Culture

Boston, MA -- Patients with type 2 diabetes who have high levels of blood sugar are at greater risk of serious complications such as chronic kidney disease, heart disease and blindness. While lifestyle changes and medications can help some patients better control their blood sugar levels, type 2 diabetes tends to progress, and patients typically need more intense treatment to continue to maintain blood sugar control. Insulin offers the most robust way to control blood glucose, but insulin therapy is often delayed, sometimes by several years. A new study by investigators from Brigham and Women's Hospital finds that more than 40 percent of patients refuse a physician's recommendation of insulin therapy. The study also finds that patients who decline insulin therapy had worse blood sugar control and it took them significantly longer to lower their blood sugar levels than patients who began insulin therapy. The team's findings are published in Diabetic Medicine.

"Type 2 diabetes is a serious disease. High blood sugar levels can have a severe impact on a person's quality of life and life expectancy," said corresponding author Alexander Turchin, MD, MS, director of quality in diabetes at the Brigham. "Saying no may bear a strong influence on blood sugar levels and, down the road, complications. A few years of uncontrolled blood sugar can have a big impact."

Previously conducted clinical trials have found that just a few years of elevated blood sugar levels can lead to an increased risk of heart attack and kidney failure 10 or 20 years later. Given the consequences of uncontrolled blood sugar levels, Turchin and colleagues set out to better understand why insulin therapy initiation is frequently delayed.

The team used natural language processing -- an artificial intelligence tool that can scan through large amounts of data to pull out key phrases -- to comb through clinical narratives that physicians had recorded in patients' medical records. This allowed researchers, for the first time, to identify documented insulin decline by patients in electronic medical records notes. The study included more than 5,000 adults with type 2 diabetes who were followed by primary care physicians (PCPs) affiliated with the Brigham and Massachusetts General Hospital between 2000 and 2014.

More than 2,000 patients (43 percent) in the study declined insulin therapy. It took patients who declined insulin an average of 50 months to reach target blood sugar levels, whereas it took an average of 38 months for those who started insulin therapy when their physician recommended it. Participants were more likely to accept insulin therapy if they had diabetes complications or higher blood sugar levels or if they were already seeing an endocrinologist. Older participants and those taking other diabetes medications were less likely to accept insulin therapy.

The authors note that the study does not address the reason patients decline insulin therapy -- that generally is not noted in a patient's record. All patients in the study received care in Massachusetts where insulin costs are generally lower than in other parts of the country. Turchin would like to further investigate possible reasons in future studies as well as the long-term complications that patients who decline insulin may experience.

"Our study calls into question an assumption of therapeutic inertia -- the idea that if a patient with diabetes has high blood sugar, it's always the fault of the health care provider for not treating the condition more aggressively," said Turchin. "We find that the situation is far more complicated. The patient is at the center of their health care and makes their own health care decisions. When we think about improving health care, we must take into consideration that both the provider and patient are involved in these decisions."

Complaints from patients and their family members could signal future violence against nurses and should not be ignored, suggests new research from the University of British Columbia.

By tracking and addressing such complaints, hospitals and other health care organizations can help curb aggressive behaviour towards their employees.

"Health care workers are four times more likely to face physical and emotional abuse on the job as workers in other professions," says study author Farinaz Havaei, an assistant professor of nursing at UBC. "Other studies have shown that addressing patient complaints contributes to positive patient outcomes. Now, for the first time, we have evidence that acting on these complaints can also protect nurses' safety."

The researchers analyzed the results of the B.C. Nurses' Workload Impact Study, comparing workload factors (such as how many tasks nurses say they left unfinished during their last shift and how often they experienced heavy workloads) with patients' complaints and reports of emotional and physical abuse towards nurses. Results showed a strong correlation between patients' complaints and violence, says Havaei.

Nurses said they received an average of one complaint a month, and experienced emotional or physical abuse from patients or their families with about the same frequency.

"What we think happens is a spiral of aggression is created. Patients get frustrated by what they see as poor-quality performance--often caused by factors such as staff shortages and large workloads," says Havaei. "They respond initially with complaints, and if those complaints aren't addressed in a timely manner, they can then escalate into more serious acts of aggression. Unfortunately, the resulting injuries, stress and burnout lead to a further decline in quality of patient care."

The researchers also found a direct connection between workload factors and violence, supporting earlier research by others. For example, caring for patients with chronic or complex conditions was linked to experiences of emotional violence. Interruptions on the job and inability to finish tasks during a shift--typically caused by short-staffing--were linked to increased reports of both physical and emotional violence.

Study co-author Maura MacPhee says the results highlight the need for policies and systems improvements that alleviate workload pressures.

"For example, we need a way to better match patient needs with individual nurses' competencies and experience levels," said MacPhee, a UBC nursing professor who studies nurses' working environments. "Nurses and their managers should also treat patient complaints as they do any other adverse event in health care and always seek to identify their causes."

