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After nearly four years of work, a group of researchers and clinicians from the University of Colorado (CU) published a paper this week in the Clinical Cancer Research that shares findings from research looking at how the composition of ovarian cancer tumors changes during chemotherapy and contributes to therapeutic response.

While the standard of care consisting of surgery and chemotherapy for ovarian cancer patients is usually effective, disease recurrence and resistance are common. In fact, according to the American Cancer Society, ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. In 2020 it is estimated that 13,940 women will die from ovarian cancer. There is currently an unmet clinical need to predict patients' response to chemotherapy, which was the focus of the research team.

"Almost all patients initially respond, however, almost all patients will recur," says Benjamin Bitler, PhD, CU Cancer Center member and corresponding author. "On the other hand, there is a small percentage of patients will never recur or remain in remission beyond five years. We are working to be able to better predict a patients' response to chemotherapy."

This group of researchers and clinicians set out in November 2016 to focus on identifying potential biomarkers or pathways to better predict how a patient's tumor would respond to therapy. This information could change maintenance and surveillance and will take a step towards a precision medical approach for each patient.

"Our ultimate goal is that someone who is diagnosed with ovarian cancer would be able to come in and we would be able to take the primary tumor and use the two major technologies described in the research study, transcriptomics using Nanostring and multi-spectral immunohistochemistry (IHC), to get an idea about what is being expressed and what the tumor microenvironment looks like," says Bitler.

Multi-spectral IHC is a way of characterizing the tumor's composition. Tumors are not made of only tumor cells; they also include among other things, blood vessels, stroma and immune cells. Other research leading up to this has shown the tumor composition correlates to the patient's prognosis suggesting that the composition of the tumor likely holds clues as to therapeutic response. The major strength of multi-spectral IHC is that the location of the different cell types is kept intact, allowing for an added dimension of data, which is the physical location of each cell type.

"However, there is a limitation with multi-spectral IHC, which is that right now we can only identify nine different markers. This is a problem when you think there are likely more than 9 different subpopulations of cells within the tumor," explains Bitler. "Therefore, to improve our resolution of the tumor composition we are using transcriptomic analysis in parallel to further infer into the tumor composition."

Between these two technologies, the team can characterize the important players that might be involved in promoting the tumor progression or response to therapy. In the present study, the research group examined ovarian cancer tumors before and after chemotherapy, with the goal of describing how chemotherapy remodels the tumor composition. Building on this research study the long-term objective of the ovarian cancer research group to leverage our understanding of the effects of chemotherapy on the tumor to predict response and disease recurrence.

Looking forward in ovarian cancer care

One of the groups' major funding sources to this point was an award through the Developmental Therapeutics program, one of four CU Cancer Center research programs.

"That award let us get to where we are right now but ultimately, we want to examine primary tumors from 500 patients."

The team is getting ready to submit for a large federal grant later this year that will help with achieving our long-term goals. Dr. Aaron Clauset from CU Boulder is an expert in machine learning and network analysis. He will significantly contribute to aspects of the grant by developing machine learning approaches that predict therapeutic response.

"It is not going to happen in the next year or two but our long-term vision is that patients come in, get their tumor biopsied and within weeks we inform the clinician of the likelihood that his/her patient will be a good responder or be resistant to chemotherapy," says Bitler.

Bringing two campuses together

"Another part of this project that I think is a strength, is that we were starting to bridge the gap between the CU Anschutz and CU Boulder campus to leverage the expertise, computer modeling and machine learning that is being developed in Boulder and apply it to some of the biomedical questions we have on the Anschutz campus," says Bitler.

This study is made up of 15 researcher or clinicians, nine of which are CU Cancer Center members:

Kimberly R. Jordan, PhD, co-first author, Department of Immunology and Microbiology.

Matthew J. Sikora, PhD, co-first author, Department of Pathology.

Jill E. Slansky, PhD, co-leader CU Cancer Tumor Host Interactions program, Department of Immunology and Microbiology.

Angela Minic, MS, Department of Immunology and Microbiology.

Jennifer K Richer, PhD, co-leader CU Cancer Tumor Host Interactions program, Department of Pathology.

Marisa R. Moroney, MD, Department of OB/GYN, Division of Gynecologic Oncology.

Junxiao Hu, MS, Department of Biostatistics and Informatics.

Rebecca J. Wolsky, MD, Department of Pathology.

Zachary L. Watson, PhD, Department of OB/GYN, Division of Reproductive Sciences.

Tomomi M. Yamamoto, PhD, Department of OB/GYN, Division of Reproductive Sciences.

James C. Costello, PhD, Department of Pharmacology.

Aaron Clauset, PhD, Department of Computer Science.

Kian Behbakht, MD, Lead clinician and Translational Scientist, Department of OB/GYN, Division of Gynecologic Oncology.

Rajendra Kumar, PhD, Department of OB/GYN, Division of Reproductive Sciences.

Benjamin G. Bitler, PhD, corresponding author, Department of OB/GYN, Division of Reproductive Sciences.

This group used a multidisciplinary approach to get to this point, which demonstrates the strength of putting the expertise of the two campuses together.

