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Certain therapies that have proven effective in treating some types of breast cancers are ineffective for women diagnosed with triple-negative breast cancer (TNBC). In fact, there is limited targeted drug therapy for this type of breast cancer -- the most aggressive type, diagnosed in about 20 percent of breast cancer patients.

But a new study by University of Notre Dame researcher Siyuan Zhang and collaborators, published in Nature Communications, shows that an existing, FDA-approved drug that treats other types of breast cancer may work for TNBC.

Zhang, the Dee Associate Professor of Biological Sciences and faculty member of the Harper Cancer Research Institute, discovered that TNBC cells may be vulnerable to a targeted therapy after his team used a whole-genome screening method that evaluated 27,000 genes at once. Unexpectedly, they identified that one gene, the death effector domain-containing (DEDD) gene, makes multiple copies of itself in more than 60 percent of TNBC tumors. Regular cells contain only two copies.

"Because the tumor expressed a very high level of this gene, we knew that the gene must do something, because evolutionarily the cell just doesn't need that many copies," Zhang said. "There's no reason for it to be there; it's inefficient."

The gene acts essentially like a spark plug in a car, encouraging it to run, and the cell becomes addicted to the protein the DEDD gene releases. "The cell needs to consume more and more, but it also makes the cells very vulnerable," Zhang said, likening the process to a person who is addicted to drugs.

Traditional therapies for breast cancer include radiation therapy, chemotherapy or surgery, which have been the primary options for treating TNBC. More recently, gene-based, targeted therapy has been added to the mix for other types of breast cancer. Targeted anti-cancer therapy allows researchers to tackle one feature of a cancer cell that makes it vulnerable to a drug, but which other, "normal" cells don't have. "Targeted therapy works really well, and everybody tries to find unique markers for each type of cancer, so the drug therapy can target it," Zhang said. "But triple-negative breast cancer is a type that doesn't have a clear marker yet."

Zhang's research showed that one of the targeted drugs used to treat other types of breast cancer, called a CDK4/6 inhibitor, combined with another FDA-approved anti-cancer drug, an EGFR/HER2 inhibitor, killed TNBC cells.

Researchers may take the information from Zhang's study to begin clinical trials, or, because the drug is already FDA-approved, offer the new treatment off-label.

Repurposing FDA-approved drugs for new patient groups is one of Zhang's passions and what he looks toward when designing his mechanistic studies of how cancer cells live and die. Treatment using a repurposed drug is faster to implement because new drugs may not be available for years, but "for repurposed drugs, we already have a safety profile out there, and know how they work in certain tissue context," Zhang said.

BOSTON - Knowledge of the biological processes involved in the development of the uterus is important for understanding uterine health and fertility. A research team led by investigators at Massachusetts General Hospital (MGH) has uncovered important insights on a type of cell that is critical for the formation of a functioning uterus.

These cells are defined by their expression of Misr2+, the receptor for Mullerian Inhibiting Substance (MIS), which is secreted by the testes of male embryos to prevent the maturation of structures that would give rise to female reproductive organs.

While it is not surprising that Misr2+ cells would play a role in inhibiting the formation of a uterus in males, researchers found that these cells also actively participate in the formation of the uterus in females. The findings are published in eLife.

"The fate of these reproductive gatekeeper cells in the female, in the absence of MIS, was unknown," says senior author David Pépin, PhD, an assistant molecular biologist at MGH and an assistant professor of Surgery at Harvard Medical School. "In this study, we found that in females the cells continued to express the receptor to MIS, past the period of sexual differentiation in mice, rats, and humans. Furthermore, we showed that in rodents, these cells retained sensitivity to MIS, even after birth."

Treating rodents with MIS during the first week after birth interfered with uterine development and led to infertility later in life. "The findings suggest that the period of response to sexual differentiation signals in mammals may not be as restricted as previously thought," says Pépin.

To uncover more details, the scientists analyzed cells in the uterus of newborn rodents following treatment with MIS, and discovered that certain key cell types that contribute to the uterus' endometrium (the lining) were absent. The investigators suspect that Misr2+ cells normally develop into these cell types but were blocked when exposed to MIS.

"In the absence of these cells, a large number of important signals are disrupted, leading to abnormal uterine development," says Hatice Duygu Saatcioglu, the first author of the study. "This period is so critical for the specification of the uterine layers, that exposure to MIS for just a few days after birth leads to irrecoverable infertility later in life, with adults having a thin uterus composed almost entirely of myometrium," says Saatcioglu.

Patricia K. Donahoe, MD, a coauthor and director of surgical research laboratories at MassGeneral Hospital for Children (MGHfC), herself a longtime investigator of MIS functions, notes that the results may provide a better understanding of infertility caused by problems with the uterus. "Finding cells marked by Misr2 allows further investigation of how these cells can contribute to uterine pathologies causing infertility."

Conversely, some of the study's findings related to MIS may also be relevant to men, including those with a rare disorder called persistent Mullerian duct syndrome in which tissues such as the uterus may be partially retained due to mutations in MIS or its receptor.

BIRMINGHAM, Ala. - A de novo gene mutation that encodes a brain protein in a child with autism has been placed into the brains of mice. These mice then showed severe alterations of specific behaviors that closely resemble those seen in human autism spectrum disorder, or ASD.

This major finding from a study published in the Journal of Clinical Investigation "presents the exciting possibility of a potential mechanistic underpinning -- in at least a subset of patients -- for some of the altered behaviors observed in ASD and attention deficit hyperactivity disorder, or ADHD," said Aurelio Galli, Ph.D., professor of surgery at the University of Alabama at Birmingham.

The research was led by corresponding authors Galli and Mark Wallace, Ph.D., a neurobiologist and dean at Vanderbilt University.

