Body

For centuries, the mental world of the mind and the physical world were treated as utterly distinct. While the movement of inanimate objects could be measured and ultimately predicted with the help of mathematics, the movement of organisms - their behavior - appeared to be shaped by different forces, under the control of the will.

About 200 years ago, the German physician Ernst Heinrich Weber made a seemingly innocuous observation which led to the birth of the discipline of Psychophysics - the science relating physical stimuli in the world and the sensations they evoke in the mind of a subject. Weber asked subjects to say which of two slightly different weights was heavier. From these experiments , he discovered that the probability that a subject will make the right choice only depends on the ratio between the weights.

For instance, if a subject is correct 75% of the time when comparing a weight of 1 Kg and a weight of 1.1 Kg, then she will also be correct 75% of the time when comparing two weights of 2 and 2.2 Kg - or, in general, any pair of weights where one is 10% heavier than the other. This simple but precise rule opened the door to the quantification of behavior in terms of mathematical 'laws'.

Weber's observations have since been generalised to all sensory modalities across many animal species, leading to what is now known as Weber's Law. It is the oldest and most firmly established law in psychophysics. Psychophysical laws describe precise rules of perception and are important because they can be used to obtain mathematical explanations of behavior in terms of brain processes, just like the precise patterns of movement of the planets in the sky were useful to understand gravitation.

Many explanations for Weber's law have been proposed through the years. Although they can all account for Weber's findings, no experimental test had been found to identify which model was correct. Thus, the puzzle of a mathematical explanation of Weber's law remained open.

Now, a team of researchers at the Champalimaud Centre for the Unknown in Lisbon, Portugal, has discovered that Weber's Law can be described as the consequence of a new psychophysical rule involving the time that it takes to make a choice, not just the outcome of the decision. The team has shown that this new rule is sufficient to derive a unique and accurate mathematical model describing the cognitive process underlying Weber's Law. Their results are described in an article published in the scientific journal Nature Neuroscience.

Time is key

In this new study, Alfonso Renart, the principal investigator that led the study, and his team, trained rats to discriminate between two sounds of slightly different intensities. They constructed miniscule headphones, specially adapted to the head of rats, and used them to deliver sounds simultaneously to both ears.

In each trial, the sound on one of the two speakers would be slightly louder, and the rat's job was to report which speaker played the louder sound by orienting towards the corresponding side. "This behaviour is natural to rats, because they orient their heads towards the source of a sound, just like we do", explains José Pardo-Vazquez, one of the article's co-authors. The rats could experience the sound as long as they needed in order to make up their mind. Thus, every attempt provided a choice, and a decision time.

"Our experiments confirmed that the animals' behaviour matched Weber's Law", says Pardo-Vazquez. "Their ability to tell which of the two sounds was louder only depended on the ratio between the sounds' intensities. If the rat had to compare the intensities of two sounds that were played softly, its accuracy was just as good as with a pair of sounds that were played loudly, as long as both pairs had the same intensity ratio."

Then, the team started to analyze in detail how long the rats took to make their decisions, a step that turned out to be critical. "Typically, studies of Weber's law focussed on the accuracy of the discrimination, which is what Weber himself described", Pardo-Vazquez explains. "Surprisingly, the time taken to decide has received little attention." The team realized decision times and the loudness of the pair of sounds were linked - the louder the sounds, the shorter the decision time. In fact, they showed that the nature of this link was unique and mathematically precise, making the decision times observed, for instance, in a discrimination between two quiet sounds, exactly proportional to the decision times measured when the subject discriminated between two loud sounds -- as long as their relative intensities were constant.

Beyond Weber's Law

The team had, in fact, discovered a new "psychophysical law", which they referred to as 'Time-Intensity Equivalence in Discrimination' (TIED), because it linked the overall intensity of a pair of sounds and the time it took to discriminate between them. The TIED is more stringent than Weber's Law, because it not only links the accuracy of pairs of discriminations, it also links their associated decision times. "The precision of this relationship between the decision times in our experiments is amazing", says Pardo-Vazquez, "it is unusual that the behavior of animals can be described with such mathematical precision".

To investigate if the TIED held also in different conditions, the team ran the same kind of experiment with human subjects, obtaining similar results. They also analyzed experiments done by others in which rats perform olfactory discriminations of odor mixtures, again with the same outcome. "It is still early to say if the TIED is as general as Weber's law, but the fact that we obtained the same results in two species and across two sensory modalities is an encouraging first step", Pardo-Vazquez concluded.

Closing in on the right model

Dozens of mathematical models have been proposed through the years to explain Weber's law, but there was no clear experimental test to distinguish them. The researchers reasoned that the TIED offered a way forward. Their analysis revealed that in order to be consistent with the TIED, a mathematical model of the discrimination task would need to satisfy a set of strict conditions. "This was fantastic", says Juan Castiñeiras, another co-author of the study. "The TIED constrained the world of possible explanations, and thereby resolved the ambiguity between the many proposed models of Weber's law." A previously proposed model by the psychologist Stephen Link at the end of the 80s came close to the solution, but missed an important condition describing how the intensity of sensory stimuli is encoded by the activity of sensory neurons.

The final step was to take this set of conditions, and construct a model to test how accurately it accounted for the behavior of the rats. "We analyzed the simplest model with the fewest possible number of parameters", explains Castiñeiras. When the values of these parameters were chosen to maximize the similarity to the behavior of the rats, they discovered that the fit of the model was remarkable. "Even the simplest model effectively captured everything we could measure with almost no error. This greatly strengthened our confidence that the model describes something true about how perception works", says Renart.

