Body

DARIEN, IL – Seeking medical care after springing forward to daylight saving time could be a risky proposition. Researchers at the Mayo Clinic found a statistically significant increase in adverse medical events that might be related to human error in the week after the annual time change in the spring.

The study is the first to examine patient safety-related adverse events in the week before and after the biannual time change. Preliminary results show that over an eight-year period, adverse events increased in the week following the time change in both the spring and fall; however, the only statistically significant change was an 18% increase in adverse events related to human errors following the change to daylight saving time in the spring. This increase was significantly greater than the 5% increase in human error-related safety incidents after the return to standard time in the fall.

“Medical errors can result in significant morbidity and mortality. We need to do everything to mitigate these risks,” said lead author Dr. Bhanu Kolla, associate professor of psychiatry and psychology and consultant at the Center for Sleep Medicine at the Mayo Clinic’s campus in Rochester, Minnesota. “Our results indicate that the week following the spring time change might be a high-risk period for patient safety-related incidents. Health care organizations should factor this in and develop countermeasures to reduce this risk.”

The authors suggested that the increase in medical errors may be related to sleep loss caused by the time change in the spring. Because of the risks to patient safety, the authors concluded that it might be best to eliminate daylight saving time.

Researchers at the University of Alberta are preparing to launch clinical trials of a drug used to cure a deadly disease caused by a coronavirus in cats that they expect will also be effective as a treatment for humans against COVID-19.

"In just two months, our results have shown that the drug is effective at inhibiting viral replication in cells with SARS-CoV-2," said Joanne Lemieux, a professor of biochemistry in the Faculty of Medicine & Dentistry.

"This drug is very likely to work in humans, so we're encouraged that it will be an effective antiviral treatment for COVID-19 patients."

The drug is a protease inhibitor that interferes with the virus's ability to replicate, thus ending an infection. Proteases are key to many body functions and are common targets for drugs to treat everything from high blood pressure to cancer and HIV.

First studied by U of A chemist John Vederas and biochemist Michael James following the 2003 outbreak of severe acute respiratory syndrome (SARS), the protease inhibitor was further developed by veterinary researchers who showed it cures a disease that is fatal in cats.

The work to test the drug against the coronavirus that causes COVID-19 was a co-operative effort between four U of A laboratories, run by Lemieux, Vederas, biochemistry professor Howard Young and the founding director of the Li Ka Shing Institute of Virology, Lorne Tyrrell. Some of the experiments were carried out by the Stanford Synchrotron Radiation Lightsource Structural Molecular Biology program.

Their findings were published today in the peer-reviewed journal Nature Communications after first being posted on BioRxIV, a research website.

"There's a rule with COVID research that all results need to be made public immediately," Lemieux said, which is why they were posted before being peer-reviewed.

She said interest in the work is high, with the paper being accessed thousands of times as soon as it was posted.

Lemieux explained that Vederas synthesized the compounds, and Tyrrell tested them against the SARS-CoV-2 virus in test tubes and in human cell lines. The Young and Lemieux groups then revealed the crystal structure of the drug as it binds with the protein.

"We determined the three-dimensional shape of the protease with the drug in the active site pocket, showing the mechanism of inhibition," she said. "This will allow us to develop even more effective drugs."

Lemieux said she will continue to test modifications of the inhibitor to make it an even better fit inside the virus.

But she said the current drug shows enough antiviral action against SARS-CoV-2 to proceed immediately to clinical trials.

"Typically for a drug to go into clinical trials, it has to be confirmed in the lab and then tested in animal models," Lemieux said. "Because this drug has already been used to treat cats with coronavirus, and it's effective with little to no toxicity, it's already passed those stages and this allows us to move forward."

"Because of the strong data that we and others have gathered we're pursuing clinical trials for this drug as an antiviral for COVID-19."

The researchers have established a collaboration with Anivive Life Sciences, a veterinary medicine company that is developing the drug for cats, to produce the quality and quantity of drug needed for human clinical trials. Lemieux said it will likely be tested in Alberta in combination with other promising antivirals such as remdesivir, the first treatment approved for conditional use in some countries including the United States and Canada.

Many modern medicines, including analgesics and opioids, are derived from rare molecules found in plants and bacteria. While they are effective against a host of ailments, a number of these molecules have proven to be difficult to produce in large quantities. Some are so labour intensive that it is uneconomical for pharmaceutical companies to produce them in sufficient amounts to bring them to market.

In a new study published in Nature Communications, Vincent Martin outlines a method to synthesize complex bioactive molecules much more quickly and efficiently.

One of the principal ingredients in this new technique developed by the biology professor and Concordia University Research Chair in Microbial Engineering and Synthetic Biology is simple baker's yeast.

