotid arteries had been treated with localised radiation therapy.

The problem of vascular damage caused by radiation is increasing as more people continue to survive cancer. In addition to the increased risk of cardiovascular disease, there is also a greater risk of surgical complications. Blood vessels that have been exposed to radiation are more prone to vascular complications than normal. This complicates reconstruction with free tissue transfer of healthy tissue to the part of the body affected by cancer.

"Not all patients treated with radiation suffer, but our results lead us towards possible therapy for the group affected by radiation-induced vasculitis," says Martin Halle. "The study can also increase understanding of other vessel-related tissue damage in this growing group of cancer survivors."

Inequalities in life expectancy by income in Norway were substantial, and increased between 2005 and 2015, according to a study from the Norwegian Institute of Public Health in collaboration with the Institute For Health Metrics And Evaluation (IHME). Although considerable differences in life expectancy by income levels were found in both Norway and the USA, the shape of the association differed.

The differences in life expectancy between the one per cent richest and one per cent poorest in Norway were 14 years for men and 8 years for women.

"It has surprised researchers and policy makers that even with a largely tax-funded public health care system and relatively evenly distributed income, there are substantial differences in life expectancy by income in Norway" says Dr Jonas Minet Kinge, senior researcher at the Norwegian Institute of Public Health. He is also Associate Professor in Health Economics at the University of Oslo.

"We also observe important differences between the USA and Norway. Life expectancy was higher in Norway than in the USA across most of the income distribution, except for the very highest and very lowest income percentiles, in which life expectancies were similar in the two countries. The largest differences in life expectancy between the countries were seen for the lower to middle income men and women," he explains. Here, low and medium income refers to those who earn less than the median income but more than the five per cent lowest.

The purpose of the study was to describe income-based differences in life expectancy and causes of death in Norway during the period from 2005 to 2015, compared with corresponding calculations from the USA.

This is the first time that life expectancy is estimated by income percentiles in Norway and then analysed for cause of death. Furthermore, this is the first time that the association between income and life expectancy in Norway is compared directly with corresponding estimates for the USA, which was a very demanding analysis process.

Results

When comparing the 1 per cent richest with the 1 per cent poorest in Norway:

Life expectancy in Norway was high among the richest one per cent of women. In this group, the average age was 86.4 years. These women lived on average 8.4 years longer than the one per cent of women with the lowest income.

The poorest one per cent of men had the lowest life expectancy. In this group, the average age was 70.6 years, which was 13.8 years lower than among the one per cent of men with the highest income.

When comparing the 25 per cent richest with the 25 per cent poorest, the differences in life expectancy are 8 years for men and 6 years for women. Higher mortality rates from cardiovascular disease, chronic obstructive pulmonary disease (COPD), lung cancer and other cancers explain the higher mortality overall among the low-income groups. Cancer deaths are more significant for men than women.

Deaths due to substance abuse and suicide were highest for the low-income groups under the age of 60, particularly among men in the 40-49 age group.

Life expectancy gap has increased

In the period 2005-2015, the life expectancy gap between the richest 25 per cent and the poorest 25 per cent increased (see figure 2):

The richest 25 per cent women increased life expectancy by 3.2 years while the poorest 25 per cent reduced life expectancy by 0.4 years.

The richest 25 per cent men increased life expectancy by 3.1 years and the poorest 25 per cent by 0.9 years.

Chronic diseases explain much of the life expectancy gap
Deaths from cardiovascular disease and cancer contributed most to the difference in life expectancy. Cardiovascular disease has decreased in all income groups but there is still some way to go before mortality in the low-income groups is on par with the high-income groups.

In the high-income groups there has been a decrease in cancer deaths but not among the low-income groups.

Smoking explains parts of the life expectancy gap and why low-income women did not increase their life expectancy in the period from 2005 to 2015. About 20 per cent of the income-based differences in life expectancy could be explained by smoking in this study.

"This is a descriptive study. We know little about why the differences are so great and why they are increasing. Studies from Sweden and other countries suggests that other factors besides money in itself explain why those with lower income have lower life expectancy. For example, those who have a low income live more often alone and often have a lower education. Furthermore, foetal life, upbringing and other environmental conditions can be important," says Kinge.

"We need more research on the causes of the gradient. Fortunately, the research environment in Norway has the competence to link the health registries on an individual level with income, education and household information. Via such data merging we can perform more advanced analyses than most other countries, as this study also demonstrates," he concludes.