Precise experiments and theories lead to definite progress

These results stand out in their field because of the precision of both the new psychophysical rule and of the mathematical model that describes the experimental data. "Although less frequently observed, in biology and in the study of behavior -- like in physics -- precise experimental results permit precise explanations which resolve previous ambiguities and therefore constitute progress", says Renart. For instance, their results suggest that one of the main theories in psychophysics was not adequate to describe the TIED. "Producing mathematical explanations that rule out competing theories is very rare in neuroscience, because there is always the possibility to slightly modify one model to make it compatible with the experimental data", Castiñeiras points out. "We showed that a very influential theory in psychophysics (called Signal Detection Theory) did not model decision times and could therefore not describe the TIED. It missed the essence of the explanation of Weber's law".

One of the next goals of the team is to understand how the mathematical model they have identified is implemented by the brain: "We want to determine which brain areas are important in our task, and how neurons in these circuits carry out the different computational elements of the model", Renart concludes.

Study finds achievement of diabetes treatment targets has not improved in the United States since 2005

Advances in diabetes care over the past two decades have not effectively improved diabetes outcomes for American adults, in particular young, female and non-white adults with diabetes

BOSTON -- More than 30 million Americans are living with diabetes. Diabetes treatment is generally focused on controlling blood sugar, blood pressure and cholesterol level, as well as promoting smoking cessation. A new study by investigators at Massachusetts General Hospital (MGH) published online in JAMA Internal Medicine suggests that the achievement of these targets has not improved for U.S. adults with diabetes since 2005.

Using 2005-2016 nationally representative survey and examination data from Centers for Disease Control and Prevention (CDC), the authors conducted statistical analyses to evaluate the cascade of diabetes care in the United States which is defined as diabetes diagnosis, linkage to care and achievement of treatment targets. They found that more than one in four U.S. adults with diabetes were not diagnosed and nearly one in three were not receiving appropriate care for diabetes in the study period.

"Fewer than one in four American adults with diagnosed diabetes achieve a controlled level of blood sugar, blood pressure and cholesterol and do not smoke tobacco. Our results suggest that, despite major advances in diabetes drug discovery and movement to develop innovative care delivery models over the past two decades, achievement of diabetes care targets has not improved in the United States since 2005," says lead and corresponding author Pooyan Kazemian, PhD, of the MGH Medical Practice Evaluation Center, and instructor in Medicine at Harvard Medical School (HMS).

The authors also investigated potential age, gender and racial disparities in U.S. diabetes care. They found that certain populations demonstrated persistent disparities in meeting diabetes care targets over the study period.

"Younger age (18-44), female and non-white adults with diabetes had lower odds of achieving the composite blood sugar, blood pressure, cholesterol and non-smoking target," says Kazemian.

Insurance coverage was the strongest indicator of diagnosis, linkage and achievement of the composite treatment targets.

"Barriers accessing health care, including lack of health insurance and high drug costs, remain major factors that have not been adequately addressed on a population level," says senior author Deborah J. Wexler, MD, MSc, of the MGH Diabetes Unit, and associate professor in Medicine at HMS.

The authors note that continued monitoring of diabetes care cascade can help shed light on the population-level steps required to improve diabetes care in the United States.

"Treatment advances in diabetes mellitus can meaningfully improve outcomes only if they effectively reach the populations at risk. Our findings suggest this is not the case in the U.S. and indicate an immediate need for better approaches to diabetes care delivery including a continued focus on reaching underserved populations with persistent disparities in care," says Wexler.

Aided by a high-powered brain scanner and a 3D printer, NIH researchers peered inside the brains of hundreds of multiple sclerosis patients and found that dark rimmed spots representing ongoing, "smoldering" inflammation, called chronic active lesions, may be a hallmark of more aggressive and disabling forms of the disease.

"We found that it is possible to use brain scans to detect which patients are highly susceptible to the more aggressive forms of multiple sclerosis. The more chronic active lesions a patient has the greater the chances they will experience this type of MS," said Daniel S. Reich, M.D., Ph.D., senior investigator at the NIH's National Institute of Neurological Disorders and Stroke and the senior author of the paper published in JAMA Neurology. "We hope these results will help test the effectiveness of new therapies for this form of MS and reduce the suffering patients experience."

Affecting more than 2 million people worldwide, multiple sclerosis is a disease for which there is no cure. The disease starts when the immune system attacks myelin, a protective coating that forms around nerve cells in a person's brain and spinal cord, to produce a variety of initial symptoms, including blurred or double vision, problems with muscle strength, balance and coordination, and abnormal sensations. Treatment with anti-inflammatory medications designed to quiet the immune system has helped some patients fully or partially recover. Nevertheless, a significant subset of patients will eventually suffer from a longer lasting, progressive form of the disease, which can cause further problems including paralysis, loss of bladder control and problems with attention, thinking, and memory.

Doctors often use magnetic resonance imaging (MRI) to diagnose patients as the immune system's attack produces lesions that appear as spots on scans of patients' brains. While some of the lesions heal, completely or partially, other lesions remain and rimmed ones appear to actively expand, or "smolder", for many years. Nevertheless, until recently, researchers did not fully understand the role chronic active lesions play in the disease, in part, because it was difficult to find the ones that remain chronically inflamed.

Starting in 2013, Dr. Reich's team showed that by using a high-powered, 7-tesla MRI scanner, they could accurately identify damaging, chronic active lesions by their darkened outer rims, in agreement with previous studies.

"Figuring out how to spot chronic active lesions was a big step and we could not have done it without the high-powered MRI scanner provided by the NIH. It allowed us to then explore how MS lesions evolved and whether they played a role in progressive MS," said Martina Absinta, M.D., Ph.D., the post-doctoral fellow in Dr. Reich's lab who performed these studies.

To do this, the team scanned the brains of 192 multiple sclerosis patients who had entered a trial at the NIH's Clinical Center. They found that, regardless of the treatment they were receiving, 56 percent of the patients had at least one rimmed lesion. Further analysis showed that 44 percent of patients had only rimless lesions; 34 percent had one to three rimmed lesions; and 22 percent had four or more rimmed lesions.