"This publication is a major milestone and a step in the right direction to show that we can work together as a team to address challenges that are facing patients with ovarian cancer."

PHILADELPHIA - Our bodies frequently heal wounds, like a cut or a scrape, on their own. However patients with diabetes, vascular disease, and skin disorders, sometimes have difficulty healing. This can lead to chronic wounds, which can severely impact quality of life. The management of chronic wounds is a major cost to healthcare systems, with the U.S alone spending an estimated 10-20 billion dollars per year. Still, we know very little about why some wounds become chronic, making it hard to develop effective therapeutics to promote healing. New research from Jefferson describes a novel way to sample the cells found at wounds - using discarded wound dressings. This non-invasive approach opens a window into the cellular composition of wounds, and an opportunity to identify characteristics of wounds likely to heal versus those that become chronic, as well as inform the development of targeted therapies.

The study was published in Scientific Reports on September 15th.

"Studying wound healing in humans is very challenging, and we know very little about the process in humans," says Andrew South, PhD, Associate Professor in the Department of Dermatology and Cutaneous Biology and one of the lead authors of the study. "What we do know is from animal studies, and animal skin and the way it heals is very different from human skin."

Dr. South and his lab study a group of inherited skin diseases called epidermolysis bullosa (EB), where wound healing is severely impaired. Patients, often from birth, suffer from blisters and lesions that are slow to heal, and some become chronic. In a subset of patients, chronic wounds are at high risk of developing into aggressive skin cancer. At this time, it is very difficult to predict which wounds in a given patient will heal, and which won't. Being able to sample the wounds is a key to understanding the mechanisms behind healing.

"Performing a biopsy to sample the cells in the wound would help us understand the differences between these wounds," says Dr. South "But biopsy in these patients is extremely painful and could delay healing of the wound even further. On the other hand, collecting these bandages that are just going to be thrown away, it poses no harm to the patient, and can be applied to a variety of conditions where wounds don't heal properly."

The researchers, which included collaborators in Chile and Austria, collected and analyzed 133 discarded wound dressings from 51 EB patients. Both acute and chronic wounds were sampled, with acute defined as present for 21 days or less, and chronic as present for more than 3 months.

"Previous studies had used wound dressings or bandages to collect fluid and look at what proteins are in there," says Dr. South. "But no one has actually looked at what cells are present. Applying the techniques our lab frequently uses, we were able to isolate viable or living cells from the dressings."

The researchers recovered a large number of cells from the dressings, often in excess of a 100 million. The larger the wound, and the more time a dressing was on a wound, the more number of cells were recovered.

The researchers then characterized the cells to see what type of cells are present at the wound. They detected a variety of immune cells including lymphocytes, granulocytes or neutrophils, and monocytes or macrophages. When comparing dressings from acute and chronic wounds, they found a significantly higher number of neutrophils at chronic wound sites. Neutrophils are the first line of defense in our immune system, and when a wound starts to form, they're the first ones to arrive at the scene.

"Previous findings from animal studies and protein analysis of human wound dressings had supported the idea that when neutrophils hang around longer than they should, that stalls the healing process and can lead to chronicity," says Dr. South. "Our findings support that theory more definitively, by showing that chronic wounds are characterized by higher levels of neutrophils."

These findings give more insight into wound healing, and could help develop therapies that promote the process; for instance, those that neutralize excess neutrophils, or recruit macrophages, the immune cells that begin the next stage in healing after neutrophils.

The researchers now plan to expand on their technique, by further analyzing the individual cells collected from the wound dressings, and the genetic material inside them.
"Currently we're working with colleagues in Santiago, Chile on collecting dressings from EB patients over a period of time," says Dr. South. "This allows us to follow patients longitudinally, and observe a wound and how its cellular composition changes as it heals or doesn't heal."

The team hopes that this will reveal genetic markers that can predict healing or chronicity.

"This method of sampling could be an alternative to bothersome swabs or blood draws, which are especially hard to do in newborns," says Dr. South. "Since we know EB can present at birth, this technique could give us really early insight into the how severe the disease might be."

While the current study focuses on EB, Dr. South and his colleagues hope that this technique can be applied to a variety of other conditions, such as diabetic foot ulcers and vascular leg ulcers.

"The field of wound healing has been crying out for a better understanding of what drives a chronic wound," says Dr. South. "This technique could be transformative, and eventually help patients live more comfortable and healthy lives."

Differences in biological sex can dictate lifelong disease patterns, says a new study by Michigan State University researchers that links connections between specific hormones present before and after birth with immune response and lifelong immunological disease development.

Published in the most recent edition of the Proceedings of the National Academy of Sciences, the study answers questions about why females are at increased risk for common diseases that involve or target the immune system like asthma, allergies, migraines and irritable bowel syndrome. The findings by Adam Moeser, Emily Mackey and Cynthia Jordan also open the door for new therapies and preventatives

"This research shows that it's our perinatal hormones, not our adult sex hormones, that have a greater influence on our risk of developing mast cell-associated disorders throughout the lifespan," says Moeser, Matilda R. Wilson Endowed Chair, professor in the Department of Large Animal Clinical Sciences and the study's principle investigator. "A better understanding of how perinatal sex hormones shape lifelong mast cell activity could lead to sex-specific preventatives and therapies for mast cell-associated diseases."