The brain protein studied is the dopamine transporter, or DAT. Certain brain neurons release the neurotransmitter dopamine from the ends of their axons. The dopamine crosses the junction, or synapse, between that axon and a neighboring neuron, triggering a response in that receiving neuron. DAT -- which sits in the membrane of the transmitting neuron -- has the job of dopamine reuptake, pumping released dopamine back into the transmitting neuron from the synapse, thereby terminating the response of the receiving neuron.

Brain activity involving the dopamine system in the region of the brain called the striatum is a critical regulator of motor activity, motivation, attention and reward processing. Given the integral role of the dopamine system in critical brain functions, it is no surprise that dysregulation of this neurotransmitter system has been implicated in neuropsychiatric disorders that include Parkinson's disease; substance abuse with heroin, cocaine, speed, nicotine and other drugs; bipolar disorder; ADHD; and recently ASD.

Galli, Wallace and colleagues studied a mutation in the gene for human DAT that was found in a child with ASD. This mutation generates a substitution at amino acid 356 of DAT, a change from threonine to methionine, so the mutant DAT is called DAT T356M.

A previous study led by Galli and Eric Gouaux, Ph.D., a professor at the Oregon Health & Science University, introduced the mutation into fruit fly DAT; in the flies, the DAT T356M produced abnormal behaviors of increased locomotor activity, fear, repetitive activity and altered social interaction, reminiscent of autism impairments. Bacterial studies suggested that DAT T356M is flipped inside-out compared with normal DAT, so that DAT T356M anomalously pumps dopamine out of a cell rather than into the cell.

Now Galli, Wallace, and M.D./Ph.D. student Gabriella DiCarlo have reported the first study of DAT T356M in a mammalian brain.

Mice that were homozygous with two copies of the DAT T356M gene mutation showed severe changes in behavior that resemble human ASD and ADHD behaviors and significant alterations in brain physiology. ADHD is a common comorbidity of ASD. In contrast, no changes were seen in mice that had only one copy of the DAT T356M gene mutation, as compared with normal mice.

The mice with DAT T356M showed a loss in social interactions, a loss of social dominance and diminished marble burying, an innate behavior of lab mice that is motivated by their desire to investigate. The mice with DAT T356M showed repetitive rearing behavior and enhanced learning of how to keep balance on a rotating rod, which is linked to the propensity toward repetitive behavior.

The DAT T356M mice also showed hyperactivity, as measured by increased spontaneous locomotor activity. Significantly, when the mice were treated with two different compounds that block DAT activity, their hyperactive behavior decreased. "Future work should aim to determine whether blockade of the DAT may eliminate or alleviate the more complex behavioral changes observed in DAT T356M animals," Galli said.

The altered social behavior and the hyperactivity were linked to altered dopamine neurotransmitter signaling activity in the brains of DAT T356M mice. At the physiological level, the researchers found impaired striatal dopamine neurotransmission and clearance.

A novel sensor designed by MIT researchers could dramatically accelerate the process of diagnosing sepsis, a leading cause of death in U.S. hospitals that kills nearly 250,000 patients annually.

Sepsis occurs when the body's immune response to infection triggers an inflammation chain reaction throughout the body, causing high heart rate, high fever, shortness of breath, and other issues. If left unchecked, it can lead to septic shock, where blood pressure falls and organs shut down. To diagnose sepsis, doctors traditionally rely on various diagnostic tools, including vital signs, blood tests, and other imaging and lab tests.

In recent years, researchers have found protein biomarkers in the blood that are early indicators of sepsis. One promising candidate is interleukin-6 (IL-6), a protein produced in response to inflammation. In sepsis patients, IL-6 levels can rise hours before other symptoms begin to show. But even at these elevated levels, the concentration of this protein in the blood is too low overall for traditional assay devices to detect it quickly.

In a paper being presented this week at the Engineering in Medicine and Biology Conference, MIT researchers describe a microfluidics-based system that automatically detects clinically significant levels of IL-6 for sepsis diagnosis in about 25 minutes, using less than a finger prick of blood.

In one microfluidic channel, microbeads laced with antibodies mix with a blood sample to capture the IL-6 biomarker. In another channel, only beads containing the biomarker attach to an electrode. Running voltage through the electrode produces an electrical signal for each biomarker-laced bead, which is then converted into the biomarker concentration level.

"For an acute disease, such as sepsis, which progresses very rapidly and can be life-threatening, it's helpful to have a system that rapidly measures these nonabundant biomarkers," says first author Dan Wu, a PhD student in the Department of Mechanical Engineering. "You can also frequently monitor the disease as it progresses."

Joining Wu on the paper is Joel Voldman, a professor and associate head of the Department of Electrical Engineering and Computer Science, co-director of the Medical Electronic Device Realization Center, and a principal investigator in the Research Laboratory of Electronics and the Microsystems Technology Laboratories.

Integrated, automated design

Traditional assays that detect protein biomarkers are bulky, expensive machines relegated to labs that require about a milliliter of blood and produce results in hours. In recent years, portable "point-of-care" systems have been developed that use microliters of blood to get similar results in about 30 minutes.

But point-of-care systems can be very expensive since most use pricey optical components to detect the biomarkers. They also capture only a small number of proteins, many of which are among the more abundant ones in blood. Any efforts to decrease the price, shrink down components, or increase protein ranges negatively impacts their sensitivity.

In their work, the researchers wanted to shrink components of the magnetic-bead-based assay, which is often used in labs, onto an automated microfluidics device that's roughly several square centimeters. That required manipulating beads in micron-sized channels and fabricating a device in the Microsystems Technology Laboratory that automated the movement of fluids.