They then compared the brain scans to the neurological examinations the patients received upon enrollment. Patients who had four or more rimmed lesions were 1.6 times more likely to be diagnosed with progressive MS than those without rimmed lesions. Moreover, these patients developed motor and cognitive disabilities at a younger age than the patients who had no rimmed lesions. When the researchers analyzed key parts of the patients' brains, they found that patients who had four or more rimmed lesions had less white matter and smaller basal ganglia than those who had no rimmed lesions.

"Our results point the way towards using specialized brain scans to predict who is at risk of developing progressive MS," said Dr. Reich.

The team then analyzed a subset of patients whose brains had been scanned once every year for 10 years or longer. Their results suggested that, while the rimless lesions generally shrank, the rimmed lesions either grew or stayed the same size and were particularly damaged.

Finally, the team used a 3D printer to compare the spots they had seen on scans to the lesions they observed in brain tissue samples autopsied from a patient who had passed away during the trial. They found that all expanding rimmed spots seen on the scans had the telltale features of chronic active lesions when examined under a microscope.

"Our results support the idea that chronic active lesions are very damaging to the brain," said Dr. Reich. "We need to attack these lesions as early as possible. The fact that these lesions are present in patients who are receiving anti-inflammatory drugs that quiet the body's immune system also suggests that the field of MS research may want to focus on new treatments that target the brain's unique immune system - especially a type of brain cell called microglia. At the NIH, we are actively seeking patients who want to participate in studies like these."

In a previous article, Dr. Reich's team openly shared instructions for programming lower powered MRI scanners, found at most clinics, to detect rimmed chronic active lesions. They hope researchers around the world will use the instructions to develop and monitor better diagnostic and therapeutic strategies for MS patients.

HOUSTON -- (Aug. 12, 2019) -- To combat the rise of drug-resistant bacteria, researchers are examining how one superbug adapts to fight an antibiotic of last resort, hoping to find clues that can prolong the drug's effectiveness.

Researchers at Rice University and the University of Texas Health Science Center at Houston ran experiments to track the biochemical changes that vancomycin-resistant Enterococci (VRE) underwent as they adapted to fight another antibiotic, daptomycin.

"We need to get to a stage where we can anticipate how these pathogens will become resistant to antibiotics so we can stay one step ahead of them," said Rice biochemist Yousif Shamoo, co-author of a study in the journal Antimicrobial Agents and Chemotherapy that found VRE can develop resistance to daptomycin in more than one way.

The stakes are high. In 2014, the World Health Organization reported that antibiotic-resistant infections were on pace to kill 10 million people per year worldwide by 2050.

According to the U.S. Centers for Disease Control, VRE is one of the nation's leading antibiotic resistance threats. The CDC estimated VRE will infect some 20,000 people in the U.S. this year and kill 1,300 of them.

Daptomycin, an antibiotic that first became available in 2003, is one of the last drugs doctors can use to fight multidrug-resistant superbugs like VRE, methicillin-resistant Staphylococcus aureus (MRSA) and glycopeptide-resistant enterococci (GRE).

Unfortunately, health officials documented cases of daptomycin resistance as early as 2005, and the number of cases is on the rise worldwide.

Shamoo said one of the principle findings of the study was that a specific strain of VRE, Enterococcus faecium, has an unusually diverse set of strategies for resisting antibiotics like daptomycin, and that diversity can make treatment of infections even more difficult.

"By understanding how these pathogens acquire resistance, we can develop new treatment strategies or new 'co-drugs' that target their ability to become resistant," Shamoo said.

Co-drugs that target the evolution of resistance could be administered with antibiotics like daptomycin to both help patients fight off infection and stem the spread of increasingly resistant strains of bacteria in hospitals, he said.

Study lead author Amy Prater, a Ph.D. student who graduated from Rice in July, showed that the same strain of VRE could activate different biochemical pathways to activate up to three strategies, depending upon its environment. Shamoo said the multipronged strategy will make it more difficult for health officials to fight growing daptomycin resistance in VRE, but he said the results help clear up previously confusing experimental findings about VRE resistance, which is a step in the right direction.

"If we understand how a pathogen acquires resistance, we can anticipate its next move, and hopefully act beforehand to cut it off," Shamoo said. "Predictability is the key."

Chlamydia is the most common sexually transmitted bacterial infection worldwide, but national screening programmes and antibiotic treatment have failed to decrease infection incidences.

The first ever chlamydia vaccine to reach phase 1 clinical trial has been found to be safe and able to provoke an immune response, according to a study published in The Lancet Infectious Diseases journal. The randomised controlled trial of 35 healthy women demonstrates promising early signs of what could be an effective vaccine, but further trials are required to determine whether the immune response it provokes effectively protects against chlamydia infection.

Chlamydia, caused by the bacterium Chlamydia trachomatis, presents a major global health burden - with 131 million new cases occurring annually. However, as three out of four infections are symptomless, the number of cases is likely to be underestimated. The highest number of new cases are found in teenagers and young adults.

Vaccination may be the best way to tackle the epidemic, as national treatment programmes have largely failed to curb the epidemic, despite availability of diagnostic tests and effective antibiotic treatment. Previous studies have suggested that people infected with chlamydia develop either partial or temporary natural immunity to the pathogen, but no previous vaccines for genital chlamydia have reached clinical trials.

"Given the impact of the chlamydia epidemic on women's health, reproductive health, infant health through vertical transmission, and increased susceptibility to other sexually transmitted diseases, a global unmet medical need exists for a vaccine against genital chlamydia," says study author, Professor Peter Andersen, from Statens Serum Institut, Denmark. [1]

For one in every six women infected with chlamydia, the infection travels up from the cervix and causes pelvic inflammatory disease. This can result in chronic pelvic pain and even infertility or ectopic pregnancy, especially in the developing world, where access to treatment and screening is limited. In addition, chlamydia is strongly associated with susceptibility to other sexually transmitted infections, particularly gonorrhoea and HIV, and chlamydia infection during pregnancy can increase the risk of adverse outcomes such as miscarriage, stillbirth, and preterm birth.