The single-cell organism has cellular processes that are similar to those of humans, giving biologists an effective substitute in drug development research. Using cutting-edge synthetic biology approaches, Martin and his colleagues in Berkeley, California were able to produce a large amount of benzylisoquinoline alkaloid (BIA) to synthesize an array of natural and new-to-nature chemical structures in a yeast-based platform.

This, he says, can provide a blueprint for the large-scale production of thousands of products, including the opioid analgesics morphine and codeine. The same is true for opioid antagonists naloxone and naltrexone, used to treat overdose and dependence.

A long journey from gene to market

Martin has been working toward this outcome for most of the past two decades. He began with researching the genetic code plants use to produce the molecules used as drugs by the pharmaceutical industry. Then came transplanting their genes and enzymes into yeast to see if production was possible outside a natural setting. The next step is industrial production.

"We showed in previous papers that we can get milligrams of these molecules fairly easily, but you're only going to be able to commercialize the process if you get grams of it," Martin explains. "In principle, we now have a technology platform where we can produce them on that scale."

This, he says, can have huge implications for a country like Canada, which has to import most of the rare molecules used in drugs from overseas. That's especially relevant now, in the midst of a global pandemic, when fragile supply chains are at risk of being disrupted.

"To me, this really highlights the importance of finding alternative biotech-type processes that can be developed into a homemade, Canadian pharmaceutical industry," he adds. "Many of the ingredients we use today are not very difficult to make. But if we don't have a reliable supply process in Canada, we have a problem."

Healthy savings

Martin admits he is curious to see where the technology leads us. He believes researchers can and will use the new platform for the commercialization and discovery of new drugs.

"We demonstrate that by using this platform, we can start building what is called new-to-nature molecules," he says. "By experimenting with enzymes and genes and the way we grow things, we can begin making these into tools that can be used in the drug discovery process. We can access a whole new structural space."

(COLUMBUS, Ohio) - Preventing unplanned pregnancies in adolescents with effective and easy-to-use contraception is key to ensuring that adolescents do not become parents before they are ready. Adolescents view their health care providers as trusted sources of medical information. Thus, providers are tasked with providing adolescent patients with comprehensive, age-appropriate and nonjudgmental contraception counseling.

Nexplanon, the newest version of the etonogestrel (ENG) implant, is an increasingly popular contraceptive method. Inserted subdermally over the triceps muscle, this long-acting reversible contraceptive (LARC) is safe and highly effective at preventing pregnancy, among several other benefits.

"The ENG implant has become more acceptable to adolescent patients and their parents," said Elise Berlan, MD, MPH, a faculty physician in the division of Adolescent Medicine at Nationwide Children's Hospital.

Dr. Berlan and her co-authors recently published a review in the Journal of Pediatric and Adolescent Gynecology on best practices for counseling adolescents on contraception and the ENG implant.

Contraception counseling with adolescents should be patient-centered, Dr. Berlan explains. Patient-centered counseling involves assessing the patient's pregnancy intentions and addressing her contraception concerns using clear and simple language. Common contraception concerns among adolescents include autonomy in choosing to remove a LARC, the effect on future fertility and changes in vaginal bleeding. These concerns can arise after conversations with friends and family about a particular contraceptive method or after receiving poorly-explained or inaccurate contraception information from a health care provider.

"Contraception counseling works well when providers directly address the concerns that adolescents commonly have about contraception," said Dr. Berlan.

When counseling adolescents on the ENG implant specifically, providers should explain the implant's main features, such as effectiveness, reversibility and changes in vaginal bleeding.

Pregnancy while on the ENG implant is exceedingly rare. The implant is also immediately reversible with no adverse effect on future fertility. Dr. Berlan advises providers to explain that the 3-year ENG implant can be removed at any time, allowing for the desired autonomy to have the implant removed.

Unfavorable changes in vaginal bleeding, such as frequent or prolonged bleeding, are a common reason why adolescents choose to have the ENG implant removed early. To address adolescents' concerns about the bleeding, health care providers should explain that implant-associated vaginal bleeding can be unpredictable and describe how the bleeding can look.

When providing contraception counseling on the ENG implant or other contraceptive methods, Dr. Berlan cautions health care providers against advancing their agenda and unduly influencing a patient's decision on contraception. Asking questions like "How do you feel about being pregnant in the next year?" and "Are you interested in learning about birth control options today?" keeps the focus on the patient and fosters a comfortable, shared decision-making environment.

If an adolescent patient is uncomfortable discussing contraception, however, Dr. Berlan recommends that providers not force the issue. Instead, the provider should respect the patient's comfort level and maintain an open line of communication for future contraception counseling.

With the ENG implant's many benefits, health care providers can feel comfortable recommending it among other options to adolescent patients.

"The more that adolescents hear about LARC options, the more that they will be interested in and educated about choosing what is right for them," said Dr. Berlan.

LA JOLLA--Designing a vaccine starts with finding the right ingredients. Every infectious agent has molecules, called antigens, that the immune system could potentially recognize and attack. So scientists must carefully consider which antigens should go into a vaccine.