The beads are coated with an antibody that attracts IL-6, as well as a catalyzing enzyme called horseradish peroxidase. The beads and blood sample are injected into the device, entering into an "analyte-capture zone," which is basically a loop. Along the loop is a peristaltic pump -- commonly used for controlling liquids -- with valves automatically controlled by an external circuit. Opening and closing the valves in specific sequences circulates the blood and beads to mix together. After about 10 minutes, the IL-6 proteins have bound to the antibodies on the beads.

Automatically reconfiguring the valves at that time forces the mixture into a smaller loop, called the "detection zone," where they stay trapped. A tiny magnet collects the beads for a brief wash before releasing them around the loop. After about 10 minutes, many beads have stuck on an electrode coated with a separate antibody that attracts IL-6. At that time, a solution flows into the loop and washes the untethered beads, while the ones with IL-6 protein remain on the electrode.

The solution carries a specific molecule that reacts to the horseradish enzyme to create a compound that responds to electricity. When a voltage is applied to the solution, each remaining bead creates a small current. A common chemistry technique called "amperometry" converts that current into a readable signal. The device counts the signals and calculates the concentration of IL-6.

"On their end, doctors just load in a blood sample using a pipette. Then, they press a button and 25 minutes later they know the IL-6 concentration," Wu says.

The device uses about 5 microliters of blood, which is about a quarter the volume of blood drawn from a finger prick and a fraction of the 100 microliters required to detect protein biomarkers in lab-based assays. The device captures IL-6 concentrations as low as 16 picograms per milliliter, which is below the concentrations that signal sepsis, meaning the device is sensitive enough to provide clinically relevant detection.

A general platform

The current design has eight separate microfluidics channels to measure as many different biomarkers or blood samples in parallel. Different antibodies and enzymes can be used in separate channels to detect different biomarkers, or different antibodies can be used in the same channel to detect several biomarkers simultaneously.

Next, the researchers plan to create a panel of important sepsis biomarkers for the device to capture, including interleukin-6, interleukin-8, C-reactive protein, and procalcitonin. But there's really no limit to how many different biomarkers the device can measure, for any disease, Wu says. Notably, more than 200 protein biomarkers for various diseases and conditions have been approved by the U.S. Food and Drug Administration.

"This is very general platform," Wu says. "If you want to increase the device's physical footprint, you can scale up and design more channels to detect as many biomarkers as you want."

Rheumatoid arthritis patients getting little or no relief from conventional small-molecule drugs and injectable biologic drugs saw substantial improvement in their condition from daily use of an experimental compound in a large 24-week study led by a Stanford University School of Medicine investigator.

A paper describing the results of the double-blind, randomized phase-3 clinical trial will be published July 23 in JAMA.

"For patients who haven't done well on other therapies, these findings are cause for optimism, enthusiasm and hope," said Mark Genovese, MD, professor of immunology and rheumatology and principal investigator of the study.

Stanford Health Care offers services to rheumatoid arthritis patients through its immunology and rheumatology clinic. As clinical chief, Genovese spends 3 half-days per week in the clinic, where he regularly sees and treats rheumatoid arthritis patients.

He is the paper's lead author. The senior author is Tsutomu Takeuchi, MD, PhD, professor of rheumatology and clinical immunology at Keio University School of Medicine in Tokyo, Japan.

Rheumatoid arthritis is a progressive, systemic autoimmune disease affecting at least 1 in every 100 people worldwide. For reasons that aren't understood, 3 of every 4 people with the disorder are women. While its most visible hallmarks are pain, stiffness, inflammation and eventual deterioration of joints, patients also are at heightened risk for cardiovascular disease and other inflammatory complications.

In clinical trials, about 70% of rheumatoid arthritis patients have appeared to benefit initially from small-molecule therapies in a pill form, such as methotrexate, said Genovese, who is the James W. Raitt M.D. Professor. However, "in the real world, adherence to any of them is more like 50%," he said. Patients for whom the conventional small-molecule drugs fail are switched to pricey, injectable, bioengineered-protein drugs, including three of the world's top-15 biggest-selling drugs in dollar sales. But these drugs, too, fail among about half the rheumatoid arthritis patients who use them, Genovese said.

Selective JAK-1 inhibitor

The experimental compound, filgotinib, is a selective JAK-1 inhibitor. It works by preferentially blocking 1 of a set of 4 closely related enzymes required for certain inflammatory signaling processes within cells. Two other compounds that are similar in mechanism of action to filgotinib but that impede JAK enzyme family members less selectively are licensed in the United States for use by rheumatoid arthritis patients, but only at low doses or with warning labels due to side effects.

The trial was conducted in 114 centers in 15 countries, mostly in North America and Europe. The 449 participants averaged 56 years of age, and about 80% of them were female. They were randomized to 1 of 3 study arms, in which they received daily doses of either 200 milligrams of filgotinib, 100 milligrams of filgotinib or a placebo for 24 weeks. All participants had moderately to severely active rheumatoid arthritis despite treatment with one or more biologic therapies.

The primary goal of the study was to observe whether there was an improvement at 12 weeks into the trial of at least 20% on a measure of joint swelling and tenderness called the ACR20 that was established by the American College of Rheumatology. An important secondary outcome was a score indicating low disease activity in 28 predetermined joints on a test called the DAS28-CRP.

Compared with the placebo group, a significantly greater proportion of participants on both the high- and low-dose filgotinib regimens achieved the primary endpoint: a 20% improvement in symptoms as measured by the ACR20. Sixty-six percent of participants on 200 milligrams of filgotinib, and 57.5% of those on 100 milligrams, fulfilled this criterion, versus only 31.1% of those on placebo.