In the trial, the authors aimed to assess the safety and ability to provoke an immune response, in humans, of a new chlamydia vaccine CTH522 based on the major outer membrane protein of the C trachomatis bacterium. The researchers compared two different formulations--one with added CAF01 liposomes designed to aid cellular immunity and one with aluminium hydroxide known for its ability to help produce antibodies--to examine which formulation would perform better.

The 35 women not infected with chlamydia included in the trial were randomly assigned to three different groups: two with the new vaccine, CTH522, and one to placebo (five participants received saline). Of those receiving the vaccine, 15 participants received the vaccine combined with CAF01 liposomes (CTH522:CAF01), and the other 15 received the vaccine with aluminium hydroxide (CTH522:AH).

The vaccination was given to participants in three intramuscular injections in the arm administered on day 0, 28, and 112 and two intranasal boosts administered on day 126 and 140. 32 participants received all five vaccinations.

Both formulations of the vaccine provoked an immune response in 15 out of 15 (100%) participants, whereas no participants in the placebo group achieved an immune response.

While both formulations of the vaccines were found to provoke an immune response, CTH522:CAF01 consistently performed better (producing 5.6 times more antibodies), so the authors suggest this formulation should be pursued for further clinical development. CTH522:CAF01 showed additional signs of better performance compared with CTH522:AH including an enhanced mucosal antibody profile that serves as first line of defence against the infection, and a more consistent cell-mediated immune response profile that is associated with long-lived immunity.

Although the vaccine provokes an immune response, whether this translates into protective immunity remains unclear. First author Helene B Juel, Statens Serum Institut, Denmark says: "Studies of antibodies in mice have found that antibodies in the vagina are the first line of defence against chlamydia infection, which suggests they are key to how effective the new vaccine may be. In our trial, significantly increased concentrations of these antibodies were found in both CTH522:CAF01 and CTH522:AH-vaccinated individuals. Although many more years of research are needed before this vaccine is marketed, we are planning the next stage of research - a phase 2a study of CTH522:CAF01." [1]

CTH522 with either CAF01 or aluminium hydroxide appeared to be safe and well tolerated. There were no related serious adverse events reported. The most frequent adverse events were mild local injection-site reactions (all 15 participants in the two vaccine treatment groups had a mild reaction, which seemed to occur more frequently than in the placebo group [three out of five participants affected]). The most common local reactions were injection-site pain, tenderness, and movement impairment, with 88-93% of events being reported as mild in each of the groups, lasting a median of 2-4 days in all groups.

The authors note that the main limitation of the study is its sample size. As with other phase I trials, the small sample size limits its ability to pick up rarer adverse reactions to the vaccine or provide robust evidence on its ability to provoke an immune reaction.

Writing in a linked Comment, Professor Toni Darville from University of North Carolina, USA, notes: "A vaccine for prevention of C trachomatis infection would have enormous public health and economic impact. Although clinical vaccine testing for chlamydia is in its infancy, this trial suggests optimism for the future."

Doctors urgently need a fast and accurate test for diagnosing urinary tract infections (UTIs) to reduce overprescribing of antibiotics, according to health researchers.

Dr Mar Pujades Rodriguez, from the University of Leeds, argues that without access to a reliable test doctors risk prescribing unnecessary antibiotic treatments, which increase the risk of antibacterial resistance.

Current "bedside" dipstick tests to screen a urine sample for infection are inaccurate and laboratory tests are slow. NHS guidelines currently recommend laboratory testing in particular patient groups such as children and adult men.

A UTI is a relatively common problem but in some cases complications can occur when the infection spreads to cause kidney infection or sepsis.

New research from the University of Leeds looked at nearly 500,000 cases of UTIs in patients in England, treated between 2011 and 2015, from records held at 390 GP practices.

Less than one in five patients treated for a UTI had a laboratory urine test to diagnose their problem. Tests were not carried out more often in men than women, or to those who returned for a second treatment as their symptoms persisted, contrary to NHS guidelines.

Existing laboratory tests for UTIs are therefore having little impact on the prescribing of antibiotics.

The study also found that one in five patients who have to return to their doctors for a second round of treatment for a UTI are being prescribed the same antibiotic that was first given, which is not recommended practice and could increase the chance of resistance developing.

Thousands of people across England have therefore been given repeat prescriptions that have little chance of curing their infection, and may increase the risk of antibiotic resistance developing.

Published today in the journal EClinicalMedicine (The Lancet), the study shows that doctors require more accurate and rapid testing capabilities for UTI, and need to consider different antibiotics if a first course of treatment fails.

The study was funded by the UK's National Health Service Improvement.

Lead researcher Dr Mar Pujades Rodriguez, from the University of Leeds Institute of Health Sciences, said: "Doctors are currently limited in their options when somebody shows signs of having a UTI, and they urgently need access to accurate rapid diagnostics tests.

"UTIs are one of the most common reasons that antibiotics are prescribed, so the potential contribution this is causing to antibiotic resistance might be very significant.

"In addition, many patients may be making things worse by taking leftover antibiotics that they have been prescribed and using them to treat other infections, or by not finishing their course of treatment."

Doctors can currently use a laboratory test to diagnose a UTI, but it takes around two to three days to provide the results. The test is supposed to ensure that the patient actually has a UTI, and that the right antibiotic is prescribed to treat it.

However, only 17% of patients in the current study who were treated with antibiotics had been tested.

Danger of repeat prescriptions

Guidelines by NICE state that if antibiotics do not successfully treat an infection and symptoms persist, patients should not be prescribed the same antibiotic again, to reduce the potential for antibiotic resistance and treatment failure.