Scientists know a lot about how to design vaccines, but there are many diseases that haven't been controlled through vaccination. HIV, for example, mutates quickly and is very good at hiding from the immune system, so it is hard for scientists to figure out which antigens to include in a vaccine.

In a new Immunity study, researchers at La Jolla Institute for Immunology (LJI) show that one way to improve the body's immune response to vaccines is to factor in antigen valency. Valency refers to the number of antibody binding sites on an antigen.

"Differences in valency can impact antibody responses," says Yu Kato, Ph.D., postdoctoral fellow at LJI and first author of the new study.

You can think of antigen valency like the nubbins on Lego pieces. With a higher valency, antibodies have more sites to latch onto. But including a higher antigen valency in a vaccine doesn't mean it works better.

"Different vaccines have vastly different valencies. Diphtheria toxin is a dimer, valency of 2. Hep B vaccine is 100-120," explains Kato. "There is no clear consensus as to how the differing valencies impact B cell responses since these antigens also differ in many other ways."

For the new study, the researchers worked closely with the LJI Microscopy Core and used an advanced imaging technique called two-photon microscopy to visualize the effects of valencies on B cell responses.

The researchers discovered that high-valency antigens can lead the body to make more antibody-producing B cells. It's like the immune system sees the many targets on these antigens and takes a scatter-shot approach at hitting them. In fact, a valency of 60 seems to be enough to boost B cell numbers, and a valency of four might be enough in many cases.

"Valency matters, but you don't need a valency of 1,000 engineered into your vaccine for it to make a difference," says LJI Professor Shane Crotty, Ph.D., who co-led the new study with Professor William Schief, Ph.D., of Scripps Research.

Low-valency antigens do lead to a smaller, more targeted B cell response. These B cells are rarer, but they are more likely to be sharp-shooters. These cells are said to have a "high affinity."

Scientists have known about valency for a long time, but it had been hard to test which antigen valencies would work best in vaccines.

A big problem is that different pathogens don't just differ in valency. They also have different structures, different modes of entering cells, and different strategies for evading the immune system. This means scientists studying the effects of valency are stuck comparing apples to oranges.

"Proteins are really unique, so we had to turn it into an apples-to-apples comparison," says Crotty.

To solve this problem, the researchers teamed up with the Schief lab at Scripps Research. Schief and his colleagues had developed versions of an HIV protein with antigen valencies that ranged from one to 60. These antigens were all based on proteins from HIV, making them superior to engineered antigens used for previous valency studies. The LJI and Scripps Research teams then worked together to test the antigens in mice.

"In collaboration with the Schief lab, we developed a platform that allowed us to display different antigens," says Kato. "This platform was designed in a way that allows us to compare responses in a fair way."

The researchers concluded that while vaccines need a valency of more than one binding site, choosing a valency of four over a valency of 60 doesn't have a big effect on B cell responses.

Valency will still be an important ingredient to consider in vaccine design. For example, because HIV is hard for the immune system to recognize, the B cells that target the virus are very rare. That means high-valency antigens could help boost those rare B cell populations by spurring a more-is-better immune system reaction.

Selecting antigens with the right valency will really depend on the disease scientists are trying to target. "Depending on the type of B cells we need to prime, we need to think about which valency may be best," says Kato.

Scientists may also need to consider valency when designing COVID-19 vaccines. Different labs around the world are testing vaccines that contain antigens with many different valencies. Which will work best? "It's definitely possible to address that question, and COVID researchers are playing with ways to exploit valency effects," Kato says.

"Dr. Kato did a beautiful job elucidating the impact of valency and several other molecular parameters on vaccine responses," adds Schief. "This has been a very rewarding collaboration, and we will certainly be using information from this study in our future vaccine designs for HIV, SARS-CoV-2 and other pathogens."

A new type of breast cancer drug developed by researchers at the University of Illinois Chicago can help halt progression of disease and is not toxic, according to phase 1 clinical trials. The drug is specifically designed for women whose cancer has stopped responding to hormone therapy.

The results are published in the journal Breast Cancer Research and Treatment.

Breast cancer affects one in eight women in the United States, and while there are many types of breast cancer, around 80% are categorized as estrogen receptor-positive, or ER-positive. This means the cancer cells have receptors -- molecules that can receive signals from chemicals in the body -- that are sensitive to and react to the hormone estrogen.

In the case of ER-positive breast cancer, this means that estrogen fuels cancer growth. To treat this type of breast cancer, doctors prescribe medication to block hormone production in the body or interfere with the effect hormones have on cancer cells. This type of treatment is called hormone therapy. However, nearly half of women treated with hormone therapy become resistant, leaving traditional chemotherapy and its side effects as the only option for treatment.