Of equal or even greater importance, Genovese said, was the participants' improvement on the DAS28-CRP at both 12 and 24 weeks. By 12 weeks, 40.8% of those on the 200 milligram dose of filgotinib and 37.3% of those on 100 milligrams had reached the status of low disease activity as measured by the DAS28-CRP, as opposed to only 15.5% of those on the placebo regimen. These outcomes continued or improved over the course of the trial. By 24 weeks, 48.3% of the high-dose filgotinib recipients and 37.9% of those on the low dose had reached low-disease-activity status.

By week 12 of the trial, 22.4% of high-dose and 25.5% of low-dose filgotinib recipients, but only 8.1% of placebo recipients, had DAS28-CRP scores indicating outright remission. By week 24, high-dose recipients had a remission rate of 30.6%; low-dose recipients, 26.1%; and placebo recipients, 12.2%.

Improvement seen early on

The drug's benefits to participants became apparent soon after the trial's onset. "We could see improvements as early as two weeks into the trial," Genovese said.

Also telling was a substantial difference among the study arms in how many participants completed the 24-week trial. Of the 148 participants in the placebo arm, 51 dropped out before completion. Only 20 of the 148 high-dose recipients and 34 of the 153 low-dose recipients dropped out.

Investigators' early concerns about increased susceptibility to infections, or the re-emergence of active forms of prior infections, such as tuberculosis or shingles, were assuaged by the relative smattering of such adverse events, compared with placebo.

Notably, patients for whom at least three different biologic therapies provided insufficient relief did as well in this trial as those who'd derived insufficient relief from just one biologic therapy, Genovese said.

"We found that those high levels of response were independent of how many drugs you'd failed, and independent of which drugs you'd failed," he said.

Overall response rates to filgotinib appear to surpass those of the other commercially available JAK inhibitors at doses approved for use in the United States, he said.

"This novel drug works exceptionally well in patients who've already failed traditional therapies for rheumatoid arthritis," he said.

WASHINGTON (July 23, 2019) - Physicians and consumers agree that self-care is important to health and well-being, yet 75 percent of patients say they haven't discussed self-care with their physician within the last two years, according to a new survey released today, conducted by The Harris Poll on behalf of Samueli Integrative Health Programs. Nearly half of doctors (46%) say patients do not seem very interested in the topic, while a majority of patients (72%) say they are interested in discussing self-care with their healthcare provider, which includes lifestyle changes, healthy diet, regular exercise, stress management, and other alternatives to conventional medical treatment.

"Encouraging patients to incorporate self-care practices into their daily lives is not only important for their health, it's a critical component in reducing our country's chronic disease burden," said Wayne Jonas, MD, executive director of Samueli Integrative Health Programs. "In order to truly make a difference in the health of our patients, the future of primary care - indeed all healthcare - must address the patient as a whole person and take an integrative health approach to guide and support healthy behaviors outside the clinic."

The survey - involving more than 1,000 U.S. adults ages 18 and older and more than 300 family medicine and internal medicine physicians - found that while more than nine in 10 physicians (96%) say self-care should be considered an essential part of a patient's overall health, only 39 percent of consumers say they practice it often. The survey was conducted online by The Harris Poll on behalf of Samueli Integrative Health Programs in May and June 2019.

What is Self-Care?

The survey found that despite common depictions of self-care as indulgences such as shopping and pampering, consumers understand that self-care is a broad concept that encompasses physical, mental, emotional, social, and spiritual needs. They report their top self-care practices as getting enough sleep (66%), eating healthy foods (62%), taking care of their mental health (60%), and exercising (59%).

Patients Want More Guidance

Although physicians think patients have limited interest in such topics, a majority of patients would be interested in talking to their doctors about what's important in their lives (57%), and about their life goals (55%). About two-thirds of patients wish their physician shared more resources on self-care (66%), were involved in all aspects of their health management (65%), and incorporated complementary and alternative therapies into their care (64%).

"What these results show us is that patients have a strong desire for their physicians to be involved in more aspects of their health - beyond pills and procedures," said Jonas. "They want a fuller partnership and a relationship where they can discuss their health and well-being in other, deeper ways that impact them. As physicians, it's important that we listen to these desires and adjust how we treat our patients. We need to organize our practices to support behavior change."

Barriers and Disconnects

Doctor-patient disconnects emerged on several points:

Despite knowing the importance of self-care, 43 percent of consumers say they have more pressing issues to focus on, and more than one in four (28%) say they feel guilty when practicing self-care. Women are more likely than men to cite any barriers to self-care (77% vs. 68%). Specifically, women are more likely to be too tired (31% vs. 20%) or to feel guilty for taking time for themselves (16% vs. 7%).

The top reason that physicians cite for not discussing topics related to self-care more often is a lack of time during appointments (78%). More than nine in 10 (93%) would like to be able to provide their patients more information on self-care, but only one in four (26%) feel very confident in doing so.

Other highlights of the study findings include:

Forty-four percent of consumers believe self-care is only possible for people with enough time, and 35 percent believe self-care is only possible for those with enough money.

80 percent of physicians say it's very important for them personally to practice self-care, but only 57 percent report doing so often.

A majority of physicians (59%) say the demands of their job prevent them from practicing self-care as much as they would like.

One in four physicians (25%) report that feeling burnt out prevents them from practicing self-care.

Nearly the same proportion of physicians and consumers say they are prevented from practicing self-care because they are unable to get out of bad habits (20% and 19%, respectively).

Researchers at the Icahn School of Medicine at Mount Sinai have developed a novel vaccine consisting of DNA and recombinant proteins?proteins composed of a portion of an HIV protein and another unrelated protein. This vaccine was tested in monkeys and was shown to induce antibodies similar to those associated with protection from HIV, the virus that causes AIDS.