When people are treated for an infection with antibiotics, some of the friendly bacteria that usually live in the body develop resistance to the antibiotics. These bacteria can pass on resistance to other bacteria that might cause infections in the future, making those new infections more difficult to treat.

In their study, researchers looked at nearly 500,000 cases of UTIs in patients in England, treated between 2011 and 2015. The majority of patients were treated with antibiotics, and of those, 17,000 (4%) cases required patients to return to their doctor because their infection had not cleared up.

For those repeat visitors, a significant proportion were prescribed the same antibiotic they were treated with originally, with just 80 per cent correctly given a different antibiotic capable of tackling their infection.

Worryingly, the rate at which male patients had to return for a second treatment for the same UTI increased by about 20% over the study period (from 5.2% in 2011 to 6.2% in 2015).

This increase in re-prescribing of antibiotics needs to be monitored, as it could be related to an increase in antibiotic resistance.

Researchers also found that patients who had been prescribed antibiotics more recently were more likely to need further treatment to tackle their UTI.

Patients who had been prescribed antibiotics in the past three to six months were 37% more likely to require a second treatment for their UTI, compared with those who had not been given antibiotics in the last year.

Those who had been prescribed antibiotics in the past one to three months were nearly twice as likely to need a second treatment. And those prescribed antibiotics in the past month were more than three times more likely to need a second treatment, compared to those who had not been given antibiotics in the last year.

According to the researchers, these figures all suggest that antibiotic resistance was the cause of treatment failure.

False teeth need to be taken out before a general anaesthetic, doctors warn in the journal BMJ Case Reports after a 72 year old's dentures got stuck in his throat during surgery to remove a harmless lump in his abdominal wall, and weren't discovered for eight days.

Aside from experiencing considerable pain, bleeding, and swallowing difficulties, the oversight led to repeated hospital visits, additional invasive tests, blood transfusions, and eventually more surgery for the man.

The doctors describe how six days after abdominal surgery, the man turned up at A&E complaining of blood in the mouth and swallowing difficulties and pain, which had prevented him from eating solid food ever since.

Nothing in his test results prompted doctors to consider anything other than a respiratory infection and the side effects of having had a tube down his throat during his operation.He was therefore prescribed mouthwash, antibiotics and steroids, and sent home.

Two days later he returned with worsening symptoms. He had been unable to swallow any of the medicine he had been prescribed. He was admitted to hospital with suspected aspiration pneumonia--a severe chest infection usually caused by inhaling food or stomach acid or saliva into the lungs.

During this hospital stay, a diagnostic procedure to look at his throat and voice box revealed a semi-circular object lying across his vocal cords, which had clearly caused internal swelling and blistering.

When this was explained to him, the man revealed that his dentures, which consisted of a metal roof plate and three false teeth, had been lost during his previous hospital stay.

He then had emergency surgery to remove the dentures and was discharged after six days. But six days later a bout of bleeding prompted his return. As tests revealed the bleeding had stopped, he was sent home, only to reappear 10 days later with the same problem.

After a couple of days he was again discharged, but returned six days later because of further bleeding. Tests revealed that he had internal wound tissue around the site of the blistering which was cauterised to prevent further bleeding. Because he had lost so much blood, he also required a blood transfusion.

He was discharged after two days, but returned again nine days later with further bleeding, which required emergency surgery as the source of the bleed was a torn artery in the wound.

A check-up a week after this procedure showed that the tissue was healing well, and six weeks later he had not needed further emergency care and his blood count was back to normal.

The authors note that this isn't the first documented case of dentures being inhaled while anaesthetic is being infused.

"There are no set national guidelines on how dentures should be managed during anaesthesia, but it is known that leaving dentures in during bag-mask ventilation allows for a better seal during induction [when the anaesthetic is being infused], and therefore many hospitals allow dentures to be removed immediately before intubation [when a tube is inserted into the airway to assist breathing]," write the authors.

The presence of any false teeth or dental plates should be clearly documented before and after any surgical procedure, with all members of the surgical team made aware of what is to be done with them, they add.

Podcast post-embargo link: https://soundcloud.com/cmajpodcasts/190281-view

A new review to help physicians manage the risk of ovarian cancer in women who carry the BRCA1/2 gene mutations is published in CMAJ (Canadian Medical Association Journal).

BRCA1 and BRCA2 genetic variants are a clinically important risk factor for the development of ovarian and breast cancer, and women who carry these variants have a lifetime risk of ovarian cancer of 39%-44% and 11%-17%, respectively.

"Given the substantial lifetime risk and high mortality of ovarian cancer in women with BRCA1/2 variants, risk reduction is a priority," says Dr. Melissa Walker, a fifth-year resident in obstetrics and gynecology at the University of Toronto, Toronto, Ontario.

The review, which looked at 46 articles published between 2014 and 2019, provides guidance on screening, preventive surgery, contraception and management of menopausal symptoms.

Highlights:

Testing - women with a family history of BRCA1/2 should be tested for the variants, as should women with a diagnosis of ovarian cancer but without family history.

Screening - there is no effective screening test to detect ovarian cancer accurately. Ultrasonography and blood tests have high levels of false positives, which can cause anxiety and lead to unnecessary surgery, early menopause and other harms.

Surgery to reduce risk - as there are no effective screening programs, surgery to remove ovaries and fallopian tubes can reduce the lifetime risk by 80%. Surgery should be performed between ages 35 and 40 years in women with BRCA1 and between 40 and 45 years in women with BRCA2. Other types of surgery, such as fallopian tube removal and hysterectomy, are also discussed.

Contraception and fertility - although evidence is controversial, it appears hormonal contraception is safe for this population. Given that decisions around fertility and family planning are complex, early consultation with a fertility specialist is encouraged.