Mast cells are white blood cells that play beneficial roles in the body. They orchestrate the first line of defense against infections and toxin exposure and play an important role in wound healing, according to the study, "Perinatal Androgens Organize Sex Differences in Mast Cells and Attenuate Anaphylaxis Severity into Adulthood."

However, when mast cells become overreactive, they can initiate chronic inflammatory diseases and, in certain cases, death. Moeser's prior research linked psychological stress to a specific mast cell receptor and overreactive immune responses.

Moeser also previously discovered sex differences in mast cells. Female mast cells store and release more inflammatory substances like proteases, histamine and serotonin, compared with males. Thus, female mast cells are more likely than male mast cells to kick-start aggressive immune responses. While this may offer females the upper hand in surviving infections, it also can put females at higher risk for inflammatory and autoimmune diseases.

"IBS is an example of this," says Mackey, whose doctoral research is part of this new publication.

"While approximately 25% of the U.S. population is affected by IBS, women are up to four times more likely to develop this disease than men."

Moeser, Mackey and Jordan's latest research explains why these sex-biased disease patterns are observed in both adults and prepubertal children. They found that lower levels of serum histamine and less-severe anaphylactic responses occur in males because of their naturally higher levels of perinatal androgens, which are specific sex hormones present shortly before and after birth.

"Mast cells are created from stem cells in our bone marrow," Moeser said. "High levels of perinatal androgens program the mast cell stem cells to house and release lower levels of inflammatory substances, resulting in a significantly reduced severity of anaphylactic responses in male newborns and adults."

"We then confirmed that the androgens played a role by studying males who lack functional androgen receptors," says Jordan, professor of Neuroscience and an expert in the biology of sex differences.

While high perinatal androgen levels are specific to males, the researchers found that while in utero, females exposed to male levels of perinatal androgens develop mast cells that behave more like those of males.

"For these females, exposure to the perinatal androgens reduced their histamine levels and they also exhibited less-severe anaphylactic responses as adults," says Mackey, who is currently a veterinary medical student at North Carolina State University.

In addition to paving the way for improved and potentially novel therapies for sex-biased immunological and other diseases, future research based will help researchers understand how physiological and environmental factors that occur early in life can shape lifetime disease risk, particularly mast cell-mediated disease patterns.

"While biological sex and adult sex hormones are known to have a major influence on immunological diseases between the sexes, we're learning that the hormones that we are exposed to in utero may play a larger role in determining sex differences in mast cell-associated disease risk, both as adults and as children," Moeser said.

A team of scientists has unraveled the molecular mechanism behind one of the causes of colorectal cancer, and a treatment target.

The Wnt signaling pathway is a cell signaling pathway that promotes cell proliferation and is essential for the development and optimal function of cells and tissues in many organisms. Many molecules are involved in the regulation of this pathway; a mutation in the molecules could lead to cancer. RNF43 is such a molecule, a protein that is found in the cell membrane of intestinal stem cells (ISCs). It functions as a negative regulator of the Wnt signaling pathway, and mutations of RNF43 are commonly found in colorectal cancer. However, the mechanisms by which RNF43 mutations cause cancer were not fully elucidated.

In an extensive series of experiments, a team of scientists, including Tadasuke Tsukiyama from the Faculty of Medicine at Hokkaido University, has described a molecular mechanism by which mutations at one site in RNF43 cause cancer - and have also described a potential method to treat these cancers. Their findings were published in the journal Nature Communications.

They first identified the exact region of RNF43 in which mutations lead to activate Wnt signaling. From experiments with induced mutations, they found that some serine residues in RNF43 must be modified with phosphate (phosphorylated) in order to become functional. Mutations which block phosphorylation in RNF43 lead to cancer. They designed RNF43 mutants which had properties similar to phosphorylated RNF43. These mutants retained their function, confirming their hypothesis.

In a normal cell, RNF43 negatively regulates Wnt signaling pathway by initiating the degradation of the receptor for Wnt. When RNF43 mutates into oncogenic RNF43, it can no longer downregulate Wnt signaling. Furthermore, the group found that the oncogenic RNF43 cooperates with active Ras, another oncogene, to induce tumors. This was verified in mice models as well as in cellular experiments. From this information, the scientists analyzed data from colorectal cancer collected from The Cancer Genome Atlas (TCGA) and identified that mutant RNF43 works with Ras to induce tumorigenesis in humans, as well. Interestingly, other experiments by the group suggested that further expression of oncogenic RNF43 was induced by positive feedback of the Wnt signaling pathway, which accelerates RNF43's suppressive role on anti-cancer gene p53.

A separate question the scientists addressed was the role of normal and mutant RNF43 in other species. In experiments conducted on zebrafish embryos and mouse intestinal organoid models, they demonstrated that phosphoregulation of RNF43 plays a key role in the morphogenesis and the maintenance of ISCs, confirming the conserved role of this regulation.