Researchers first identified a part of the virus which, when bound to antibodies, results in the destruction of the virus and of virus-infected cells. Then they designed a vaccine that would induce these types of antibodies. This approach to vaccine design is called "reverse vaccinology."

The target identified by the researchers on the virus is called the V1V2 loop of the gp120 envelope protein. In studies of monkeys vaccinated with gp120 DNA and a combination of three novel recombinant proteins carrying the V1V2 region, antibodies were induced that display many different antiviral functions. These antibodies were of the type that had been associated with a reduced rate of HIV infection in previous human clinical trials, according to the study published in Cell Reports in July.

"Our lab, together with researchers from several institutions in the United States, has been working for more than a decade on a novel approach to developing a vaccine against HIV/AIDS," said lead author Susan Zolla-Pazner, PhD, Professor of Medicine and Microbiology at the Icahn School of Medicine at Mount Sinai. "The vaccine we have developed is safe, in that it contains nothing that is infectious to the individual vaccinated. In the study now being published, we show that this novel vaccine induces the desired antibodies in monkeys, which suggests strongly that similar protective antibodies can be induced in humans and may play an important role in preventing HIV infection."

Showing that a vaccine will induce antibodies in monkeys is important since it suggests that humans will react similarly. The successful production of antibodies in monkeys with the novel vaccine studied in this report indicates that the vaccine should move forward to first-in-human studies to determine if it is as safe, well-tolerated, and immunogenic as it was in monkeys.

Hyperglycemia, or high levels of glucose, is common in patients with acute ischemic stroke and is associated with worse outcomes compared to normal blood sugar levels. Animal studies also pointed to an effect of high blood sugar in worsening stroke injury. Stroke experts have debated whether intensive glucose management after acute ischemic stroke leads to better outcomes but a new study in JAMA finds that aggressive methods are not better than standard approaches. The study was supported by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

"After decades of uncertainty about how to manage blood sugar in acute stroke patients we finally have strong clinical evidence that aggressive lowering does not improve patient outcome," said Walter Koroshetz, M.D., NINDS director.

The Stroke Hyperglycemia Insulin Network Effort (SHINE) study, a large, multisite clinical study led by Karen C. Johnston, M.D., professor of neurology and Associate Vice President of Clinical & Translational Research at the University of Virginia, Charlottesville, compared two commonly used strategies for glucose control in ischemic stroke patients. More than 1100 patients underwent intensive glucose management, which required the use of intravenous delivery of insulin to bring blood sugar levels down to 80-130 mg/dL, or standard glucose control using insulin shots, which aimed to get glucose below 180 mg/dL, for up to 72 hours. After 90 days, the patients were evaluated for outcomes, including disability, neurological function, and quality of life.

The results suggested that the two treatments were equally effective at helping the patients recover from their strokes. After 90 days, about 20% of the patients showed favorable outcomes regardless of whether they were given intensive or standard treatment.

Intense glucose therapy increased the risk of very low blood glucose (hypoglycemia) and required a higher level of care such as increased supervision from nursing staff, compared to standard treatment.

The study was stopped early when a pre-planned interim analysis revealed that intensive glucose control did not improve outcomes compared to standard treatment.

"We found that the extra risks associated with aggressive treatment were not worth it," said Dr. Johnston. "We are so grateful to the patients and research teams from across the country who helped us answer this important question. As a result of their participation, patients around the world will benefit."

This study was supported by NINDS' Neurological Emergencies Treatment Trials (NETT) Network, a system of research institutions dedicated to emergency medical issues, including stroke. The study was also conducted in collaboration with NINDS' StrokeNet, which is a network of hospitals providing resources for multi-site clinical trials evaluating new therapies to treat stroke.

More research is needed to better understand the role of glucose in stroke recovery and to identify additional treatments to improve outcomes in hyperglycemic stroke patients. Future studies will also determine whether high blood sugar is a cause or effect of unfavorable stroke outcomes.

Whether they need to commiserate about the trials of parenthood, get advice, or simply brag about their youngsters' achievements, today's parents often turn to an ever-ready forum: social media.

Mariea Grubbs Hoy, DeForrest Jackson Professor in the School of Advertising and Public Relations in the College of Communication and Information, worked with Alexa K. Fox, an assistant professor of marketing at the University of Akron, to study "sharenting," a parent's habitual use of social media to share news and images about their children. Their findings were published in "Smart Devices, Smart Decisions? Implications of Parents' Sharenting for Children's Online Privacy: An Investigation of Mothers" published online in the Journal of Public Policy and Marketing.

In two related studies, Fox and Hoy found evidence that women's feelings of vulnerability about being a mother are linked to their posting on social media--and those posts sometimes include their children's personally identifiable information, such as names, birthdates, and photographs.

"Providing updates on [a child's] progress with posts of photos, videos, and other personal information about the child has almost become a social norm, but it puts the child's online privacy and, potentially, safety at risk," the researchers wrote.

The researchers suggest the need for enhanced governmental guidance to protect children's online privacy from commercial entities. They also suggest that parents need more education about the consequences of sharing their children's personal information.

While the Children's Online Privacy Protection Act prevents marketers from collecting data from children 12 and younger without parental permission, that regulation was enacted in 1998--six years before Facebook launched.

"Today's parents, many of whom grew up sharing their own lives on social media, may not comprehend the full impact and potential consequences of posting such information about their children," they wrote.

Their research suggests that mothers are "an important yet under-addressed vulnerable consumer segment who may be uniquely susceptible to particular types of social media marketing engagement tactics."

In their first study, Fox and Hoy interviewed 15 experienced and first-time mothers ages 24 to 40. The interviewees were all Caucasian, highly educated, and had children ranging in age from 14 weeks to 11 years. The women reported using social media anywhere from less than 30 minutes to nearly two hours per day.