PORTLAND, Ore. - Gene-infused nanoparticles used for combating disease work better when they include plant-based relatives of cholesterol because their shape and structure help the genes get where they need to be inside cells.

The findings by Oregon State University researchers, published today in Nature Communications, are important because many illnesses that can't be treated effectively with conventional drugs can be treated genetically - delivering nucleic acids to diseased cells so they can make the correct proteins needed for health.

Those genetic treatments rely on the transport devices reaching their destination with a high success rate and releasing their cargo effectively.

Gaurav Sahay, assistant professor of pharmaceutical sciences in the OSU College of Pharmacy, studies lipid-based nanoparticles as a gene delivery vehicle, with a focus on cystic fibrosis.

Cystic fibrosis is a progressive genetic disorder that results in persistent lung infection and afflicts 30,000 people in the U.S., with about 1,000 new cases diagnosed every year.

More than three-quarters of patients are diagnosed by age 2, and despite steady advances in alleviating complications, the median life expectancy of cystic fibrosis patients is still just 40 years.

One faulty gene - the cystic fibrosis transmembrane conductance regulator, or CFTR - causes the disease, which is characterized by lung dehydration and mucous buildup that blocks the airway.

Two years ago, Sahay and other scientists and clinicians at OSU and Oregon Health & Science University demonstrated proof-of-concept for a new, improved cystic fibrosis therapy: loading chemically modified CFTR messenger RNA into lipid-based nanoparticles, creating molecular medicine that could simply be inhaled at home.

The mRNA-loaded nanoparticle approach causes cells to make the correct protein, allowing cells to properly regulate chloride and water transport, which is critical to healthy respiratory function.

Cholesterol, a waxy substance the body uses to make healthy cells, is thought to provide stability in these gene nanocarriers. In the latest study, Sahay and collaborators boosted gene delivery by using plant-based analogs of cholesterol instead. Another plus of these plant-derived sterols is a cardiovascular health benefit, he adds.

The type of nanoparticle used to deliver genes in this study has already been clinically approved; it's being used in a drug, trade-named Onpattro, given to patients with a progressive genetic condition called amyloidosis, which disrupts organ function through harmful deposits of the amyloid protein.

Sahay and graduate student Siddharth Patel, first author on the study, found that phytosterols - plant-based molecules chemically similar to cholesterol - change the shape of the nanoparticles from spherical to polyhedral and cause them move faster.

That's important because once inside a cell, the nanoparticles need maneuverability for the escape they need to make: from a cell compartment known as an endosome into the cytosol, where the delivered genes can perform their intended function.

"One of the biggest challenges in the delivery of genes is that less than 2% of the nanoparticles reach the cytosol," said Sahay, who also holds an adjunct faculty position with OHSU. "If you up the dose to get more genes there, now you have problems with toxicity, plus the cost goes higher. But the nanoparticles' shape changes because of these naturally occurring cholesterol analogs, and the new shape helps them deliver genes better. The analogs boost gene delivery 10-fold and sometimes 200-fold."

The finding can be used to make inhalable particles that can cross several barriers in the lung in a cystic fibrosis patient, enabling patients to be treated with much higher efficacy, Sahay added.

"In this latest research, we hypothesized that with the analog inclusions, there would be shape changes and changes with how the nanoparticles interact with the cell and how the cell perceives them," Patel said. "For instance, the sterols might help them get to the ribosomes for translation faster. This opens up a whole new area of research - the shape and structure and composition of the liquid nanoparticles now become quite relevant. We're just scratching the surface on the way to building LNPs with a rational design to get different properties for treating different diseases with cell-type specificity."

A new eye scan could help identify autism in children years earlier than currently possible.

The non-invasive eye scan utilises a hand-held device to find a pattern of subtle electrical signals in the retina that are different in children on the autism spectrum, which are directly linked to differences in their brain development.

The scan was tested on about 180 people with and without autism between the ages of 5 and 21 in collaboration with Yale University in the US, University College London and Great Ormond Street Hospital in the UK, as part of a study published in the Journal of Autism and Developmental Disorders.

These potential biomarkers for autism spectrum disorder (ASD) could allow for early detection of other disorders, such as attention deficit hyperactivity disorder (ADHD).

Dr Paul Constable, a senior lecturer at the College of Nursing and Health Sciences at Flinders University, has been searching for an autism "biomarker" since 2006, in an effort to improve early detection and intervention methods after his own child was diagnosed.

"The retina is an extension of the brain, made of neural tissue and connected to the brain by the optic nerve, so it was an ideal place to look," says Dr Constable.

"The test is a quick, non-intrusive eye-scan using a hand-held device and we anticipate it will be equally effective on younger children. Very early diagnosis means not only can children receive important interventions, but families are empowered to get the necessary supports in place, come to terms with the diagnosis, and make informed decisions."