"While there are many treatments for breast cancer, about half of women with ER-positive cancers become resistant to hormone therapy, leaving them with few treatments other than chemotherapy, with its well-known toxic side effects," said Debra Tonetti, professor of pharmacology at the UIC College of Pharmacy and an author on the paper.

Tonetti, together with Gregory Thatcher, the Hans W. Vahlteich Chair of medicinal chemistry at UIC and co-author on the paper, developed the new drug, called TTC-352. Preclinical studies showed that TTC-352, which is a selective human estrogen receptor partial agonist, causes complete tumor regression, but unlike tamoxifen, may pose a reduced risk of uterine cancer development.

In the phase 1 clinical trial, 15 women who had metastatic breast cancer and previously were treated with several rounds of hormone therapy and, in some cases, chemotherapy including a CDK4/6 inhibitor, were enrolled. The researchers found that there were no toxic side effects, even at the highest doses.

In total, six patients experienced stable disease with a lack of disease progression: two for 6 months and four for 3 months.

"This is very encouraging because these participants were at an advanced stage of their disease, and we saw that their cancers stopped growing for a significant amount of time," said Tonetti, who is also a member of the University of Illinois Cancer Center.

The doses given to participants were in line with what the researchers believe are therapeutic levels -- in other words, participants received doses equivalent with what patients would be given to treat their disease.

"The results of the phase 1 trial indicate that TTC-352 is a safe and tolerable alternative to chemotherapy -- therefore, without the side effects of chemotherapy -- for patients who have already been treated with hormone therapy," Thatcher said.

DARIEN, IL - A new study found that the fear of being out of mobile phone contact -- "nomophobia" -- is extremely common among college students and is associated with poor sleep health.

Preliminary results show that 89% of a sample of college students had moderate or severe nomophobia. Greater nomophobia was significantly related to greater daytime sleepiness and more behaviors associated with poor sleep quality.

"We found that college students who experience more 'nomophobia' were also more likely to experience sleepiness and poorer sleep hygiene such as long naps and inconsistent bed and wake times," said lead author Jennifer Peszka, PhD, professor of psychology at Hendrix College in Conway, Arkansas.

While Peszka anticipated that nomophobia would be common among the study participants, she was surprised by its high prevalence.

"Because our study suggests a connection between nomophobia and poorer sleep, it is interesting to consider what the implications will be if nomophobia severity continues to increase," she said.

The study involved 327 university students with a mean age of 20 years. Participants completed several questionnaires, including the Nomophobia Questionnaire, the Epworth Sleepiness Scale, and the Sleep Hygiene Index.

Peszka also noted that one common recommendation for improving sleep habits is to limit phone use before and during bedtime. However, she said that for people who have nomophobia, this recommendation could exacerbate bedtime anxiety and disrupt sleep, rather than improve it.

"The recommendation to curtail bedtime phone use, which is meant to improve sleep and seems rather straightforward, might need adjustment or consideration for these individuals," she said.

The research team included co-investigators David Mastin, PhD, and Bruce Moore, PhD, from the University of Arkansas at Little Rock, where the other co-authors are undergraduate student researchers: Shalonda Michelle, Benjamin T. Collins, Nataly Abu-Halimeh, Monnar Quattom, Maya Henderson, Madison Sanders, and Jeremiah Critton.

The research abstract was published recently in an online supplement of the journal Sleep and will be presented as a poster Aug. 28-30 during Virtual SLEEP 2020. SLEEP is the annual meeting of the Associated Professional Sleep Societies, a joint venture of the American Academy of Sleep Medicine and the Sleep Research Society.

The number of NHS patients presenting to cardiology services for serious heart problems more than halved while the number of heart attacks diagnosed fell by 40% at one centre in Scotland during the coronavirus lockdown, finds research published in the online journal Open Heart.

The period coincided with the restrictions imposed on the NHS earlier this year while it prioritised its resources to focus on coping with an anticipated surge in patients infected with COVID-19.

While the findings reflect the experiences of only one centre in the UK, they are nevertheless consistent with other research on the health consequences of lockdown measures. "Therefore, it is likely that similar changes will be seen in other medical and surgical specialties," point out the researchers.

In line with government guidelines, cardiology services adopted virtual outpatient clinics, redeployed staff to acute medical services and rescheduled non-urgent procedures, while also dealing with the cardiac complications of COVID-19, such as myocarditis (inflammation of the heart muscle), heart attack and heart failure.

How this might have directly and indirectly affected cardiology services and clinical activity hasn't been measured to date.

The researchers therefore analysed key performance indicators in cardiology services in a district general hospital (Dumfries and Galloway Royal Infirmary, Dumfries) and a supporting tertiary service (Golden Jubilee National Hospital, Glasgow) before and after lockdown.

They compared four time intervals - each one month long - from January through to May of this year to identify any changes in cardiology service provision and clinical activity.