Management of menopausal symptoms - the risk of early menopause resulting from removal of ovaries can be managed with hormone replacement therapy to reduce the negative effects of bone loss, heart disease and other conditions. Women who have had breast cancer are at increased risk of recurrence and should be treated with non-hormonal options. Referral to a menopause specialist is recommended.

"Women with these variants have unique and broad medical needs that cross medical specialties and areas of expertise, from surgery to genetics, oncology to nursing, menopause specialists to social work." says Dr. Walker. "Multidisciplinary management of these women is essential."

New findings suggest that women with specific DNA characteristics in certain areas of the genome may live longer if they take aspirin before they are diagnosed with breast cancer. Published early online in CANCER, a peer-reviewed journal of the American Cancer Society, the findings point to the need for studies on the potential of aspirin to prevent or treat breast cancer in some individuals.

It is often unclear why some patients benefit from a particular therapy while others do not. In some cases, gene sequences play a role, but in other cases, chemical modifications to DNA may be important. The latter are termed epigenetic changes, and they include a process called DNA methylation.

Tengteng Wang, PhD, MSPH, and her mentor Marilie Gammon, PhD, of the University of North Carolina at Chapel Hill, wondered whether DNA methylation may influence the effects of aspirin in patients with breast cancer. The team examined DNA methylation in breast tumor tissues--including at DNA sites that control the expression of 13 breast cancer-related genes--and also in cells circulating in patients' blood. The study is the first to examine the effect of DNA methylation on the association between aspirin use and mortality in women with breast cancer.

In the study of 1266 women who were diagnosed with breast cancer during the 1996-1997 period, 476 died from any cause and 202 died specifically from breast cancer by the end of 2014. In women who used aspirin, the risk of dying from any cause and the risk of dying from breast cancer was lower among those whose DNA was not methylated in the region that controlled expression of the breast cancer-related BRCA1 gene. Other methylation patterns related to aspirin use and mortality were also observed.

The authors noted that the findings could help identify individuals who may benefit from aspirin after a breast cancer diagnosis due to their cells' DNA methylation profile. Future research should consider a more comprehensive DNA methylation profile in order to better characterize women who are at risk.

"Consideration of DNA methylation profiles as potential modifiers of the aspirin-mortality association may provide new insights on the underlying biological mechanisms on aspirin use in relation to mortality after breast cancer diagnosis," said Dr. Wang. "Our findings, if confirmed, may also impact clinical decision-making by identifying a subgroup of patients, using epigenetic markers, for whom pre-diagnosis aspirin use impacts subsequent mortality, and may help refine risk reduction strategies to improve survival among women with breast cancer," added Dr. Gammon.

In an accompanying editorial, Kristen Malecki, PhD, MPH, of the University of Wisconsin-Madison, noted that the findings support the importance of research examining interactions between epigenetics and low-cost therapies such as aspirin. According to Dr. Malecki, "The study by Wang et al. shows that beyond gene-environment interactions, epigenetic and environment interactions also exist, and suggest that DNA methylation could in the future help to support the identification of individuals for whom treatment may or may not be successful.

Philadelphia, August 12, 2019 - Ninety-nine percent of cervical cancers are caused by human papillomavirus (HPV). More than 200 HPVs, some of which are associated with varying degrees of
cancer risk, complicate diagnosis and treatment. A report in The Journal of Molecular Diagnostics, published by Elsevier, describes a new "two-for-one" diagnostic approach that not only detects the type of HPV infection, but also indicates precancerous markers. This test may improve the ability to diagnose the riskiest forms of HPV infection, provide rapid results at low cost, and help avoid unnecessary diagnostic procedures.

"We have developed HPV RNA-Seq, a novel in vitro molecular diagnostics procedure for the detection of high-risk HPV infection and the identification of patients with high-grade squamous intraepithelial lesions (HSIL), which is a precancerous stage of the cervix. HPV RNA-Seq is a unique test that combines the advantages of molecular assays (HPV typing) and cervical cytology (cell phenotyping)," explained lead investigator Marc Eloit, DVM, PhD, of the Pathogen Discovery Laboratory, Biology of Infection Unit, Institut Pasteur, Paris, and the National Veterinary School of Alfort, Paris-Est University, Maisons-Alfort, France.

Cervical cancer screening allows detection and treatment of precancerous lesions before cancer develops. Currently, screening either focuses on testing for HPV or identifying abnormal cervical cells with cytology. However, molecular diagnostic tests that detect the DNA or RNA of viruses are poor at identifying cancer or precancerous lesions. Analysis of cervical cells with the Pap test, even when combined with molecular detection of high-risk HPV, results in a significant number of unnecessary colposcopies, an invasive test by which the physician visually checks for cervical lesions.

In this proof-of-concept study, HPV RNA-Seq was used to analyze samples from 55 patients, 28 with low-grade squamous intraepithelial lesions (LSIL) and 27 patients with precancerous HSIL.

HPV RNA-Seq was able to detect and determine the type of HPV infection among a panel of 16 high-risk HPVs with results comparable to a widely used and officially approved HPV DNA molecular diagnostic kit. In fact, HPV RNA-Seq detected two more HPV-positive patients than the DNA test and also identified more patients with multiple HPV infections.

The test was found to have a sensitivity (ability to detect the presence of an HPV) of 97.3 percent and negative predictive value (NPV, likelihood of not having HPV) of 93.8 percent. "Effective cervical cancer screening requires high sensitivity and NPV for high-risk HPV infection, since women with a negative HPV test are usually tested again only after several years," noted Prof. Eloit.

Cytology is used as a rapid method to triage patients with HPV whereas histology is considered the gold standard for cervical cancer diagnosis. Histological analysis, however, is more invasive and requires more time to yield results. To determine if the new test has a place in cervical cancer triage, the investigators also compared cytology to HPV RNA-Seq and found markers of high-grade cytology, with encouraging diagnostic performances of HPV-RNA-Seq as a triage test. They also found the positive predictive value (PPV, likelihood of having HPV infection) of HPV RNA-Seq vs. histology was always greater than the PPV of cytology vs. histology. "This observation constitutes a solid argument in favor of a potential added medical value of HPV RNA-Seq compared with cytology," commented Prof. Eloit.