The scientists concluded that modification of RNF43 phospho-status to maintain its function may be a potential treatment for some types of colorectal cancer. What remains to be understood is the exact role different RNF43 mutations play in cancer. To do this at a useful scale, it is important to collect more detailed molecular data from patients recorded in TCGA.

Assistant Professor Tadasuke Tsukiyama from the Department of Biochemistry, Faculty of Medicine at Hokkaido University studies the development of cancer using cell lines and zebrafish, mouse organoid and mouse allograft models. He is especially interested in how aberrations in the signal transduction pathways lead to cancer.

Rochester, MN, September 15, 2020 - A survey of 607 women who suffer from severe migraine found twenty percent of the respondents are currently avoiding pregnancy because of their migraines. The women avoiding pregnancy due to severe migraine tend to be in their thirties, are more likely to have migraine triggered by menstruation, and are more likely to have very frequent attacks (chronic migraine) compared to their counterparts who are not avoiding pregnancy, according to a new study in Mayo Clinic Proceedings. Their decision appears to be based on perceived fears about their own health and the health of their child, even though evidence shows that migraine improves in up to 75 percent of women during pregnancy.

Migraine is one of the leading causes of disability worldwide, particularly affecting women during their childbearing years. "A large number of women with migraine might avoid pregnancy due to migraine. So they can make informed decisions, it is important that women with migraine have access to reliable information about the relationship between migraine and pregnancy," explained lead author Ryotaro Ishii, MD, PhD., a visiting scientist at Mayo Clinic, Phoenix, AZ, USA.

The study investigated the impact of migraine on pregnancy plans among patients being treated in headache specialty clinics and enrolled in the American Registry for Migraine Research (ARMR), the American Migraine Foundation's national prospective longitudinal patient registry and biorepository. Corresponding author Todd J. Schwedt, Mayo Clinic, Phoenix, AZ, USA, and Principal Investigator of ARMR, remarked, "ARMR is a multicenter patient registry that collects in-depth clinical data, biospecimens, and neuroimaging data from a large number of individuals with migraine and other headache types. ARMR provides deep insights into the clinical manifestations, management, and outcomes of patients with headache."

Patients provide demographic data when they enroll in ARMR and complete questionnaires about their medical history. A family planning questionnaire is included. The database includes a specialist's diagnosis of migraine subtypes, such as migraine with aura, migraine without aura, chronic migraine (at least 15 headache days per month), and/or menstrual migraine.

The family planning questionnaire was completed by 607 patients within ARMR between February 2016 and September 2019. Patients were asked, "Have migraines impacted your plans for pregnancy?" They selected one of the following answers: "Avoid pregnancy - Significant;" "Avoid pregnancy - Somewhat;" "No Impact/Not Sure;" "Increased Desire to Get Pregnant - Somewhat;" and "Increased Desire to Get Pregnant - Significant." Six individual questions that asked about how migraine might impact pregnancy, the ability to raise a child, and the child's health were rated on a scale from "Strongly agree" to "Strongly disagree."

Patients were divided into two groups according to whether or not they reported avoiding pregnancy because of migraine. Twenty percent of the patients indicated that they avoided pregnancy because of their migraine. The average age for those who reported avoiding pregnancy was 37.5 years, younger than that of the group who reported no impact of migraine on their pregnancy plans (47.2 years). Women who experienced migraine attacks associated with their menstrual cycle more commonly avoided pregnancy compared to those who did not experience menstrual-related migraine attacks. They more frequently reported a history of depression, a higher monthly frequency of days with headache, and higher migraine-related disability over the three previous months.

Among those who avoided pregnancy due to migraine, 72.5 percent believed that their migraine would be worse during or just after pregnancy, 68.3 percent believed their disability would make pregnancy difficult, and 82.6 percent believed that the disability caused by migraine would make raising a child difficult. There were also concerns that medications they take would negatively affect their child's development and that they would pass on genes to their baby that increase the risk of the child having migraine.

The investigators noted that research does not support what the patients in the ARMR believed about the impact of migraine on pregnancy. About one half to three fourths of women with migraine experience a marked improvement during pregnancy, with a significant reduction in the frequency and intensity of attacks according to published literature. Because the prognosis of migraine during pregnancy is generally good, it may be possible to limit the use of medications, thereby reducing the risk of medication-related adverse events. Migraine does not appear to increase the risk for fetal malformations, although some studies suggest a small increase in poor pregnancy and fetal outcomes.

The authors cautioned that because ARMR patients are enrolled from specialty headache centers and are more severely affected by migraine, the results cannot necessarily be generalized to the general population of people with migraine. There may be certain patient characteristics associated with an individual being more likely to enroll.

It is essential that women of childbearing potential with migraine receive education about the potential impact of migraine on pregnancy, the authors observed. "As the leading cause of years lived with disability in the world, and one that affects one in three women during their lifetime, these data highlight the substantial impact migraine has on pregnancy and family planning," added co-author David Dodick, MD, Mayo Clinic, Phoenix, AZ, USA, and Principal Investigator of ARMR. "Clinicians must be alert to and proactively manage these important concerns of their female patients."