Dr Constable's research team is also investigating the scan to detect autism in younger children and other conditions including attention deficit hyperactivity disorder, and other neurodevelopmental disorders.

"Now we have found a likely candidate biomarker for autism, the next stage is to look at young children, even infants, as the earlier we can get to intervention stages the better," Dr Constable says.

He says his team often encounters parents who have two or three young children with autism, as the chance of having a second autistic child is much higher for parents with one child on the spectrum. Autism in Australia is usually diagnosed after the age of four.

Early detection in firstborn children could give parents the opportunity to decide if they want to have more kids, with previous studies indicating an increased likelihood siblings of autistic children are more likely to develop the disorder.

"Detection inevitably changes family dynamics and goals, and creates consideration about the time required to help the child," Dr Constable says.

"Very early diagnosis means not only can children receive important interventions, but families are empowered to get the necessary supports in place, come to terms with the diagnosis, and make informed decisions."

A Simon Fraser University-led research team has found significant evidence that human activity in estuaries is impacting juvenile Pacific and Atlantic salmon. The team's review of 167 peer-reviewed studies (from an initial search of 13,000) identified negative impacts from several stressors, including the effects of flood-protecting tidal gates, pollution and habitat modification.

Their results were published today in Global Change Biology.

Emma Hodgson, an SFU postdoctoral researcher at the time of the research and lead author on the paper, says the review is the first to synthesize what is known, and not known, about how human activities in estuaries may impact juvenile salmon.

"Risk can be defined by the severity of the impact and the certainty we have about whether that impact is likely--that certainty is based on the amount of evidence and agreement between the evidence," Hodgson says.

The review summarized more than 1,300 statistical tests related to the biological impacts from 14 stressors to determine the environmental impacts of human activities.

The review also identified such stressors as light and noise pollution, which have potentially severe negative impacts on salmon, but which have been poorly studied.

SFU professor Jonathan Moore, co-author on the paper, hopes this review will help guide stakeholders and decision-makers in being effective stewards of juvenile salmon and their estuarine habitats.

"Natural resource managers need to make tough decisions, in short timeframes, about the potential environmental risks of proposed developments and whether they should go ahead," says Moore. "They won't have time to wade through thousands of papers when making these decisions, so we did it for them."

One stressor the review identified as likely to have a negative impact on salmon populations, is a reduction in connectivity from the presence of tide gates. These metal gates are designed to reduce flood risks, but can also cut off access for salmon to parts of a river.

For example, in one study reviewed, the number of juvenile salmon found above tide gates was 2.5 times lower than in free-flowing rivers.

Aaron Hill, executive director of Watershed Watch Salmon Society, says the review reveals the importance of conservation planning and restoration in estuaries for the long-term benefit of salmon.

"Estuaries are critical nursery habitats for juvenile salmon and this study showcases the ways in which human activities can cause real harm," says Hill.

He says this review also validates calls by First Nations, local governments and conservation groups to mitigate this harm through changes to infrastructure and land use management.

"For example, tide gates and other flood control structures can be upgraded to restore access for young salmon to these important estuarine habitats."

Studying the African turquoise killifish, which enters into a suspended state called "diapause" during dry and unfavorable growing seasons, researchers uncovered mechanisms that allow the arrested fish to be maintained for long periods while being protected from the normal consequences of aging. Their results are potentially relevant to understanding human aging and aging-associated disease. To survive extreme environments, many species throughout the animal kingdom have evolved the ability to enter one of several unique types of suspended life. One of the most common types, diapause, suspends embryonic development during harsh conditions and enables organisms to hold out for favorable conditions before resuming development. Remarkably, the time spent in diapause doesn't affect the longevity, nor the overall aging of the organism once it "wakes up" and continues to grow. However, the physiological mechanisms by which diapause protects organisms from aging remain unknown. Chi-Kuo Hu and colleagues investigated diapause and its effects on subsequent life in the African turquoise killifish, an emergent model for studying aging in vertebrates. This killifish lives in temporary ponds that dry to dust for long periods of the year. To survive drought, killifish embryos enter diapause - sometimes spending a lifetime in the state - until the rains refill their shallow homes. The authors found that diapause protects the fish embryos against the ravages of time without consequences for the total lifespan or fitness of the adults. Genes involved in muscle development and function appear to play an especially important role in diapause. Also during diapause, chromatin remodeling factors are critical in regulating gene expression, specifically members of the Polycomb family of transcriptional repressors. The study "provides some of the first insight into the anti-aging mechanisms of vertebrate diapause," writes Marc Van Gilst in a related Perspective.