They asked the women about their feelings regarding motherhood and whether they post content about their children on social media. They also asked questions to gauge the women's understanding of information co-ownership, privacy rules, and other principles of social media behavior. Finally, they asked questions to determine if the women were willing to share personally identifiable information about their children when engaging with a commercial brand on social media.

The women articulated a variety of risk factors for vulnerability--a changing body, a changing view of self, new responsibilities associated with motherhood, demands of nursing, exhaustion, and issues such as postpartum depression or anxiety.

"Posting about their experiences and sharing personal information about themselves and their children served as a coping strategy, primarily related to seeking affirmation/social support or relief from parents stress/anxiety/depression," the researchers wrote.

"Every mother mentioned posting milestones ranging from the infant reaching the 'month birthdays' to children's firsts and other 'cute' moments. They then waited, at times eagerly, for affirmation in the form of likes or comments."

At the same time, the researchers note, the mothers acknowledged concerns about other social media users sharing their information in unwelcome ways.

In their second study, Fox and Hoy gathered data from a Twitter chat by Carter's Inc, a children's apparel company, to see how feelings of vulnerability seemed to influence mothers' willingness to share their children's personally identifiable information with a business.

Some companies provide engagement opportunities though social media marketing tactics such as contests and virtual chats, or by asking parents to post stories, photos, and videos about their children. By doing this, "they may also be triggering sharenting," the researchers wrote.

"The chat provided a case study opportunity to observe how a brand creates a social media event designed to generate engagement with mothers of young children that might prompt the mothers to post their children's personally identifiable information."

The Twitter chat involved 116 unique participants, all mothers, who generated 1,062 original tweets. The company tweeted a link to their disclosure that said the company would own all content and could share it with anyone without compensating the parents.

Carter's asked 10 questions, tweeted a coupon and link to their website, tweeted several affirming comments in response to photos, and concluded by soliciting child photos, tweeting "We'd love seeing your little one today!"

The researchers determined that 69 percent of the participants posted something indicating they felt vulnerable as a parent. Forty-seven percent of the participants posted some aspect of their child's personally identifiable information in response to at least one question. About a third of the participants posted something that expressed their vulnerability and also revealed personally identifiable information about their child.

"In other words, if a mother did not express a risk factor for vulnerability during the chat, we saw less sharing of her children's personally identifiable information," the researchers concluded.

"This area is ripe for future research," the researchers said. Future studies need to explore how new fathers, single parents, and grandparents may experience vulnerability, and explore parents' motivations to post on social media and engage with brands.

"Academics and practitioners alike should seek to understand the pressures of being a 'good mother' (or father or grandparent) in an increasingly technologically connected society."

The large-scale analysis carried out by La Trobe University researchers and published in Heart found that many Australians living with CHD are under-prescribed recommended medications, are not monitored for major risk factors and have treatments that do not achieve recommended goals. In particular, women and those aged less than 45 years were more likely to be under-treated compared with similarly affected men and older people.

The study, led by La Trobe epidemiologist Professor Rachel Huxley, analysed GP records of 130,926 patients with a history of CHD from 2014-2018. Findings included:

Women were less likely than men to be prescribed with any of the four recommended medications for CHD, namely antiplatelet agents, ACE inhibitors, beta-blockers and statins

Of the four medications recommended for daily use, only about 22 per cent of women and 34 per cent of men were prescribed all four

In contrast, 21 per cent of women and 10 per cent of men were not prescribed any of these four medications

According to Australian Institute of Health and Welfare figures for 2015, 44 per cent of all deaths from CHD are women, and CHD remains a leading cause of death among women in Australia.

"There's a widely-held assumption that CHD only affects older men, but almost half of people who die from the disease are women," Professor Huxley said.

"Our study shows that people with a history of CHD, particularly women and people aged less than 45 years, are less likely to have their condition managed according to current clinical guidelines. Despite the differences in CHD management, women were more likely to achieve treatment targets than men."

Professor Huxley said sex disparities in the management of CHD in primary practice needed addressing to improve the outcomes for all affected people and their families.

The National Heart Foundation welcomed the latest findings. The Foundation's Director of Prevention, Ms Julie Anne Mitchell, said research consistently highlighted that women were "invisible when it comes to heart disease".

"Heart health checks, lifestyle changes and appropriate medications are just as important for women as they are for men, and these findings challenge all clinicians to keep this in mind when assessing patients," Ms Mitchell said.

"Australian research highlights that total healthcare spending on women with heart disease is less than half of that spent on men, and this latest research shows yet again why we need to redress the imbalance," she said.

The research was funded by a National Heart Foundation of Australia Vanguard Grant, with data accessed from Medicine Insight, a national GP data program.

Individuals at high risk for cardiovascular events, including those with familial hypercholesterolemia (FH) or atherosclerotic heart disease (ASCVD) experienced more heart attacks, strokes and other cardiovascular events when they were unable to obtain their prescribed LDL-cholesterol lowering medication.

In a new study published today in Circulation: Cardiovascular Quality and Outcomes, researchers with the FH Foundation found that individuals with ASCVD or FH whose PCSK9 inhibitors (PCSK9is) were rejected by their insurance plan had an immediate 16 percent increased risk of a cardiovascular event during the 12-month study period.

High cholesterol is a major risk for heart disease, which is the number one killer worldwide. PCSK9is have been shown to lower LDL-cholesterol and improve cardiovascular outcomes in multiple randomized trials, yet many individuals unable to obtain treatment.