"This study is a testament to the unrelenting, destructive nature of this chronic invisible diagnosis, which can permeate all aspects of life if left unchecked, including potentially depriving women of the opportunity of motherhood should they desire as well as other important relationships," commented Rashmi B. Halker Singh, MD, Department of Neurology, Mayo Clinic, Phoenix, AZ, USA, and Joseph I. Sirven, MD, Department of Neurology, Mayo Clinic, Jacksonville, FL, USA, in an accompanying editorial. "We need to not only support women who have migraine by addressing this patient education gap and improving our treatments to better meet their needs, but also must be deliberate in our efforts to improve societal understanding and acceptance of this prevalent neurobiological disease."

Providing general practitioners (GPs) with financial incentives to offer information about long-acting contraceptives, such as the hormonal implant, is associated with an increase in their use, and a fall in the number of abortions .

This is the finding of researchers from Imperial College London, who conducted the first large-scale analysis of an incentive scheme for GPs to provide women with information about long-acting reversible contraceptives, termed LARCs. The team analysed data from the anonymised health records of over three million women in England, Wales and Scotland between financial years 2004/2005 to 2013/2014.

The study, funded by the National Institute for Health Research, and published in the journal PLOS Medicine found that the scheme was associated with a 13 per cent increase in LARC prescriptions (or absolute increase of 4.5 prescriptions per 1,000 women), above what would have been expected, four years after the scheme was introduced.

This was accompanied by a fall of nearly 17% in number of prescriptions for non-LARC contraception (or absolute decrease of 42 prescriptions per 1,000 women) in the same four-year period, suggesting a major switch in the choice of contraceptive method used.

The findings also showed a 38 per cent more than expected reduction in abortions (or absolute reduction of 5.3 per 1,000 women) four years after the incentive was introduced. This is the equivalent of 95,170 fewer abortions than expected, if the results were extrapolated across the whole UK population.

Most of the impact on LARC prescriptions and abortions were among women under 25 years old, and those from poorer areas.

Dr Richard Ma, a GP and lead researcher on the study from Imperial's School of Public Health said: "Our study suggests if women were better informed about more effective and reliable methods such as long-acting contraceptives, they might choose these over less reliable methods. This could reduce the number of unplanned and unwanted pregnancies. We expected this study would show the incentive had led to some change in behaviour - but we never expected it to reveal such a profound effect, especially for a simple intervention and a relatively modest incentive."

The UK government introduced a financial incentive scheme called the Quality and Outcomes Framework (QOF) in 2004/05 which rewarded primary care practices for improving the quality of care. A new target was introduced under this pay for performance (P4P) scheme in 2009/10 for GPs to provide information about LARC to any female patient between the ages of 13-54 who had previously received a prescription for contraceptives, including emergency hormonal contraception. This advice was given in person, as a text message or leaflet. This target was worth about £700 (US$900 or €760) per year for an average sized practice of 6,000 patients. The GPs were not paid for the number of LARC prescriptions issued, only for reaching a target (50% to 90%) of women given information about LARCs.

LARCs include the contraceptive injection which is effective for 3 months, contraceptive implant (effective for 3 years), intrauterine system (IUS, effective for 5 years), and intrauterine device (IUD or "coil", effective for up to 10 years).

The scheme was introduced in 2009, and the study examined the number of LARCs prescribed for five years before, and four years after the scheme, while giving the scheme one full year to take effect. The study also examined the number of prescriptions for non-LARC contraceptives, such as the contraceptive pill, in this time period. Abortions were examined as a proxy marker for unplanned and unwanted pregnancies, as these could not be reliably measured.

The data was from the Clinical Practice Research Datalink, a database which contains the anonymised health records of 17 million patients in England, Scotland and Wales from over 600 GP practices.

The study authors stress the research does not show a direct link between the information being provided to women, and the number of LARC prescriptions and abortions - but simply an association. Furthermore, this study looked at outcomes at the population level, and therefore cannot say conclusively that providing a specific individual with information about LARC will result in a reduced likelihood of an unplanned and unwanted pregnancy. Other awareness campaigns and improved access to contraceptive methods might explain the findings, but to a smaller extent.

Professor Sonia Saxena, GP and co-author of the study from the School of Public Health added: "There are two important points to make clear about this scheme. The first is the aim of the incentive was not to nudge women to choose LARC methods, but to consider the best options available to match their needs. The second point is that as women's circumstances change, regular review of contraceptive needs from primary care professionals, such as their GP or practice nurse, may help women to make better decisions about contraceptive methods that are appropriate for their life stage"

Medical experts have worked for decades to improve the chances that patients will get the scans, routine tests and medicines that can do them the most good - and avoid the ones that won't help them at all.

But in the push toward evidence-based medicine, a new study says, a key step has mostly gotten overlooked: helping doctors stop or scale back - or deintensify - treatment once it has started, and take the screening, testing and treatment down a notch as evidence changes or the patient's health, age and lifestyle change.