Overall, there were significant reductions in every area of service provision, including outpatient clinics, investigations, procedures and specialist community services, such as heart failure and cardiac rehabilitation.

During the first month of lockdown, the numbers of people seen for chest pain/breathlessness fell sharply, with cardiology ward and coronary care unit (CCU) admissions falling to 39 from 83 before lockdown--a drop of 53%.

Similarly, the number of patients diagnosed with a heart attack fell by 40%:18 compared with 30 before lockdown.

There was also a significant fall in the number of acute cardiac tests performed, with a 46% reduction in cardiac troponin T blood tests--used to detect heart muscle damage (374 down from 691)--and an 87% reduction in 12-lead ECGs (26 down from 199). Inpatient ECGs also fell to 43 from 77 before lockdown, a reduction of 44%.

Even though these reductions improved during the second month of lockdown, they were still below pre-lockdown levels of activity, suggesting an ongoing fall in the overall number of patients presenting to cardiology services, say the researchers.

During lockdown, clinicians at the Dumfries hospital adopted phone and video consultations to minimise infection risks to patients and staff while new and return clinic appointments were triaged into virtual or face-to-face clinics.

Overall, the number of patients referred from primary care to cardiology outpatient clinics fell by 80% (from 386 to 76) and as a result, face-to-face clinics dropped by 93% (from 474 to 30) alongside a substantial increase in the use of the virtual clinics.

There were various reasons for these changes, such as the restructuring and prioritisation of NHS services, reduced access to primary care, and patients' reluctance to seek medical help due to fear of catching the virus, suggest the researchers.

"At the height of the pandemic, it is acceptable to deviate from the standard level of care and agreed guidelines in order to prioritise the delivery of essential services," they write.

"However, adverse consequences for some patients presenting with worsening of their underlying cardiac conditions have been inevitable. Consequently, cardiology services should be ready to offer them urgent input and early intervention."

One positive consequence of the changes brought in to deal with the pandemic has been the central role of technology in the delivery of care. The use of virtual clinics will be a "long-lasting legacy," they add.

And they warn: "As ischaemic heart disease continues to be the leading cause of death nationally and globally, cardiology services need to prepare for a significant increase in workload in the recovery phase and develop new pathways to urgently help those adversely affected by the changes in service provision."

Almost a third fewer cases of stroke and mini-stroke (TIA) were seen in US hospitals during the height of the COVID-19 pandemic between March and April this year compared to the same time in 2019, finds research published in the journal Stroke and Vascular Neurology.

This may have led to worse health outcomes for patients, who must now be encouraged to seek medical care, say the researchers.

Patients with stroke-like symptoms need urgent help to minimise the damage caused. But it is thought that many patients may have underused emergency medical services and avoided going to hospital for fear of catching SARS-CoV-2, the virus that causes COVID-19.

A team of US researchers looked at patterns in admissions for stroke and mini-strokes (TIAs) and emergency department stroke alerts to assess the impact of the pandemic on stroke services and patients.

They retrospectively compared total weekly hospital admissions, including transfers, for stroke and TIA between 31 December 2018 and 21 April 2019 and between 30 December 2019 and 19 April 2020 at five US specialist stroke centres in cities with early COVID-19 outbreaks: Boston, New York City, Providence and Seattle.

They also collected available data on emergency department stroke alerts, defined as stroke team notification of an emergency department patient with stroke-like symptoms within 24 hours of arrival; stroke severity; and time from symptom start to arrival at hospital.

Analysis of the results showed that compared with the same period in 2018-19, stroke/TIA admissions and emergency department stroke alerts fell in 2019-20. The declines coincided with US state stay-at-home recommendations in late March.

The greatest fall in stroke and TIA admissions occurred between 23 March and 19 April 2020, when there were 281 in total, compared with 410 in the same period in 2019--equal to 31% fewer admissions.

At three of the five stroke centres with stroke alert data for 2019 and 2020, emergency department stroke alerts in late March and April 2020 dropped to 301 from 561 in 2019, a fall of 46%.

But there were no differences in the time between symptom start and arrival at hospital.

The researchers acknowledge that their findings may not be representative of smaller community or rural hospitals.

Nevertheless, they conclude: "Acute stroke therapies are time-sensitive, so decreased healthcare access or utilisation may lead to more disabling or fatal strokes, or more severe non-neurological complications related to stroke.

"Our findings underscore the indirect effects of this pandemic. Public health officials, hospital systems and healthcare providers must continue to encourage patients with stroke to seek acute care during this crisis."

BOSTON - Selpercatinib (Retevmo), a drug targeted precisely against cancers driven by mutations or alterations in the gene RET, was effective in a clinical trial at shrinking tumors in patients with medullary thyroid cancer, with a majority of patients living for more than a year without disease progression.

The drug was effective both in patients with no prior treatment with targeted anti-cancer drugs and in those who had disease progression following treatment with other multitargeted agents, report Lori J. Wirth, MD, investigator in the Massachusetts General Hospital (MGH) Cancer Center, and colleagues.