"Over eighty thousand individuals at high risk for cardiovascular events experienced delays in treatment. Unprecedented high insurance denials, high drugs costs and related out-of-pocket costs resulted in individuals not receiving therapy and caused a significant increase in cardiovascular events, including heart attacks and stroke. In other words, real people had real heart attacks and strokes because they could not get the medicine prescribed by their doctors," said Kelly Myers, FH Foundation chief technology officer and study author.

To identify whether rejected, unfilled or paid PCSK9i prescriptions had an impact on outcomes, researchers analyzed healthcare encounter data from 139,036 individuals over the age of 18 between August 2015 and December 2017. A status of "paid prescription" was assigned to those who received 338 or more days of therapy within 12 months, "rejected" if the final claims status was rejected, and "unfilled" if the prescription was approved but not filled.

In addition, individuals who did not fill their prescriptions had an immediate 21 percent increased risk of a cardiovascular event during the study period. Approximately 65 percent of unfilled claims were among Medicare patients, likely due to higher co-pay costs.

Myers added, "Higher co-pays led to more individuals giving up their therapy even if they were approved. Unfortunately, we found these treatment delays disproportionately impact the most vulnerable groups, including women, minorities and individuals with lower incomes, who are already undertreated for heart disease."

The study also revealed that individuals with FH, a common genetic condition that causes high LDL-cholesterol from birth, are at an even greater risk than other high-risk groups in the study. All of the individuals in the study had a seven-times higher risk of cardiovascular events than the general population. In addition, individuals with FH had a further three-times increased risk of a cardiovascular event compared to those in the study that did not have FH or ASCVD. In fact, individuals with FH had no difference in risk of a cardiovascular event compared to someone with diagnosed ASCVD. The study's highest risk group was an individual with FH who also had cardiovascular disease. This group had more than five-times the risk of other individuals in the study that did not have FH or ASCVD. Yet, 63 percent of their prescriptions were rejected.

"While we know that someone who has had a heart attack or other cardiovascular event is much more likely to have a second event and is at much higher risk than the general population, this new finding underscores that individuals with FH are at as high a risk. It is imperative that we initiate comprehensive treatment early in life, and that individuals receive the medications they have been prescribed," said Daniel J Rader, M.D., chair of the department of Genetics in the Perelman School of Medicine at the University of Pennsylvania, Chief Scientific Advisor of the FH Foundation and senior author of the paper.

"This real-world evidence highlights how much at risk FH individuals are for a heart attack or surgical intervention if their LDL-C is not adequately lowered. Individuals like myself, who have FH and have had a heart attack, are at the highest immediate risk of a life-threatening cardiovascular event, yet over two-thirds of prescriptions for this group are still being rejected," said Katherine Wilemon, Founder and CEO of the FH Foundation.

A new study, "Wavelength-encoded laser particles for massively multiplexed cell tagging," by scientists in the Wellman Center for Photomedicine has been published in Nature Photonics.

According to the study's researchers, "We have developed a new class of probes, laser particles, which are tiny lasers that can be inserted inside living cells. These laser particles are biocompatible, occupy only 0.1% of the volume of a typical cell and don't interfere with its normal behavior. We use the light emitted by these probes to tag and track cells as they move throughout complex biological samples. They can be thought as barcodes that can be used to distinguish cells from one another.

Conventional probes used to tag cells are based on fluorescence emission; scientists use different fluorescent molecules with different colors to distinguish different cells. Due to intrinsic limitations, however, fluorescence can only provide a handful of distinguishable colors, usually up to 4-5. Our new probes emit laser light, which can produce many more distinguishable colors, around 400 in this work.

We have used these laser particles to tag tumor cells and track their individual movement for days in a tumor spheroid (a system which mimics the growth of a tumor). In the future, we will be able to use this information to understand how tumors grow and identify specific cells with a higher potential of forming metastasis. It will be possible to single out these cells and perform further studies on them, like sequencing of their genetic profile. This will allow us to target specific genes with more intentionality, improving the options with which we can treat tumors in order to stop their spreading and formation of metastases."

WASHINGTON, DC (July 22, 2019): Women with breast cancer should start postoperative chemotherapy, when recommended, ideally within four months of their cancer diagnosis because new study findings show that waiting longer is associated with poorer overall survival. The study, which used nationwide data, is published as an "online first article" on the Annals of Surgical Oncology website in advance of print and was presented at the American College of Surgeons (ACS) Quality and Safety Conference, concluding today in Washington, DC.

Results of a growing number of studies suggest that timeliness in breast cancer care affects patient outcomes and could be considered a metric of the quality of care, but few guidelines exist that recommend time points for combination treatment, said the study's senior author, Judy C. Boughey, MD, FACS, professor of surgery and vice chair for research, Mayo Clinic Department of Surgery, Rochester, Minn.

"Our study findings confirm that timely care is important for breast cancer patients and should be considered in their treatment plan," Dr. Boughey said.

The researchers looked at 172,043 records of patients with stages I to III breast cancer (has not spread outside the breast) diagnosed between 2010 and 2014 who received both surgical removal of the cancer and adjunctive ("combination") chemotherapy--anticancer drugs given afterward to try to kill any remaining microscopic cancer cells. Patients who received preoperative chemotherapy, hormone therapy, or radiation therapy were excluded from the study.

Patients' records came from the National Cancer Database (NCDB), which includes information on more than 70 percent of all newly diagnosed cancer cases in the United States. The ACS cosponsors the database with the American Cancer Society.

The investigators defined a delay in chemotherapy as greater than 120 days from cancer diagnosis to the first dose of combination chemotherapy. They based this time on a 2008 quality measure from the ACS Commission on Cancer,* which recommends administering combination chemotherapy within four months to breast cancer patients under age 70 with hormone receptor negative cancers with tumors larger than 1 centimeter (0.4 inches) or stages IB to III.