To truly help patients, it's time to include clear off-ramp instructions for providers and patients, especially in primary care, say the authors of a new study published in JAMA Internal Medicine.

They lay out a process for doing so, based on an intensive review of hundreds of recommendations built on reams of research and evidence. Backed by a panel of expert advisors from a wide range of fields, they identify an initial set of 37 specific instances where physicians could deintensify care safely for certain patients.

"For many years, we've been focused on making sure patients get all the care they need, because there were deficits," says Eve Kerr, M.D., M.P.H., lead author of the study and a professor in the Department of Internal Medicine at the University of Michigan and Senior Investigator at the VA Center for Clinical Management Research. "But there are times when patients are getting care too frequently or more intensely than they might have once needed. Those are opportunities to improve their care without harming their health, or perhaps even reducing risk and increasing quality of life."

A new framework to build on

Kerr and her colleagues from Michigan Medicine, U-M's academic medical center, and the VA Ann Arbor Healthcare System emphasize that their new paper sets out a framework for future efforts by guideline developers to offer specific guidance on right-sizing care.

The initial set of recommendations is tailored for adult primary care. But the authors hope that the professional societies that create treatment guidelines will be able to adopt their approach to more precisely frame future recommendations to encompass not only when to start treatments or screening, but also when to stop or scale them back.

For instance, as people with diabetes get older, they don't need to take multiple medications to lower their blood sugar or blood pressure to the same target number they aimed for when they were younger. That's because the evidence that supports those low targets comes from studies that focused on preventing diabetes-related problems decades in the future. Plus, older patients are at higher risk from low blood sugar that these medications may cause.

Or, in another example, men who have been used to getting a periodic blood test for prostate specific antigen to look for possible signs of prostate cancer can stop getting tested after about age 69 - unless they're African-American or have a family history of prostate cancer and thus at higher risk.

These types of guideline-based deintensifications were only included in the new paper's appendix after undergoing a thorough review using a formal structure that clearly stated when and for whom a treatment or test should be scaled back, and confirmatory ratings by experts in the field.

"We hope this can be a reproducible process for identifying and specifying opportunities to deintensify care, with enough information to guide measurement," says Kerr.

But she and her colleagues firmly note that no individual physicians should be penalized for failing to deintensify care, because of the important role of patient preference and clinical nuance. Instead, health care systems could use the highly specified recommendations from this study to track and improve deintensification for their population of patients.

Moving forward

Over time, if health systems incorporate deintensification recommendations into their electronic health record systems, they could help prompt physicians to discuss deintensification with appropriate patients. And they could track aggregate data about how well the system as a whole is doing.

"We need to move toward a place of balance in our clinical care delivery," says senior author Timothy Hofer, M.D., M.Sc., professor of internal medicine at U-M and investigator at the VA CCMR. "If we make recommendations about starting a form of care, we should also say when to stop, and include specification about populations and times and actions for doing so."

The authors point to data from the National Poll on Healthy Aging, based at U-M's Institute for Healthcare Policy and Innovation, which found that only 14% of older adults believe that "more is usually better" when it comes to medical care, and that 25% agree with the statement that their health providers often order tests and treatments that the patients don't feel are needed.

In an accompanying editorial also published today, evidence-based medicine researchers Raj Mehta, M.D., and Richard Lehman, BM, BCh, write that "clinical practice has always involved decisions to do less--it just lacks the momentum and formalization needed for broad support. Guidelines focused on deintensification may be the signal of change needed to empower health care practitioners to reverse the trend of unnecessary care and counter the existing bias to do more."

The team that wrote the new paper is working to study how often patients are receiving care that might once have been right for them but is now too intense. Kerr heads the Michigan Program on Value Enhancement at IHPI, which brings together IHPI researchers and Michigan Medicine clinicians to develop and test new ways to right-size care in real-world settings.

NEW YORK (September 14, 2020) -- Neonatal intensive care units (NICU) should balance prevention of Staphylococcus aureus infections in critically ill infants with the need for skin-to-skin contact with parents and siblings, according to a Society for Healthcare Epidemiology of America (SHEA) white paper published in the journal Infection Control & Hospital Epidemiology. The paper serves as a practical clinical companion to the newly released recommendations from the Centers for Disease Control and Prevention's (CDC) Healthcare Infection Control Practices Advisory Committee to help clinicians in NICUs make decisions about infection prevention, detection, and control practices.

"Infants remain at risk for Staph infections, yet there are effective strategies to decrease transmission that can easily be applied within the NICU without sacrificing the vital benefits these very young, tiny infants receive from care and bonding with parents, caregivers or other close relatives," said Ibukun Akinboyo, MD, an author of the paper and medical director of pediatric infection prevention at Duke University Hospital. "Limited literature exists on prevention of Staph in the NICU, so this document looks to address common challenges faced by healthcare personnel in this environment."

The paper, SHEA neonatal intensive care unit (NICU) white paper series: Practical approaches to Staphylococcus aureus disease prevention, provides expert opinion and evidence-based responses to frequently asked questions clinicians may have in implementing the updated CDC guidance for preventing, detecting, and controlling the spread of Staph infections, including methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA). Staph infections can become serious in NICU patients and are often associated with medical devices, like catheters used for feeding and medication, as well as direct and indirect exposure to bacteria on healthcare personnel, parents, caregivers, family members, other critically ill infants, and the healthcare environment.