"What we're seeing is a combination of very good efficacy and also very good tolerability with selpercatinib," says Wirth. "The response rates are high, responses are very durable, and overall the drug does not cause a lot of toxicity."

Wirth is the lead author of a study published in the New England Journal of Medicine reporting results of the phase 1/2 trial. The trial formed the basis for the approval of selpercatinib by the US Food and Drug Administration in May 2020 for adults and children 12 and older with advanced or metastatic RET-mutated medullary thyroid cancer who require systemic therapy, adults with metastatic RET-driven non-small cell lung cancer, and patients 12 and older with advanced or metastatic RET-fusion positive thyroid cancer resistant to radioactive iodine who require systemic therapy.

Selpercatinib is the first approved drug of its kind targeted specifically to cancers driven by mutations or alterations in the gene RET. Mutations in RET are responsible for up to 70 percent of medullary thyroid cancers (MTC), while RET gene fusions (abnormal combinations of parts of two different genes) account for one-to-two percent of all non-small cell lung cancers and ten-to-twenty percent of other thyroid cancers.

Physicians typically treat patients with RET-associated cancers with drugs that target RET and multiple other enzymes (kinases) commonly found in many different types of cancer. But the two multi-kinase inhibitors currently approved for treatment of medullary thyroid cancer, vandetanib and cabozantinib, have substantial off-target side effects that limit their use in patients with RET-driven cancers.

"If you have a clean, RET-specific inhibitor such as selpercatinib, then you can really pound down RET very strongly and hit the driver alteration much harder, with a better side effect profile," Wirth explains.

In the trial objective response rates, a measure of significant and clinically important tumor shrinkage, were 69 percent for patients with RET-mutated medullary thyroid cancers treated with selpercatinib who had previously received vandetanib, cabozantinib, or both; 73 percent in similar patients who had not received either of the other drugs; and 79 percent for patients with previously treated RET fusion-positive thyroid cancers.

In all, 82 percent of previously treated patients with medullary thyroid cancer, and 92 percent of patients who had not received either vandetanib or cabozantinib lived for at least one year without further disease progression.

The most common side effects with selpercatinib were high blood pressure, increased liver enzyme levels, decrease in sodium levels, and diarrhea, all of which were manageable. Only four of 162 patients had to stop selpercatinib because of side effects.

Wirth and colleagues have launched an international phase-three trial comparing selpercatinib with either vandetanib or cabozantinib as first-line therapy for RET-mutated medullary thyroid cancer.

CHICAGO --- When breast cancer spreads to the brain, the prognosis is grim. Patients only have about six months to live.

Women with HER2-positive breast cancer tend to develop brain metastases in up to 55% of cases. Chemotherapy drugs targeting breast cancer cells in the brain aren't effective, because they can't cross the blood-brain-barrier.

But a new combination therapy targeting breast cancer tumors in the brain dramatically decreased tumor size and increased survival in a study with mice, reports a new Northwestern Medicine study. An estimated 75% of mice that had brain metastases from breast cancer were cured and cancer-free after the therapy.

"The new combination therapy we identified can cross the blood-brain barrier," said lead study author Dr. Maciej Lesniak, Northwestern Medicine chair of neurological surgery and professor of neurosurgery at Northwestern University Feinberg School of Medicine. "The therapy also targets brain metastases and significantly improves survival."

The paper will be published on August 26 in Science Translational Medicine.

The two drugs are tubulin inhibitor, vinorelbine, approved by the U.S. Food and Drug Administration (FDA) and available in clinics, and bromodomain inhibitor, I-BET-762, FDA approved for clinical trials. The bromodomain inhibitor increased βIII-tubulin, a protein found in cancer cells that metastasize to the brain. Overexpression of βIII-tubulin sensitized cancer cells to be killed by vinorelbine.

"The findings of our work set the stage for a clinical trial, whereby patients with breast cancer brain metastases can be treated with the combination of these two drugs," Lesniak said. "This will offer patients with breast cancer brain metastases, who have been systematically excluded from clinical trials, the chance to benefit from a new therapeutic regimen that has been proven to be strongly effective in experimental settings."

Breast cancer spreads to other organs like brain, lung and bone. The metastasis of breast cancer to the brain is a terminal disease and the deadliest complication.

There is a lack of targeted therapies for breast cancer brain metastases, said first study author Deepak Kanojia, research associate in neurological surgery at Feinberg.

"Patients with brain metastases are often excluded from clinical trials due to their poor outcomes and dismal survival," Kanojia said. "Regular systemic therapies, like Herceptin, do not cross the blood-brain-barrier efficiently, and offer no benefit in brain metastases," he said.