The study shows that:

Among the poorest one per cent of men and women, 50 per cent lived alone without children. Among the richest, the corresponding figure was about ten per cent.

Among the poorest one per cent, 20 per cent had university and college education compared to just over 50 per cent among the richest one per cent.

Norway versus USA

The researchers compared the Norwegian results with a similar study from the USA during the same period.

The comparisons show:

Life expectancy was higher in Norway than in the USA across most of the income distribution, except for the very highest and very lowest income percentiles.

The difference in life expectancy between the one per cent richest and poorest men in the USA is roughly the same as in Norway, while the difference is somewhat smaller for Norwegian women compared to American women.

Poor Americans have had a significantly lower increase in life expectancy than rich Americans from 2000-2014(1). We observe the same tendency in Norway.

"The comparison is of interest to researchers because Norwegian health and education systems are largely funded by government spending, whereas in the USA the share of private funding has traditionally been higher. Furthermore, Norway has relatively low income inequalities compared with the USA," says Kinge.

About the study

The study included 3 041 828 people aged at least 40 years and 441 768 deaths in Norway between 2005 and 2015.

The mean number of household members per person were 2.5.

The main outcomes were life expectancy at 40 years of age and cause-specific mortality.

Household income was defined as the sum of all household members' individual income, adjusted for household size. Income included wages, self-employment, capital income, taxable and tax-free transfers during the calendar year, after deduction of tax and negative transfers.

People without an income or with income from unregistered sources were not included in the study.

Giving a single dose of preventative antibiotics to all women after childbirth involving forceps or vacuum extraction could prevent almost half of maternal infections including sepsis--equivalent to over 7,000 maternal infections every year in the UK, and around 5,000 in the USA [1].

The first randomised trial of its kind in the UK involving 3,420 women from 27 obstetric units, published in The Lancet, also found that for every additional 100 doses of antibiotic given prophylactically, 168 doses could be avoided due to fewer postdelivery infections--meaning that a policy of universal prophylaxis after birth could help to reduce antibiotic use by 17%.

Infection rates after assisted vaginal birth without antibiotic prophylaxis are around 16% worldwide, and up to 25% after caesarean section. In 2016, an estimated 19,500 women died because of pregnancy-related infections globally. Even in high-income settings, infections account for 1 in 20 maternal deaths, and as many as 1 in 8 in the USA. For every woman who dies from pregnancy-related infection, another 70 women develop a severe infection and survive often with long-term health consequences.

"These findings highlight the urgent need to change current WHO antibiotic guidelines and other guidance from organisations in the UK, North America, and Australasia, that do not recommend routine antibiotic prophylaxis for assisted childbirth," says Professor Marian Knight from the University of Oxford, UK, who led the research. [2]

"Pregnancy-associated infection is a major cause of death and serious illness. Almost 1 in 5 women develop an infection after assisted vaginal delivery and our results show that this could be reduced by almost half by a single dose of prophylactic antibiotic." [2]

A recent Cochrane review of 95 trials showed that giving antibiotics before caesarean section reduced wound infection, endometritis, and serious maternal infection by 60-70%, and the use of antibiotics during caesarean section is widely recommended. In contrast, evidence on the use of prophylactic antibiotics in assisted vaginal birth is limited to a small trial of 393 women.

To provide more evidence, the new study investigated whether a single dose of antibiotics prevented maternal infection in the 6 weeks after assisted vaginal birth in 3,420 women (aged 16 years and older) giving birth in 27 hospital obstetric units across the UK.

Between March 2016 and June 2018, women were randomly assigned to receive intravenous amoxicillin and clavulanic acid (1,715 women) or placebo (saline; 1,705) within 6 hours of operative vaginal delivery. The researchers also assessed the effect of using prophylaxis on overall antibiotic use. Suspected or confirmed maternal infection within 6 weeks of giving birth was identified by a new prescription for antibiotics, confirmed systemic infection on culture, or endometritis.

Overall, around two-thirds of babies were delivered by forceps and about a third by vacuum extraction. Data were missing for 195 (6%) of women who were not included in primary outcome analyses.

Results suggested that women who received a single dose of antibiotics had significantly fewer suspected or confirmed infections than women given placebo (180/1,619; 11% vs 306/1,606; 19%).

Importantly, women receiving antibiotic prophylaxis were also much less likely to have confirmed culture-proven sepsis compared to those receiving placebo (56% reduction - 11/1,619; 0.6% vs 25/1,606; 1.5%).