The document discusses how to safely handle Staph bacteria colonization and infection in parents or visitors and in NICU patients, including hospitalized multiples (e.g., twins or triplets) with different colonization or infection statuses. The document can also help guide decisions about when and how to decolonize infants who have asymptomatic S. aureus or MRSA, while taking into account safety considerations for this patient population.

The authors note that recommendations may need to be adjusted during outbreaks of S. aureus or MRSA to address specific issues.

Thermography has been a hot topic this year, due to the need for quicker diagnostics to detect and prevent the spread of COVID-19. Noncontact infrared thermometers (NCITs) are currently a primary tool for fever screening, but their widespread use has been prone to inaccuracy. A related medical technology, thermography using infrared thermographs (IRTs), enables increased options for temperature estimation with greater accuracy. Although the use of thermography as a stand-alone detection method for COVID-19 is unlikely to prevent spread, emerging evidence and international consensus suggest that it is indeed possible to use IRTs effectively for detecting elevated body temperatures.

A report published in the Journal of Biomedical Optics provides robust insights for optimizing IRT-based fever screening. The research, performed by Quanzeng Wang and collaborators at the Center for Devices and Radiological Health of the US Food and Drug Administration (FDA), evaluated the use of IRTs under standardized conditions. They examined clinical data for more than 500 demographically diverse individuals, including 47 subjects with elevated oral temperatures (>37.5 °C), correlating facial temperatures to oral under-the-tongue thermometer measurements. The team confirmed the utility of internationally recognized (ISO) standards for obtaining consistently accurate results, and specifically reported the efficacy of ISO methods, including facial area targets.

How do IRTs work?

We radiate heat as infrared energy, which changes as we get warmer. IRTs are camera systems that can sense infrared energy, allowing us to "see" the infrared waves. These readings display as a two-dimensional temperature distribution that correlates to temperature levels at the source. A human face typically shows varying temperatures, warmer where the larger arteries are closer to the surface of the skin such as the inner canthi (the eye corners where the tear ducts reside) and temples.

Optimizing IRTs

Like any technology, IRTs are subject to fundamental device and performance variations, which affect overall accuracy when used in medical practice. To minimize such variations, FDA researchers incorporated the ISO guidelines in their experiments (e.g., controlling ambient conditions, requiring individuals to acclimatize for 15 minutes prior to screening, etc.). They reported excellent IRT performance with clear correlations between IRT readings and oral temperature baseline data.

Aside from demonstrating the effectiveness of standardized methods for fever screening, some key insights emerged from the team's analysis.

One of the most significant insights was that targeting the full face for temperature screening resulted in greater accuracy than narrowly targeting the inner canthi, as recommended by the ISO guidelines. This insight could be helpful in establishing future directions with these devices, as full-face imaging is much easier to implement since it does not require complex facial feature detection software to identify the inner canthi regions. The next-best performance included the extended inner canthi area that includes but is wider than the inner canthi regions recommended by the ISO guidelines. Targeting the narrow canthi regions produced third-best accuracy.

FDA researchers calculated a series of cutoff levels to optimize the sensitivity and specificity values of the IRT readings. Although there is no uniform consensus on what temperature constitutes a fever, an oral temperature in the range of 37.5°C to 38°C (99.5°F to 100.4°F) is most commonly used in the medical profession as the threshold. The authors caution that determining an appropriate cutoff temperature for real-world fever screening involves complex considerations, such as the likely rate of false positives or negatives, as well as such matters as delay times, staffing, asymptomatic illness, and related costs to health agencies.

IRT-based fever screening

If conducted according to standardized protocols to ensure accuracy, IRT-based fever screening may effectively identify individuals with elevated body temperatures including low-grade fevers (oral temperature?37.5°C) associated with early-stage infections and moderate symptoms. According to Zane Arp, Director of the Division of Biomedical Physics at the FDA, "IRT-based fever screening, especially in regard to addressing COVID-19, should be one element in a multilayered diagnostic process that would include other helpful tools. When used in combination with other diagnostics and medical screening it is a much more useful tool in detecting those who are ill." For COVID-19 in particular, the FDA has published fact sheets on the proper use and limitations of these systems.

Given the potential value of IRTs for medical diagnostics, optimizing IRT-based fever screening is important, yet there remains much to learn. According to Wang, the FDA team plans further analysis to assess the potential impact of such factors as environmental and intersubject variability.

ITHACA, N.Y. - Posted on Facebook, milestones such as birthdays and anniversaries prompt users to reflect on the passage of time and the patterns of their lives - and help the social media giant recycle content in order to boost engagement, according to new Cornell research.

And although these anniversaries seem like a signature product of the social media age, they stem from newspapers' tradition of printing historical events that happened "on this date," said Lee Humphreys, associate professor of communication in the College of Agriculture and Life Sciences.