Demonstrating an unprecedented degree of cognitive complexity in an insect, researchers report that bumblebees are capable of recognizing objects across senses. While cross-modal object recognition was previously thought to be a highly complex cognitive capacity capable by few animals outside humans, the results suggest that the bumblebee - with a brain with fewer than one million neurons - can create mental images of objects using information from multiple senses and form sophisticated mental representations of their surrounding world. "This is a remarkable finding, showing that these little invertebrates with very different brain structures to vertebrates are capable of experiencing an object with one sensory modality and later recognizing it with another," write Gerhard von der Emde and Theresa Burt de Perera in a related Perspective. Cross-modal recognition is the ability to recognize objects across different senses. Humans, for example, can easily recognize something they've previously seen through touch alone, for example when they find a set of keys by fishing around sightlessly at the bottom of a backpack. Outside of humans, cross-modal object recognition has been shown only in primates, rats dolphins and a single species of fish. Whether it is widespread throughout the animal kingdom, however, has been debated. According to Cwyn Perry and colleagues, because bumblebees are known to be able to forage in both light and dark conditions, they are ideal creatures to examine to understand if the small brains of invertebrates are capable of cross-modal recognition across vision and touch. In their experiment, Perry et al. trained bumblebees to differentiate two differently shaped objects - cubes and spheres, and using only touch or vision - and tested to see if they could identify the same objects using only the other sense. The authors discovered that the bees were able to successfully recognize the objects cross-modally in both directions; sight-to-touch and touch-to-sight.

How are we able to find things in the dark? And how can we imagine how something feels just by looking at it?

It is because our brain is able to store information in such a way that it can be retrieved by different senses. This multi-sensory integration allows us to form mental images of the world and underpins our conscious awareness.

It turns out that the ability to recognise objects across different senses is present in the tiny brains of an insect.

Researchers at Queen Mary University of London and Macquarie University in Sydney have published new work in the journal Science showing that bumblebees can also find objects in the dark they've only seen before.

In the light, but barred from touching the objects, bumblebees were trained to find rewarding sugar water in one type of object (cubes or spheres) and bitter quinine solution in the other shape.

When tested in the dark, bees preferred the object that was previously rewarding, spending more time exploring them.

Bumblebees also solved the task the other way around. After bees learned to find a particular shape in the dark, they were tested in the light and again preferred the shape they had learned was rewarding by touch alone.

This ability is called cross-modal recognition and it allows us to perceive a complete picture of the world with rich representations.

Dr Cwyn Solvi is the lead author on the paper who was based at Queen Mary University of London and is now at Macquarie University in Sydney. She said: "The results of our study show that bumblebees don't process their senses as separate channels - they come together as some sort of unified representation."

Professor Lars Chittka, head of the lab at Queen Mary University of London in which the study was performed, said: "We've long known that bees can remember the shapes of flowers. But a smartphone can recognise your face, for example, and does so without any form of awareness. Our new work indicates that something is going on inside the mind of bees that is wholly different from a machine - that bees can conjure up mental images of shapes."

Selene Gutierrez Al-Khudhairy, co-author on the paper, and now PhD student at the University of York, said: "This is an amazing feat when you consider the miniscule size of a bee's brain. Future investigations of the neural circuitry underlying this ability in bees may one day help reveal how our own brains imagine the world as we do."

Dr Solvi cautions: "This doesn't mean bees experience the world the same way we do, but it does show there is more going on in their heads than we have ever given them credit for."

For three years, anthropologist Alan Rogers has attempted to solve an evolutionary puzzle. His research untangles millions of years of human evolution by analyzing DNA strands from ancient human species known as hominins. Like many evolutionary geneticists, Rogers compares hominin genomes looking for genetic patterns such as mutations and shared genes. He develops statistical methods that infer the history of ancient human populations.

In 2017, Rogers led a study which found that two lineages of ancient humans, Neanderthals and Denisovans, separated much earlier than previously thought and proposed a bottleneck population size. It caused some controversy--anthropologists Mafessoni and Prüfer argued that their method for analyzing the DNA produced different results. Rogers agreed, but realized that neither method explained the genetic data very well.

"Both of our methods under discussion were missing something, but what?" asked Rogers, professor of anthropology at the University of Utah.

The new study has solved that puzzle and in doing so, it has documented the earliest known interbreeding event between ancient human populations--a group known as the "super-archaics" in Eurasia interbred with a Neanderthal-Denisovan ancestor about 700,000 years ago. The event was between two populations that were more distantly related than any other recorded. The authors also proposed a revised timeline for human migration out of Africa and into Eurasia. The method for analyzing ancient DNA provides a new way to look farther back into the human lineage than ever before.

"We've never known about this episode of interbreeding and we've never been able to estimate the size of the super-archaic population," said Rogers, lead author of the study. "We're just shedding light on an interval on human evolutionary history that was previously completely dark."

The paper was published on Feb. 20, 2020, in the journal Science Advances.

Out of Africa and interbreeding

Rogers studied the ways in which mutations are shared among modern Africans and Europeans, and ancient Neanderthals and Denisovans. The pattern of sharing implied five episodes of interbreeding, including one that was previously unknown. The newly discovered episode involves interbreeding over 700,000 years ago between a distantly related "super-archaic" population which separated from all other humans around two million years ago, and the ancestors of Neanderthals and Denisovans.