Rates of perineal wound infection or breakdown (burst stiches), perineal pain, use of pain relief for perineal pain, and need for additional perineal care were also substantially lower in the group who received antibiotics compared to the placebo group. Additionally, women who received antibiotics were much less likely to report any GP, nurse, or midwife home visits, or hospital outpatient visits due to their wound healing compared to the placebo group (table 3).

The researchers estimate that the total average NHS costs 6 weeks after birth were £52.60 less per women in those who received the single dose of antibiotic compared to women given placebo (£102.50 vs £155.10; appendix table S8).

One woman in the placebo group reported a skin rash and two women in the antibiotic group reported other allergic reactions, one of which was reported as a serious adverse. Two other serious adverse events were reported, neither was considered related to the treatment.

"With increasing recognition of the need to reduce unnecessary caesarean births, the incentive to minimise the harms associated with other types of assisted delivery are even greater," says Professor Knight. "This simple intervention could also be used to prevent maternal infections in low- and middle-income countries in which intravenous antibiotics are available." [2]

The authors note several limitations, including that presumed rather than culture-proven infection was the primary outcome, and that only three-quarters of women were followed up for secondary outcomes, both of which could have influenced the results. They also point out that despite being given antibiotics, 1 in 10 women still had a suspected or confirmed infection, highlighting the importance of more studies to investigate the mechanism of action and whether earlier administration, prenatal administration, or repeated administration is likely to be more effective. Finally, it is unclear whether oral prophylactic antibiotics would have the same preventative efficacy.

Commenting on the implications of the findings in a linked Comment, Dr Vincenzo Berghella from Thomas Jefferson University, USA, says the ANODE study is "practice changing" and writes: "Even if one conservatively estimates 2% of babies are born by operative vaginal delivery globally, about 2,700,000 of the world's 135 million annual births are operative vaginal deliveries. Up to 16% of these births can be associated with infection without antibiotics prophylaxis, representing about 432,000 annual infections associated with operative vaginal delivery worldwide...Clinical guidelines should be updated to reflect the new recommendation of giving a single dose of intravenous amoxicillin and clavulanic acid within 6 h after operative vaginal delivery, in particular to women who also have an episiotomy."

Las Cruces, NM -- Researchers at the Burrell College of Osteopathic Medicine (BCOM) have found that cancer patients in New Mexico have lower chances of survival when compared to the rest of the nation.

The research was presented by third-year medical student Zac Taylor at the annual meeting of the Arizona Osteopathic Medical Association (AOMA). It was awarded first place among all poster presentations.

"Our preliminary data indicates that some populations, namely Hispanics living in the border region, may have a lower five-year survival rate for some types of the cancers, and there appears to be an association with the stage of the cancer at diagnosis," says Michael Woods, PhD, BCOM assistant professor of physiology and pathology who oversaw the research. "There could be several reasons for this, including access to health care or other societal factors that we don't fully understand yet."

For the project, the team sifted through cancer statistics collected by the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program. SEER specifically collects and publishes cancer incidence and survival data, such as disease type and stage and patient treatment and outcomes. The database represents 34.6 percent of the U.S. population.

BCOM researchers analyzed the U.S. incidence and five-year survival rates for patients with 14 of the most common cancers, including breast cancer, stomach cancer and prostate cancer.

They then narrowed in on the data for the state of New Mexico. Cancer incidence and survival rates were broken down further by counties located on the U.S-Mexico border, which were defined as Hidalgo, Luna, Dona Ana, Grant, Sierra and Otero counties.

When compared to the national average, the results revealed that New Mexicans with 10 of the most common cancers--prostate, thyroid, melanoma, bladder, kidney, colorectal, stomach, lung, liver and pancreas--have a significantly worse 5-year survival rate.

Kidney and liver cancer patients may fare worst. The national five-year survival rate for kidney cancer patients is 60.4 percent, according to the SEER data. However, in New Mexico, that number drops to 56 percent. Similarly, patients with liver cancer have a 13.4 percent survival rate nationally. In New Mexico, however, liver cancer patients have a 9 percent five-year survival rate.

Those living in New Mexico along the U.S.-Mexico border have even higher cancer mortality rates, with an average five-year cancer survival rate of 55.8 percent compared to the New Mexico average of 59.3 percent.

For his presentation and research, Taylor received a $750 prize as well as a plaque from the AOMA.