Prof. Eloit suggests that the use of HPV RNA-Seq in certain patients can help eliminate unnecessary colposcopies. He also foresees a time when technology will allow many samples to be run simultaneously, lowering the cost to perhaps $10 to $20 per test. The test may also be applicable for other HPV-associated cancers such as anal cancer and head and neck cancer.

HPV RNA-Seq is based on the dual combination of multiplexed reverse transcription PCR (RT-PCR) and next-generation sequencing (NGS). RT-PCR is a sensitive way to measure small amounts of RNA, the genetic material that reflects the activity of the HPV genes, and NGS makes it possible to finely characterize the diversity of the amplified viral sequences. This enables detection of up to 16 high-risk or putative high-risk HPV in a sample as well as the presence of precancerous markers.

"Our approach follows the current trend of developing NGS amplicon panels for molecular diagnostics, while remaining adaptable to traditional molecular assays formats. This flexibility can make HPV RNA-Seq a convenient, robust, and affordable solution for many laboratories," added lead author Philippe Pérot, PhD, Pathogen Discovery Laboratory, Biology of Infection Unit, Institut Pasteur, Paris, France.

CHICAGO -- Injuries have overtaken infectious disease as the leading cause of death for children worldwide, and psychologists have the research needed to help predict and prevent deadly childhood mishaps, according to a presentation at the annual convention of the American Psychological Association.

"Many different factors contribute to unintentional injuries, so if we are able to stop just one of these risk factors, the injury could be prevented," said David C. Schwebel, PhD, of the University of Alabama Birmingham, who presented at the meeting. "By using novel behavioral strategies, we can possibly prevent injuries that have previously been seen as unavoidable accidents."

Injuries were responsible for the deaths of over 11,000 and emergency room visits by more than 6.7 million American children in 2017, according to the Centers for Disease Control and Prevention. The Global Burden of Disease project estimates that more than 2 million children under age 19 worldwide died as a result of injuries in 2017. While these numbers represent all injuries, the presentation focused on only unintentional injuries (i.e., accidents) instead of intentional injuries such as suicide, homicide and abuse.

Schwebel outlined a model that psychologists could use to reduce accidental injuries in children. The model groups risk factors in three categories: environment-based, caregiver-based and child-based factors. Each category contributes in some form to almost every incident, according to Schwebel, and preventing just one risk factor could stop an injury from occurring.

Environment-based factors can include many different aspects of the environment with which children interact. For example, children could choke on toys if they are not designed well or be harmed in a car accident due to an incorrectly installed car seat.

Schwebel described one case where he and his colleagues reduced an environmental risk by comparing the look and shape of bottles containing either juice or torch fuel. Children were shown many bottles, some with torch fuel and others with juice, and were asked if they would drink them or not. Children tended to identify liquids in clear plastic bottles as drinks and those in opaque containers as not drinks. After the findings were published, there were evident changes in the torch fuel industry as fuel began to be sold in dark opaque bottles.

Caregiver-based factors can involve anyone who is supervising a child, including parents, teachers, babysitters or even lifeguards. According to Schwebel, preschool teachers can often be underpaid and fatigued from the intense work of supervising children all day and sometimes use outdoor playground time as a break for themselves, allowing children to run free, even though the majority of injuries at preschools occur on playgrounds.

"To solve this problem, we developed the Stamp in Safety Program where children wear a nametag, and teachers have stamps to reward the children on their nametags for engaging in safe behavior," he said. "While on the surface this seems to focus on rewarding children for safe behavior, its primary goal is to get teachers engaged and paying attention."

Child-based factors include motor skills, how children perceive their environment and how they interact with others. These skills vary greatly by age, so different approaches are needed when confronting risks. For example, 7-year-olds struggle more with the cognitive demands of crossing the street than 14-year-olds. Interventions for child-based factors can include reinforcing common parenting practices such as teaching children how to cross the street safely or showing them how to interact with stray dogs.

How the specific situations targeted for interventions are chosen can be a mixed bag, said Schwebel. For example, the idea for a program on drowning prevention came after Schwebel observed lifeguards while his own kids were playing at a pool. Other intervention ideas are drawn from the personal experiences and ideas brought to him by his students, such as the Stamp in Safety program.

And while psychological researchers are essential, this work will require collaboration across a variety of disciplines, said Schwebel. Throughout his research, Schwebel has worked with computer scientists, visual artists, electrical engineers, biostatisticians, physicians, epidemiologists and others.

"Globally, we are amid an unprecedented decrease in health burden from communicable and infectious diseases. As the world develops, health risks change," said Schwebel. "Psychologists have the expertise, the needed behavioral theory, and the needed methodologies to understand and take steps to prevent the significant health burden of unintentional injuries."

The 'mind-muscle connection'. Ancient lore for bodybuilders, latest buzz for Instragram fitness followers.

Focusing one's attention on a particular muscle when lifting promotes its activation - and by extension, its development. So it goes. But when the goal is muscle performance rather than growth alone, does this long-held notion still carry any weight?

Published in Frontiers in Sports and Active Living, new analysis suggests that to lift heavier, or longer, it is better to focus on moving the weight itself - not your muscles.

Think outside the bod

Proponents of the mind-muscle connection cite increased muscle activity, when focusing on specific muscles while lifting, as evidence of benefit. That increased activity might just translate to increased muscle hypertrophy, but put another way: mind-muscle connection makes you expend more effort to lift the same weight.