The super-archaic and Neanderthal-Denisovan ancestor populations were more distantly related than any other pair of human populations previously known to interbreed. For example, modern humans and Neanderthals had been separated for about 750,000 years when they interbred. The super-archaics and Neanderthal-Denisovan ancestors were separated for well over a million years.

"These findings about the timing at which interbreeding happened in the human lineage is telling something about how long it takes for reproductive isolation to evolve," said Rogers.

The authors used other clues in the genomes to estimate when the ancient human populations separated and their effective population size. They estimated the super-archaic separated into its own species about two million years ago. This agrees with human fossil evidence in Eurasia that is 1.85 million years old.

The researchers also proposed there were three waves of human migration into Eurasia. The first was two million years ago when the super-archaics migrated into Eurasia and expanded into a large population. Then 700,000 years ago, Neanderthal-Denisovan ancestors migrated into Eurasia and quickly interbred with the descendants of the super-archaics. Finally, modern humans expanded to Eurasia 50,000 years ago where we know they interbred with other ancient humans, including with the Neanderthals.

"I've been working for the last couple of years on this different way of analyzing genetic data to find out about history," said Rogers. "It's just gratifying that you come up with a different way of looking at the data and you end up discovering things that people haven't been able to see with other methods."

Researchers at McMaster University have peered into the most intimate moments of sexually active women and men across Canada to ask if they're using condoms, all in an effort to gather data that could inform decisions around public health and sex education.

What's emerged is a blended picture of trends in the use of condoms to prevent sexually transmitted infections and pregnancy.

The researchers looked at penile-vaginal intercourse, a broad area that lead author Tina Fetner says has been under-explored in recent decades, when condom-use research has focused on specific communities such as sex workers and men who have sex with men.

The McMaster researchers, working with Environics Canada, surveyed 2,300 people, balanced to mirror the gender, age, linguistic, educational, minority and regional make-up of Canada itself. The survey, discussed in a paper published today in the journal PLOS ONE, included adults who have had intercourse at least 10 times in the last six months.

Among the survey findings:

* Thirty per cent of Canadians use condoms in penile-vaginal intercourse. Use is highest among young adults. (71 per cent among 18- to 35-year-olds)

* Men who have been diagnosed with sexually-transmitted infections are about 3 times more likely to never use condoms than men who haven't received an STI diagnosis.

"The conclusion in the field is that there is a group of people who are just risk-takers, who are more likely to get STIs and continue with their risky behaviour," says Fetner, a sociologist specializing in sexuality. "It is an important public health problem and it does not have an easy solution."

Men from visible minority groups are much more likely (67 per cent) than white men (40 per cent) to use condoms.

"They're just much more careful than white men in terms of their condom usage," Fetner says. "I think this really suggests they're more vulnerable to social consequences that are associated with their sexual choices."

Condom use is greater among more educated people (50 per cent of college and university graduates) and among people who have received some kind of instruction in how to use condoms. (50 per cent of those who have received instruction)

"The indications that condom education is associated with increased condom usage is an important reminder," Fetner says. "If that education did not exist, condom use would decline and risk would rise."

People having sex with casual partners are more than twice as likely (85 per cent) to use condoms as people in committed relationships (36 per cent).

The survey is the first stage of Sex in Canada, a long-term project Fetner is leading with her McMaster colleagues sociologist Melanie Heath and political scientist Michelle Dion.

In later stages, the group plans to survey people in other countries where data is lacking, and to analyze how the results compare to existing policies that might be changed to minimize STIs and unwanted pregnancies through improved condom use.

"There's an open question about why people do what they do sexually and what are the social forces that influence them," Fetner says. "In a country with more liberal policies, such as access to legal and safe abortion, same-sex marriage and no-fault divorce, do we see different kinds of sexual behaviour?"

The lack of oxygen in the period antipating child birth - a condition that may affect children of pregnant women subjected to a high blood pressure disorder called pre-eclampsia - has been pointed as was one of the causes of schizophrenia. In an article published in Scientific Reports, researchers at Santa Casa de São Paulo Medical School (FCM-SCSP) in Brazil described the way this phenomenon, called hypoxia in the medical jargon, affects astrocytes, one of the most abundant types of brain cells.

In experiments with rat astrocytes, the researchers observed that hypoxia affects the functioning of mitochondria, energy-producing organelles in cells. This study paves the way for the future development of therapies to halt the process which leads to mitochondria dysfunction, thus preventing damage to the fetal brain in the case of pre-eclampsia.

"We began with astrocytes because they're the most abundant and also because they metabolize neurotransmitters like glutamate, one of the most important and a key factor in schizophrenia. We're now investigating the effect of hypoxia on neurons," said Tatiana Rosado Rosenstock, a professor at FCM-SCSP and principal investigator for the study. "We want to find out what signals a given type of cell sends another to avoid brain damage."