"I felt that the project would be interesting to Arizona physicians since Arizona also shares a border with Mexico," Taylor says. "It was great to be recognized for the work that we have been doing here at BCOM."

The team hopes their findings can help with public health efforts in New Mexico, such as creating targeted interventions and health education campaigns to improve cancer diagnosis and ultimately, survival rates, in populations with historically poor outcomes.

Although surgically induced abortion is a low-risk procedure, women whose physician infrequently performs it have almost twice the risk of severe complications, found new research published in CMAJ (Canadian Medical Association Journal).

"A physician who performs more procedures, regularly, most likely gains proficiency, as well as the ability to recognize and troubleshoot potential problems," say Ms. Ning Liu and Dr. Joel Ray of ICES, Toronto, Ontario. "Experience and practice lower the likelihood of major complications."

Low physician procedure volume is known to be associated with an increased risk of complications after complex surgery for cardiac, cancer and pelvic conditions, but little was known about its association with a common and technically simpler procedure like surgical abortion.

The study looked at Ontario data over 13 years, on 529 141 induced surgical abortions performed before 20 weeks' gestation, and compared low-volume and high-volume physicians. Severe adverse events occurred in 194 out of 52 889 procedures (3.7 per 1000 procedures) in the low-volume group and in 656 out of 476 252 procedures (1.4 per 1000 procedures) in the higher-volume group. Adverse events included injury to the mother, organ damage, admission to an intensive care unit and, very rarely, death within 42 days of the procedure.

"As serious adverse events are uncommon, any focus on centralizing procedures must consider geographical access to surgically induced abortion and wait times, so that women who need the procedure can have it within a reasonable time frame," says Ms. Ning Liu.

In a related commentary, Drs. Wendy Norman and Laura Schummers, Department of Family Practice, University of British Columbia, Vancouver, BC, write, "An induced abortion with the nearest provider may be the safest option for a woman with an abnormal or unintended pregnancy, and may entail lower complication rates than delaying an abortion or carrying a pregnancy to birth." They note that carrying a pregnancy to birth carries 8 times higher risk than that the accompanying article found for abortion care.

Drs. Norman and Schummers further note that "Canada needs policies, such as universal free contraception and universal access to medical abortion, that will ensure that all women are equitably supported in the prevention and management of unintended pregnancy."

"Five things to know about ... melanoma" in CMAJ (Canadian Medical Association Journal) provides a brief overview of this malignant skin cancer for physicians and patients.

Sun exposure is an important factor in the development of melanoma, so it often appears on the face, neck, arms and torso, where sun exposure is common.

Melanoma can also occur on areas with minimal sun exposure, such as palms and soles of the feet.

A specific mitogen-activated pathway is linked to mutations causing melanoma and genomic sequencing is helping identify markers for diagnosis and treatment.

About 10% of melanomas are challenging to diagnose as they may be pink, red, clear or normal skin-coloured.

Patients with any suspicious skin lesions should be referred to dermatology. Coloured lesions with any of the ABCDE criteria -- Asymmetric shape, irregular Border, Colour variation, Diameter greater than 6 mm (about the size of a pencil eraser) and Evolution (change) -- should be considered suspicious.

Men who delay starting a family have a ticking "biological clock" -- just like women -- that may affect the health of their partners and children, according to Rutgers researchers.

The study, which reviewed 40 years of research on the effect of parental age on fertility, pregnancy and the health of children, was published in the journal Maturitas.

"While it is widely accepted that physiological changes that occur in women after 35 can affect conception, pregnancy and the health of the child, most men do not realize their advanced age can have a similar impact," said study author Gloria Bachmann, director of the Women's Health Institute at Rutgers Robert Wood Johnson Medical School.

While the medical profession has no clearly accepted definition of when advanced paternal age begins -- it ranges from 35 to 45 -- infants born to fathers over 45 have risen 10 percent in the United States over the past 40 years, likely due to assisted reproductive technology.

The study found that men 45 and older can experience decreased fertility and put their partners at risk for increased pregnancy complications such as gestational diabetes, preeclampsia and preterm birth. Infants born to older fathers were found to be at higher risk of premature birth, late still birth, low Apgar scores, low birth weight, higher incidence of newborn seizures and birth defects such as congenital heart disease and cleft palate. As they matured, these children were found to have an increased likelihood of childhood cancers, psychiatric and cognitive disorders, and autism.