Most women with hormone receptor negative breast cancer receive chemotherapy after their operation, Dr. Boughey said.

Besides comparing overall survival rates at the last follow-up visit in patients whose time from diagnosis to chemotherapy did and did not exceed 120 days, the researchers evaluated the influence of type of operation on time to chemotherapy. They analyzed groups by lumpectomy (breast conservation) versus mastectomy (breast removal), and for mastectomy, immediate breast reconstruction versus no reconstruction.

New findings

Their research, Dr. Boughey said, is noteworthy for several new findings.

Despite the Commission on Cancer recommendation that appropriate patients start combination chemotherapy within 120 days from their cancer diagnosis, 11 percent of patients did not.
The delay between diagnosis and chemotherapy initiation largely stemmed from a longer time from diagnosis to the first operation.
The type of breast cancer operation did not influence the time from the operation to starting chemotherapy, even after the researchers adjusted the statistical analyses for multiple differences in patients and treatment.

The investigators were surprised by this last finding, Dr. Boughey commented.

"Compared with breast conservation," she explained, "a more extensive operation, such as mastectomy with immediate breast reconstruction, tends to have a slightly higher complication rate, which theoretically could delay initiation of postoperative chemotherapy."

Although the researchers found a statistically significantly longer time from the operation to starting chemotherapy for women who underwent mastectomy with immediate reconstruction versus those treated without immediate reconstruction, Dr. Boughey said the difference was not clinically, or practically, important. Both groups had a median (middle value) of 44 days from their operation to chemotherapy, according to the article.

For women with breast cancer, Dr. Boughey said: "Our findings show there is no harm in having immediate reconstruction if that's a woman's choice."

The researchers also found that having both breasts removed together did not lengthen the time from operation to chemotherapy--a finding Dr. Boughey called "reassuring" for women who choose a prophylactic mastectomy of the noncancerous breast.

"It is also encouraging that 89 percent of women who are recommended chemotherapy postoperatively do get it within 120 days of their diagnosis, but there is still room for improvement," Dr. Boughey said.

She recommended that hospitals evaluate their times from breast cancer diagnosis to surgical procedure to determine if they can decrease this interval.

Data from the NCDB do not show why this time from diagnosis to surgical treatment is longer in patients undergoing mastectomy with reconstruction than those not having reconstruction. Possible reasons, according to Dr. Boughey, include poor access to care, longer wait times for second opinion, and for patients desiring immediate breast reconstruction, coordinated availability of a plastic surgeon and breast surgeon.

Herbs, including cilantro, have a long history of use as folk medicine anticonvulsants. Until now, many of the underlying mechanisms of how the herbs worked remained unknown. In a new study, researchers uncovered the molecular action that enables cilantro to effectively delay certain seizures common in epilepsy and other diseases.

The study, published in FASEB Journal, explains the molecular action of cilantro (Coriandrum sativum) as a highly potent KCNQ channel activator. This new understanding may lead to improvements in therapeutics and the development of more efficacious drugs.

"We discovered that cilantro, which has been used as a traditional anticonvulsant medicine, activates a class of potassium channels in the brain to reduce seizure activity," said Geoff Abbott, PhD, professor of physiology and biophysics at the UCI School of Medicine and principal investigator on the study. "Specifically, we found one component of cilantro, called dodecenal, binds to a specific part of the potassium channels to open them, reducing cellular excitability. This specific discovery is important as it may lead to more effective use of cilantro as an anticonvulsant, or to modifications of dodecenal to develop safer and more effective anticonvulsant drugs."

Researchers screened cilantro leaf metabolites, revealing that one - the long-chain fatty aldehyde (E)-2-dodecenal - activates multiple potassium channels including the predominant neuronal isoform and the predominant cardiac isoform, which are responsible for regulating electrical activity in the brain and heart. This metabolite was also found to recapitulate the anticonvulsant action of cilantro, delaying certain chemically-induced seizures. The results provide a molecular basis for the therapeutic actions of cilantro and indicate that this ubiquitous culinary herb is surprisingly influential upon clinically important potassium channels.

Documented use of botanical folk medicines stretches back as far as recorded human history. There is DNA evidence, dating back 48,000 years, that suggests the consumption of plants for medicinal use by Homo neanderthalensis. Archaeological evidence, dating back 800,000 years, suggests a non-food use of plants by Homo erectus or similar species. Today, evidence of the efficacy of botanical folk medicines ranges from anecdotal to clinical trials. In many cases, these "medicines" are currently consumed, often on a large scale, as foodstuffs or food flavoring. Cilantro, known as coriander in the UK, is one example. Cilantro has been consumed by human beings for at least 8,000 years. It was found in the tomb of Tutankhamen and is thought to have been cultivated by the ancient Egyptians.

"In addition to the anticonvulsant properties, cilantro also has reported anti-cancer, anti-inflammatory, anti-fungal, antibacterial, cardioprotective, gastric health and analgesic effects," said Abbott. "And, the best part is it tastes good!"

Bottom Line: Major league baseball (MLB) players had lower death rates overall and from many underlying causes of death compared with men in the general U.S. population, differences that could be associated in part with the physical fitness required for their jobs. This research letter reports on an analysis of mortality rates among 10,451 baseball players who debuted in the MLB from 1906 through 2006, including differences in mortality rates by position and career length. Having a longer playing career was associated with a lower rate of cardiovascular-related death and an increased rate of cancer deaths. Limitations of the study include an inability to account for physical activity, head injuries and other environmental or genetic factors.

Authors: Marc G. Weisskopf, Ph.D., Sc.D., Harvard T.H. Chan School of Public Health, Boston, and coauthors

(doi:10.1001/jamainternmed.2019.1218)

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.