"The higher overall muscle activity with an internal 'muscle focus' is not specific to the muscles mentally isolated during lifting," says review author Professor David Neumann, of Griffith University, Australia. "Rather, it seems to represent increased activity of non-target muscles, too."

In contrast, studies have consistently shown that when weightlifters instead focus their attention on the external effects of their efforts, such as the movement of a barbell, lifts are done more economically and with less effort.

"It appears that this external focus allows automatic control processes to operate, removing the attentional demands and mechanical inefficiency of conscious muscular control," poses Neumann.

In any case, as the load increases - at 80% of maximum effort in one bench press study - the muscle activity advantage of a muscle focus, over an external focus, seems to disappear altogether.

The mind-muscle connection still holds

Neumann recommends an external focus, on moving a load, to maximize athletes' performance in training and competition - and as a potential complement to 'dissociative' focus strategies, like listening to music, for promoting exercise adherence in those who are less active.

This recommendation comes with many caveats.

Whether any particular attentional focus strategy actually affects meaningful outcomes, like muscle fatigue or strength gains, remains to be determined. Moreover, most relevant study samples are small - with 11-29 participants, prototypically young, Western, male and experienced in weightlifting. Larger, more demographically diverse studies should probe the issue further.

"It would be worthwhile to examine whether transfer of these effects occurs to similar sporting tasks," suggests Neumann. "For example, some sports like shot put and discus, require a short-term maximal muscular effort.

"We should also explore ways to maximize the beneficial effects of an external focus. Using VR for instance, completing a deadlift could be translated into an imperative like virtually lifting a heavy bar to free a trapped virtual person."

Regardless, there will remain a place in exercise regimens for mind-muscle connection. Off-target and ill-coordinated muscle activity notwithstanding, a focus on muscles involved in lifting still increases activation of their fibers - useful for hypertrophy, particularly since one cannot lift heavy all the time. It also increases awareness of form - important in beginners, who have not yet learnt correct lifting form so are less likely to benefit from "automatic" movements.

Bottom Line: An examination of a combined 28 years of data finds similarities in the characteristics and illnesses of patients requesting medical aid in dying in Oregon and Washington. The study included 3,368 prescriptions written for medical aid in dying, with 2,558 patients dying by lethal ingestion of medication, in the two states from 1998 to 2017 in Oregon and from 2009 to 2017 in Washington. Most of the patients were insured, non-Hispanic white individuals with some level of college education, 65 or older, and diagnosed with cancer. Loss of autonomy, impaired quality of life and loss of dignity were the most common reasons for pursuing medical aid in dying. Limitations of the study include physicians, not patients, providing the underlying reasons for requesting medical aid in dying as part of a follow-up questionnaire.

Authors: Charles D. Blanke, M.D., Oregon Health & Science University, Portland, and coauthors

(doi:10.1001/jamanetworkopen.2019.8648)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Bottom Line: This observational study looked at whether extreme heat is associated with increased risk of hospitalization or death among the vulnerable population of patients with end-stage renal disease (ESRD). The study included 7,445 patients with ESRD who underwent long-term hemodialysis treatment at clinics in Boston, Philadelphia or New York from 2001 to 2012. During that time, 2,953 of the patients died. Researchers used historical weather data to identify extreme heat days and investigated if exposures to such extreme heat days increased risk of hospitalizations and deaths among the patients. Extreme heat was associated with increased risk of same-day hospital admission and same-day death, with the risk of death greater among patients living with congestive heart failure, chronic obstructive pulmonary disease or diabetes. Risk varied between cities and by race/ethnicity. Limitations of the study include a lack of data to verify indoor conditions for patients and the study didn't account for multiple-day heat waves, which could present a more severe threat for patients with ESRD.

Authors: Amir Sapkota, Ph.D., University of Maryland School of Public Health, College Park, and coauthors

(doi:10.1001/jamanetworkopen.2019.8904)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

A new study from the University of Bristol has linked bone strength to the timing of puberty.

Published today (Friday 9 August) in JAMA Network Open researchers looked at six repeated bone scans from 6389 children in Bristol's Children of the 90s study between the ages of ten and 25 to assess if the timing of puberty had any influence on bone density throughout adolescence and into early adulthood.

They found that although teens who had their pubertal growth spurt later than their peers did catch-up to some degree, they continued to have lower bone density than average for several years into adulthood.

Peak bone mass at the end of the teenage growth spurts is considered to be an indication of later risk of fracture and osteoporosis. Thanks to repeated measures covering 15 years in the large Children of the 90s study academics were able to examine how bone density changes over time to assess the extent to which later maturating individuals may 'catch-up' with their peers.

Lead author and Senior Research Associate in Epidemiology Dr Ahmed Elhakeem said:

"Our research adds to the evidence that children who mature later may be at increased risk of fractures as they grow. They may also have increased risk of the fragile bone condition osteoporosis in later life."

"Thanks to the Children of the 90s study we were able to look, for the first time, at children in great detail as they grow into young adults and observe their bone density. I'd like to see more advice available for people who reach puberty later on measures they can take to strengthen their bones.

"The next steps should involve more detailed assessments of the long-term effects of puberty on growth and bone development."

Alison Doyle, Head of Operations and Clinical Practice at the Royal Osteoporosis Society, said:

"This is important research that adds to a current gap in the evidence of understanding how bone density changes from puberty into early adulthood.

"Investment in this area of research is vital in furthering our understanding of the causes of osteoporosis and helping people to maintain good bone health throughout life.

"Understanding changes in bone density during puberty, and the interventions that people can take for their bone health now to prevent osteoporosis and fractures in the future, is an important step forward in finding a cure for this disease.

"The charity's Osteoporosis and Bone Research Academy, which launched earlier this year, is working to build on these findings and create a future without osteoporosis."

The study did not make conclusions on any influence of the final adult height on the findings. As the study participants are still only in their twenties follow up with them as they age will be important to reach conclusions about fractures in later life.