Bachmann attributes most of these outcomes to a natural decline in testosterone that occurs with aging, as well as sperm degradation and poorer semen quality, but she said that some correlations need more research. "In addition to advancing paternal age being associated with an increased risk of male infertility, there appears to be other adverse changes that may occur to the sperm with aging. For example, just as people lose muscle strength, flexibility and endurance with age, in men, sperm also tend to lose 'fitness' over the life cycle," she said.

Damage to sperm from stresses of aging can lead to a decrease in sperm number and a change in the sperm and egg that is passed from parent to offspring and becomes incorporated into the DNA of cells in the offspring's body. "In addition to decreasing fertilization potential, this can also influence the pregnancy itself, as is noted by increased pregnancy risks when conception is successful," she said.

These germline or heredity mutations also may contribute to the association of advancing paternal age and disorders in the offspring, such as these children being diagnosed with autism and schizophrenia. "Although it is well documented that children of older fathers are more likely to be diagnosed with schizophrenia -- one in 141 infants with fathers under 25 versus one in 47 with fathers over 50 -- the reason is not well understood," she said. "Also, some studies have shown that the risk of autism starts to increase when the father is 30, plateaus after 40 and then increases again at 50."

The study also found that older men struggled with fertility issues even if their partner was under 25.

"While women tend to be more aware and educated than men about their reproductive health, most men do not consult with physicians unless they have a medical or fertility issue," Bachmann said.

She recommended that physicians counsel older men as they do older women on the effect their age will have on conception, pregnancy and the health of their child. If men plan on delaying fatherhood, they should consider banking sperm before their 35th -- or at least by their 45th birthday -- to decrease the increased risks to the health of the mother and child.

Lisbon, Portugal - 12 May 2019: Artificial intelligence (AI) could prevent unnecessary diagnostic tests in patients with stable chest pain, according to research presented today at ICNC 2019.1 A decision support system saved one hour of testing per patient.

The International Conference on Nuclear Cardiology and Cardiac CT (ICNC) is co-organised by the American Society of Nuclear Cardiology (ASNC), the European Association of Cardiovascular Imaging (EACVI) of the European Society of Cardiology (ESC), and the European Association of Nuclear Medicine (EANM).

Study author Dr Marco Mazzanti, of the Royal Brompton Hospital, London, UK, said: "We know that doctors overtest patients and ignore recommendations about when a test justified about two-thirds of the time. Our 'super brain' decision support system, called ARTICA, strictly follows ESC guidelines and does not advise unnecessary examinations."

The study enrolled 982 patients with stable chest pain, a frequent cause of visits to emergency departments and general practitioners. The researchers compared decisions on which tests to perform made by a cardiologist and by ARTICA on the same day. ARTICA advised no further testing in 658 (67%) patients whereas a cardiologist decided that only 45 (4.6%) patients did not need more tests.

A computed tomography angiography (CTA) scan showed that 639 (97%) of the patients ARTICA said did not need tests had no significant coronary artery disease, meaning the decision was correct. Avoiding these tests would save staff one hour and patients two hours on average.

Dr Mazzanti said: "AI has the potential to save costs and staff time by identifying patients with chest pain who do not have significant coronary artery disease and therefore do not need expensive cardiac imaging."

To take one example, a CTA scan, used to look for blocked blood vessels, costs €200-400. Cardiologists recommended it for 816 (83%) patients while ARTICA recommended it for just 95 patients (10%).

Dr Mazzanti said: "As doctors we order a lot of tests which cost a lot of money and waste time. ARTICA is like a second set of eyes to make sure we follow recommendations."

He noted that ARTICA recommended exercise testing or functional imaging for 224 (23%) patients while cardiologists recommended it for just 100 (10%) patients. "We know that when ARTICA says don't do a test it is almost 100% right because the CTA scan confirmed no blocked arteries," said Dr Mazzanti. "When ARTICA decides a test is needed, we are less certain that this is correct. By adding more data to the super brain these decisions will become more accurate and enable us to deliver more personalised care."

ARTICA, which stands for ARTificial Intelligence for clinical Cardiac nAvigation, is a decision support system created by the researchers. It uses machine learning, a type of AI, to make decisions that adhere to recommended practice. The researchers inputted guidelines for patients with stable chest pain2 and routinely collected medical data. A machine learning algorithm analysed the information repeatedly until it learned to identify who needed a test (and which test) and who did not.