How the study worked

Scientists developed a mouse model that can grow multiple brain metastases to simulate what happens in human patients. They injected tumor cells in the intracarotid artery, resulting in the formation of multiple brain tumors. After the tumors grew, scientists treated the mice with the combination therapy. Final results revealed that 75% of the mice that were treated with the combination were cured and cancer-free.

PULLMAN, Wash. - Social media addicted teenagers are not the only people who experience the Fear of Missing Out also known as FoMO.

In fact, not age, but aspects of self-perception--namely loneliness, low self-esteem and low self-compassion--were more closely associated with the social anxiety that other people are having fun without you, according to a recent study by Washington State University researchers published in the Journal of Social and Personal Relationships.

"FoMO is not an adolescent or young adult problem, necessarily. It's really about individual differences, irrespective of age," said Chris Barry, a WSU psychology professor and the lead author on the study. "We expected FoMO to be higher in younger age groups, particularly because of the tremendous amount of social development happening at those times, but that's not what we found."

Barry and co-author Megan Wong, a WSU undergraduate student, conducted a survey of more than 400 people across the United States from different age cohorts ranging from 14 to 47, asking a range of questions related to self-perception, life satisfaction and social media use.

The researchers found that social media use was not a good predictor of FoMO. For instance, two people with the same social media engagement may be affected quite differently: one might have few negative feelings about seeing their friends' activities while the other might find it upsetting.

"We're not all equally prone to the Fear of Missing Out, but for those who are, social media can exacerbate it," said Barry. "Social media allows you to witness what other people are doing and what's going on in their lives. If there's already concern about missing out, then there will be distress at seeing that on social media."

For people experiencing this kind of distress, Barry suggested that it may be good to reduce social media use or cut it off altogether for a period of time.

The study did find one silver-lining: while FoMO can have negative impacts, it did not appear to relate to the respondents' sense of life satisfaction. Barry said this indicates that FoMO is not an overwhelming social anxiety.

The researchers suggest that those who want to reduce their feelings of FoMO should try addressing their negative self-perceptions such as practicing better self-compassion by viewing personal setbacks as opportunities for growth, taking steps to reduce loneliness and shifting focus away from the distant experiences of others.

"To do something about FoMO, individuals can foster a greater sense of real connectedness to others which will lessen feelings of isolation. You can also try being more in the moment, concentrating on what is in front of you as opposed to focusing on what else is going on out there," Barry said.

Kanazawa, Japan - Gastric cancer, one of the leading causes of cancer-associated mortality worldwide, is renowned for its ability to disseminate throughout the peritoneal cavity. As well as causing secondary tumors in other organs, metastatic gastric cancer cells trigger extensive stromal fibrosis, or the formation of scar tissue, that can be more deadly than the cancer itself--bowel obstruction and hydronephrosis and jaundice are all common side effects of gastric cancer-associated fibrosis. What's more, the densely packed scar tissue can disturb chemotherapy drugs from reaching their target due to intra-tumoral high pressure.

Preventing fibrosis could therefore improve the prognosis for gastric cancer patients. The problem is, researchers have yet to discover what causes fibrosis, let alone how to prevent it.

But in a study published recently in Gastric Cancer, researchers from Kanazawa University found that an inflammatory protein produced by mast cells, IL-17A, triggers cellular changes in the peritoneum, leading to stromal fibrosis in gastric cancer patients.

Lead author Katsuya Gunjigake from Kanazawa University's Division of Cancer Medicine explains why the researchers targeted IL-17A.

"Over-stimulation of the immune system by IL-17A plays a major role in chronic inflammatory diseases such as rheumatoid arthritis and multiple sclerosis. It has also been associated with increased tumor growth and dissemination in various forms of cancer. Interestingly though, while studies had shown that IL-17A causes fibrosis in both Crohn's disease and lung disease, no one had investigated the link between tissue fibrosis and IL-17A in cancer."

By studying cancerous tissue from 70 gastric cancer patients with peritoneal dissemination, the researchers discovered that the degree of fibrosis was governed by the amount of IL-17A, and that IL-17A was being produced by a subgroup of white blood cells called mast cells.

Says Gunjigake, "Mast cells are most commonly associated with anaphylaxis but are also involved in pathogen defense and immune tolerance, among other things. They contain small particles called granules that are filled with molecules such as histamine, serotonin, and IL-17A that are released into the extracellular environment in a process known as degranulation."

The researchers then injected mice with human peritoneal cells and gastric cancer cells and examined the effects of IL-17A treatment, with interesting results.

"Not only did IL-17A increase tumor size and the degree of fibrosis, it also changed the structure of the peritoneal cells, enhancing their invasive and migratory capabilities," explains responsible author Sachio Fushida.

"Given the obvious role of IL-17A in driving fibrosis, our results suggest that suppression of mast cell degranulation may be a promising treatment strategy for gastric cancer patients with peritoneal dissemination."