Astrocytes are star-shaped cells and the most prevalent glial cells acting in support and insulation of neurons. Glial cells, which also include oligodendrocytes and microglia, account for 90% of the brain on average. The rest is comprised of neurons. Glia are dynamic cells that regulate the metabolism of the central nervous system, maintain homeostasis, form myelin, supply nutrients to neurons, and mediate the formation of synapses.

Three models

The study was part of a project funded by FAPESP. Its lead author, Luiz Felipe Souza e Silva, undertook the research while preparing for a the master's degree, with scholarship from FAPESP.

The research group at FCM-SCSP used three methods to observe the effect of hypoxia on rat astrocytes. First, they placed the cells in a hypoxic chamber containing no oxygen. Next, they treated the cells with cobalt chloride, which mimics hypoxia.

Finally, they analyzed astrocytes from spontaneously hypertensive rats (SHR), a strain whose fetuses suffer from hypoxia during gestation. These animals displayed behavior equivalent to the symptoms of schizophrenia in humans, who cease to manifest the symptoms in question when given antipsychotic medication.

In cells subjected to different forms of hypoxia, mitochondrial calcium balance was one of the altered variables that drew the researchers' attention.

Positive and negative electrical charges must be in equilibrium for mitochondria to produce energy. Because calcium is positively charged, alterations in calcium levels can lead to an imbalance that may ultimately cause cell death.

Compared with normal astrocytes, those subjected to the three types of hypoxia were found to have lower levels of calcium in the cytosol, the water-based solution in which organelles, proteins and other cell structures float in the space between the membrane and the nucleus.

"This happened precisely because calcium uptake by these cells' mitochondria increased [therefore leaving a much lesser amount of calcium in the cytosol], in an attempt at protection," Rosenstock said. "However, too much mitochondrial calcium leads to unbalanced charges in these organelles, altering membrane potential, electron transport and hence energy production."

In addition, a lack of oxygen disturbs redox homeostasis, which enables cells to combat oxidative stress. Any imbalance between oxidant and antioxidant molecules may also lead to cell death. According to researchers, augmented oxidative stress is another consequence of alterations in calcium levels.

The researchers were intrigued to find that hypoxia increased the quantity of mitochondria in the astrocytes. In the tests, the researchers detected the expression of the gene Pgc1-α, which plays an important role in mitochondrial biogenesis (the creation of new mitochondria).

"In conditions of stress, the cell boosts the number of mitochondria to obtain more energy. The existing mitochondria may not be able to produce enough, given the extension of cell dysfunction," Rosenstock said.

The researchers are now investigating ways to enhance mitochondrial function not only in astrocytes but also in neurons, which are less abundant but vital to normal brain development.

"If hypoxia causes problems in mitochondria, we may one day be able to improve mitochondrial function in cases of pre-eclampsia and avoid schizophrenia," Rosenstock said. "Meanwhile, the best way for expectant mothers to avoid fetal hypoxia is to attend all the required antenatal care sessions and avoid high blood pressure disorders."

February 20, 2020 - A pilot program introducing bundled payments for hip and knee replacement (HKR) in Medicare patients hasn't led hospitals to "cherry-pick" healthier patients at lower risk of complications, reports a study in the February 19, 2020 issue of The Journal of Bone & Joint Surgery. The journal is published in the Lippincott portfolio in partnership with Wolters Kluwer.

In the first year of the bundled-payment program, there was no decrease in access to HKR for sicker patients, racial/ethnic minorities, or others at a higher risk of complication or death, according to the new research by Casey Jo Humbyrd, MD, and colleagues of The Johns Hopkins University, Baltimore.

No Major Change in Access to Hip and Knee Replacement

In 2016, the Centers for Medicare & Medicaid Services introduced the Comprehensive Care for Joint Replacement program, mandating bundled payments for elective HKR in Medicare patients. Rolled out in 67 randomly selected metropolitan areas, the program involved the use of pre-determined pricing that covered physician and hospital fees and all related care, from hospital admission through 90 days after surgery.

The program was designed to decrease costs and cost variability while increasing the quality of care for HKR. However, some physicians have expressed concern that bundled payments might lead hospitals to preferentially select healthier patients at lower risk of complications or death ("cherry-picking").

Similarly, hospitals might avoid patients with additional health problems (comorbidities) or other characteristics associated with increased risk of complications or death, including black race and lower socioeconomic status ("lemon-dropping"). "Early program analyses showed cost savings," Dr. Humbyrd and coauthors write, "however, studies also demonstrated a trend toward the selection of healthier patients for HKR performed under the bundled system."

Using a sample of Medicare claims from 2015 to 2016, the researchers evaluated possible changes in patient characteristics after the start of the bundled payment program. The study included a matched set of more than 12,000 episodes of HKR and follow-up care for patients in areas where bundled payments were introduced and 20,000 episodes in other areas.