Tribal behaviour on social media widened the gulf between Remain and Leave voters in the United Kingdom's debate whether to leave the European Union, re-aligned the UK's political landscape, and made people increasingly susceptible to disinformation campaigns, new research from the University of Bath shows.

The study focused on use of tribal language on Twitter over three years since the 2016 referendum on membership of the European Union, in particular the usage and frequency of derogatory terms such as 'Remoaner' - an insult hurled at pro-EU voters by Brexiters, who in turn might be labelled 'Brextremists' by Remainers.

"Brexit is one of the first examples of political tribalism on social media. UK voters are now divided along a new line - whether they voted Leave or Remain," said Samantha North, researcher at the University of Bath's School of Management.

"Tribalism has become a central force in today's political discussion, especially due to online influence campaigns that leverage this kind of division. Our research illustrates how political tribalism unfolds on social media over time. We hope it could provide impetus for new initiatives that aim to bring people together," she said.

North said previous studies had shown tribalism was an innate human quality to which no group was immune. But the nature of social media - Twitter in this case - meant humans were increasingly susceptible or vulnerable to disinformation and fake news.

"The need to belong to a tribe can have an effect on people's psychological biases, such as confirmation bias, the willingness to believe information that supports the tribe's viewpoint while being overly critical about information that challenges it," she said.

The research showed the four keywords - Remainer, Brexiteer, Remoaner and Brextremist - were frequently used to mark group identity. She observed that Brexit voters often accused Remain voters with language related to immaturity or childish behaviour, such as 'whining' or 'throwing the dummy out of the pram' by not supporting the outcome of the vote. They tended to characterise Remainers as arrogant, elitist and traitors.

For their part, Remainers tended to characterise the Leave side as racist, uneducated or ignorant of what they were doing.

Irony played a part too in language - with some Remainers co-opting Brexit language with the sign-off 'Proud Remoaner'.

"Tribe members use information as a way to broadcast their identity as part of the tribe and, in so doing, seek approval from other members - in the form of likes, comments and shares on social media.

This has implications for the spread of online disinformation, as the search for approval may encourage people to broadcast content that reflects the views of their tribe, regardless of whether that information is accurate," North said.

North said the study showed the tribal behaviour occurred more frequently on the pro-Brexit side, with the Leave side posting a greater number of links to partisan websites, compared with the Remain side.

The study also established that real-life events - such as the UK triggering Article 50, and the second People's Vote March - generated spikes in use of the four tribal keywords on Twitter.

North observed that the current business model for social media platforms, which rely on engagement to boost their bottom lines, was a challenge for creating a more even-handed discussion. She suggested platforms could change the algorithms that dictate what content shows up on user news feeds to make it more diverse, although she also noted that this was unlikely to happen without regulation and legislation.

"Tribalism poses a distinct risk to truth and democracy. We hope our results will help inform the discussion on how to build cohesion between warring political groups," North said.

Heart failure is an endemic disease affecting 250 000 Swedes. Despite new treatments such as modern medicines and defibrillators, the mortality rate is still high and the prognosis worse than for certain cancers. A new study from Lund University in Sweden now shows a link between cognitive impairment and an increased risk for rehospitalisation, or an early death, in heart failure patients.

Researchers at Skåne University Hospital and Lund University conducted the new study, published in the medical journal ESC Heart Failure. It is the first study in which cognitive impairment is linked to worse prognoses in a larger group of heart failure patients who have received care at Skåne University Hospital in Malmö.

Cognitive ability refers to, for example, memory, the ability to orient oneself in time and place, problem solving and the use of numbers and language.

"The patients were asked to complete three different cognitive tests within the framework for the study. The independent connection we could see was that patients who performed worse on the tests arewere at an increased risk of rehospitalisation and at an increased risk of death", says Martin Magnusson, consultant in cardiology at Skåne University Hospital and adjunct professor at Lund University.

The study looked at 281 patients of whom 80 demonstrated cognitive impairment in the tests. However, only four of them were previously aware that their cognitive ability was impaired.

"It could be that this patient group has a reduced ability to comply with evidence-based treatment recommendations - particularly if they are unaware of their cognitive impairment. However, this has not been studied", says Martin Magnusson.

Hannes Holm, resident physician in cardiology at Skåne University Hospital and post doc in Martin Magnusson's research group, emphasises that the study only shows a link between the results of the cognitive tests and the rehospitalisation and death of heart failure patients.

"As yet, we still do not know if it is the cognitive impairment that has this effect on the prognosis of heart failure patients, or if it is the heart failure itself that affects the cognition", says Hannes Holm.

It has also not been studied how heart failure patients would react to being screened for cognitive function and then receive cognitive support in their heart failure treatment.

"This is something we want to look at further. If our hypothesis is correct, it could mean that this patient group can be offered greater support in their cognitive ability, which in turn can be a simple and pragmatic way to save more lives", says Martin Magnusson.