After adjustment for age and sex, there were no significant differences in the characteristics of patients undergoing HKR in bundled payment areas compared with areas with no change in reimbursement. Further analysis controlled for important risk factors for complications after HKR, including general health, smoking, or diabetes, and showed no change in the proportions of patient who were black or low-income (based on Medicaid eligibility).

For comparison, the researchers examined the characteristics of patients undergoing hip hemiarthroplasty - a "partial" hip replacement alternative. The results showed small but significant increases in the rate of comorbidity after the introduction of bundled payments. "Although small, these changes suggest that some surgeons may prefer hemiarthroplasty rather than total hip replacement in less-healthy patients to avoid treating such patients under a bundled-payment program," the researchers write. However, there was no change in the numbers of black or low-income patients selected for hemiarthroplasty.

The study helps to address concerns that the bundled payment program might lead hospitals to select healthier patients for HKR while denying access for those in need. "[W]e did not find that bundled payments were associated with decreased access to HKR for patients who had more comorbidities, were members of a minority racial group, or were of lower socioeconomic status," Dr. Humbyrd and coauthors write. They note some limitations of their study, including reliance on claims data and a relatively short follow-up period.

Within those limitations, the study provides reassurance that the Comprehensive Care for Joint Replacement program has not led to "cherry-picking" or other major changes in patient selection based on risk criteria. The researchers call for further studies to allay concerns that bundled payments might reduce access to HKR for higher-risk patients.

LOS ANGELES, Feb. 20, 2020 -- Treating stroke patients in specialized ambulances speeds treatment and reduces patients' disability, according to late breaking science presented today at the American Stroke Association's International Stroke Conference 2020. The conference, Feb. 19-21 in Los Angeles, is a world premier meeting for researchers and clinicians dedicated to the science of stroke and brain health.

The Berlin Prehospital Or Usual Delivery (B_PROUD) trial investigated if prehospital treatment in a mobile stroke unit could improve patient outcomes compared to usual care, which was emergency transportation in a conventional ambulance and in-hospital treatment. Patients (total 749, average age 73, 46% females) were assigned to treatment based on the availability of three mobile stroke units in the metropolitan area of Berlin, Germany, and compared with patients (total 794, average age 74, 48% females) who received conventional care.

Mobile stroke units are ambulances staffed with emergency medicine neurologists and equipped with a CT scanner and a lab designed to enable specific stroke treatment at the scene. Prehospital treatment consisted of administering medications to dissolve the clot blocking blood flow in or to the brain (ischemic stroke). Timing is key because the clot-busting medication alteplase should be administered within 4.5 hours of stroke symptoms.

Researchers found that:

60% of patients assigned to the mobile stroke unit received clot-busting treatment with alteplase if a mobile stroke unit was available, compared to 48% of patients who received conventional treatment in the hospital;

the time to treatment was shortened by an average of 20 minutes when a mobile stroke unit was dispatched; and

the use of a mobile stroke unit reduced the likelihood and severity of disability and death at three months by 26%.

"While we had anticipated better outcomes in the patients treated in the mobile stroke units, we are amazed by the magnitude of the effects," said lead study author Heinrich Audebert, M.D., professor in the department of neurology and Center for Stroke Research at Charité Universitätsmedizin in Berlin. "It is obvious that clot-busting treatment is most effective if it is applied in the ultra-early phase of stroke - ideally within the first or 'golden hour' of symptom onset."

Since treatment within the first hour of symptom onset happens rarely in conventional care, Audebert said health care providers should consider ways to optimize treatment so it can begin while in route to the hospital.

"Stroke treatment is more effective the earlier it starts," he said. "Just waiting until the patient arrives at the hospital is not enough anymore."

LOS ANGELES, Feb. 20, 2020 -- New research confirms that the lower 0.25mg/kg dose of the clot-busting agent tenecteplase is appropriate for eligible stroke patients and can reduce the need for mechanical clot removal, according to late breaking science presented today at the American Stroke Association's International Stroke Conference 2020. The conference, Feb. 19-21 in Los Angeles, is a world premier meeting for researchers and clinicians dedicated to the science of stroke and brain health.

The clot-busting medication alteplase was approved by the U.S. Food and Drug Administration (FDA) 25 years ago for treating clot-caused stroke (ischemic stroke) within 3 hours of symptom onset and AHA guidelines recommend alteplase up to 4.5 hours after stroke onset. Alteplase is administered as an IV drip over an hour. Alternatively, tenecteplase, a genetically modified variant of alteplase, is more convenient because it is administered as a single injection directly into the vein and restored blood flow to the brain better than alteplase in a previous trial. Two different doses of tenecteplase have been used in previous trials, and AHA guidelines include recommendations for both doses. Tenecteplase use for ischemic stroke is currently not approved by the FDA.

Researchers say that, in addition, tenecteplase may be especially beneficial for patients who need to be transferred from the hospital where they initially present to a specialized stroke center for mechanical clot removal treatment- also known as a endovascular thrombectomy, a minimally-invasive procedure in which a small tube is inserted into the arteries of the brain to remove the clot causing the stroke.

Researchers investigated whether a dose of 0.25mg/kg or 0.40mg/kg of tenecteplase prior to mechanical clot removal is optimal for stroke patients.

Three hundred ischemic stroke patients with large vessel occlusion within 4.5 hours of onset were randomized to the two doses of tenecteplase. Researchers found:

the clot was largely dissolved prior to mechanical removal in 19.3% of patients with both groups;

there were no differences in functional outcome; and

symptomatic intracranial hemorrhage occurred in numerically fewer patients treated with the smaller dose (1.3%) compared to the larger dose (4.7%), although the difference was largely due to thrombectomy-related wire perforations.

"The two doses behaved very similarly overall, and there was no advantage to increasing the dose beyond 0.25mg/kg in this study," said Bruce Campbell, M.B.B.S., B.Med.Sc., Ph.D., head of stroke at the Royal Melbourne Hospital and professorial fellow at the University of Melbourne in Parkville, Australia. "These results provide reassurance that there is a window of safety if the weight-based dose is inadvertently overestimated."

"In addition, about 34% of patients treated in rural centers had substantially improved blood flow by the time they arrived at a hospital capable of performing mechanical clot removal," Campbell said. "This treatment could be particularly important for them."

After 50 years of research and the testing of over 1,000 drugs, there is new hope for preserving brain cells for a time after stroke. Treating acute ischemic stroke patients with an experimental neuroprotective drug, combined with a surgical procedure to remove the clot improves outcomes as shown by clinical trial results published today in The Lancet.

The multi-centre, double-blinded, randomized trial, led by a team at the Cumming School of Medicine's (CSM) Hotchkiss Brain Institute and Alberta Health Services, investigates the use of the neuroprotective drug nerinetide, developed by NoNO Inc, in two scenarios in the same trial. In one scenario, nerinetide is given to patients in addition to the clot-busting drug alteplase. In the second scenario, patients who were not suitable for alteplase received only nerinetide. Both groups of patients had concurrent endovascular treatment (EVT) to remove the clot.

"Compared to placebo, almost 20 per cent more patients who received nerinetide along with endovascular treatment, but did not receive alteplase, recovered from a devastating stroke - a difference between paralysis and walking out of the hospital," says Dr. Michael Hill, MD, a neurologist at Foothills Medical Centre (FMC) and professor in the departments of Clinical Neurosciences and Radiology at the CSM. "In the patients who received both drugs, the alteplase negated the benefits of the nerinetide."

Hill says the study provides evidence of a biological pathway that protects brain cells from dying when they are deprived of blood flow. Nerinetide targets the final stage of the brain cell's life by stopping the production of nitric oxide within the cell.

"We really believe this is a new scientific observation," says Hill. "There is evidence nerinetide promotes brain cell survival, offering neuroprotection until we can extract the clot. It opens the door to a new way of treating stroke."

Images of patients' brains from the study show the expected size of the damage from the stroke is sizeably reduced when nerinetide is administered and EVT is performed among patients not concurrently receiving alteplase.

"After so many studies investigating neuroprotective drugs failed, we are extremely excited by these results," says Dr. Mayank Goyal, MD, PhD, a neuroradiologist at the FMC, and clinical professor in the Department of Radiology at the CSM. "While nerinetide is not approved for use yet, it shows the potential of a new tool to promote recovery from stroke."

Worldwide, 15 million people suffer a stroke each year - that's one every nine minutes in Canada and every 90 seconds in the United States. The results can be devastating. Ischemic stroke, the most common, is caused by a clot in a blood vessel in the brain. The sudden loss of blood flow causes brain cells to die, which can permanently affect speech, vision, balance and movement.

The international trial enrolled 1,105 patients between March 2017 and August 2019 at centres in North America, Europe, Australia, and Asia - a global academic collaboration bringing together scientists, clinicians, funding agencies, and industry.

"The collaboration between NoNO Inc., the University of Calgary and investigators at 48 leading stroke hospitals around the world has shown how effective such an academic-industry partnership can be in running high-quality, foundational stroke trials that can lead to positive changes in clinical practice," says Dr. Michael Tymianski, MD, PhD, CEO of NoNO Inc. and the inventor of nerinetide.

The results in the current study, called the ESCAPE-NA1 Trial, build on the success of the ESCAPE trial, in which the Calgary Stroke Program proved that a clot retrieval procedure known as EVT can dramatically improve patient outcomes after an acute ischemic stroke. During the procedure, a catheter is inserted in the groin and guided through blood vessels into the brain. A tiny metal mesh device is used to grab the clot and pull it out. The current study investigates whether administering nerinetide in addition to clot retrieval improves the patient's ability to recover.