"We find it helpful to look back at things; it helps us think about the patterns and rhythms in life," said Humphreys, author of "Birthdays, Anniversaries and Temporalities: Or How the Past Is Represented as Relevant Through On-This-Date Media," which published Sept. 3 in the journal New Media and Society.

"Looking back at our previous posts helps us to understand where we are today," Humphreys said. "We think about how much we've grown, how much we've changed, how our children have changed, how our relatives have changed. The past takes on new meaning based on our current experiences."

During the pandemic, reviewing past milestones or events might be particularly reassuring, Humphreys said, since they remind us that one day we'll be looking back at it.

"Given the amount of uncertainty in the world, it's helpful to look back," she said. "Whether they were good experiences or bad experiences, we came out of them, and we're still here. It gives us a sense of the longer term."

Birthdays in general are an unusual ritual, Humphreys said: We don't remember our own births, so the celebration is often tied both to reflection and our place in our families and communities. That's especially true on social media, because birthday announcements and wishes are public.

"There's a sense of social connectivity that comes from celebrating birthdays - it's something you wish someone because it's a way of reinforcing social ties and the familial unit," she said. "But the other element, when it gets translated to social media, is the performative aspect. When I wish someone a happy birthday on Facebook, I'm doing so publicly, so I'm reinforcing our social connection in front of a larger audience."

The paper grew out of Humphreys' ongoing work on how people incorporate social media into their everyday lives, and her 2018 book, "The Qualified Self: Social Media and the Accounting of Everyday Life," which compared social media to pre-digital traditions such as scrapbooking and diary-keeping.

"So much of the social media environment is about real time and this notion that time is speeding up; it's all about what's going on right now and fear of missing out and having to be online at all times," she said. "So what I was trying to do is point out different ways time is working, besides this real-time access. Comparing it to the newspaper lists was really helpful, because it's a daily cycle of what's relevant today."

"On this date" lists, compiled for decades by The Associated Press for use in publications or broadcasts, collect anniversaries of major national or international events - encouraging people to put time in perspective by remembering where they were at the time, for example. Although social media anniversaries and birthdays are far more customized to individual lives, both serve similar functions - for readers as well as the media companies.

"We often think about the social media environment as being incredibly new and different, and part of what we're trying to do in this paper is show how they are really drawing on very similar practices of 20th-century media companies: reusing material in ways that feel fresh and new," she said. "There's an economic incentive for media companies - whether Facebook or newspapers - to use historical content as ready-made new content."

The lists, and the anniversaries, also help orient us around a unit of time that is important to both Facebook and newspapers: the 24-hour day.

"To newspapers, it's their publication cycle; to social media companies, daily active users is one of their key performance metrics," she said. "For us, it's not just reminiscing about the past. It's about where I am today, and how I am experiencing this moment."

The United States has seen a 200% increase in the rate of deaths by opioid overdose in the last 20 years. But many of these deaths were preventable. Naloxone, also called Narcan, is a prescription drug that reverses opioid overdoses, and in more than 40 states -- including Pennsylvania -- there is a standing order policy, which makes it available to anyone, without an individual prescription from a healthcare provider.

Members of the public can carry naloxone in case they encounter a person experiencing an opioid overdose. But how do you know if someone needs naloxone and how do you administer it? Health care providers are often trained to respond in these types of situations, and prior to the onset of COVID-19, public health organizations were offering in-person trainings to the public.

But how do we get even more people trained and motivated to save lives from opioid overdoses, especially in our current socially distanced world?

A group of interdisciplinary researchers from the University of Pennsylvania and the Philadelphia Department of Public Heath developed a virtual reality immersive video training aimed at doing just that. Their new study -- published recently in Drug and Alcohol Prevention -- shows that the VR training is just as effective as an in-person training at giving the public both the knowledge and the confidence they need to administer naloxone and save lives.

"Overdoses aren't happening in hospitals and doctor's offices," says Nicholas Giordano, former Lecturer at Penn's School of Nursing. "They're happening in our communities: in parks, libraries, and even in our own homes. It's crucial that we get the ability to save lives into the hands of the people on the front lines in close proximity to individuals at risk of overdose."

The researchers adapted a 60 minute in-person training, the educational standard for health care providers, into a 9-minute immersive virtual reality video. Then the interdisciplinary team tested the VR training on members of the public at free naloxone giveaways and training clinics hosted by the Philadelphia Department of Health at local libraries. (The clinics were held in 2019 and early 2020, before the coronavirus pandemic made such events unsafe.)

Roughly a third of the 94 participants received one-on-one in-person instruction on how to administer naloxone, while the others watched the experimental VR training. After the initial training, participants answered questions about the training to determine if they'd learned enough information to safely administer naloxone in the case of an opioid overdose.

Before leaving the library, all participants were given the opportunity to receive whichever training they didn't receive initially. Since the VR training was still in testing mode, the researchers wanted to ensure that all participants had full access to what they came for: knowledge of how to save lives.

"We were really pleased to discover that our VR training works just as well as an in-person training," says Natalie Herbert, a 2020 graduate of Penn's Annenberg School for Communication. "We weren't looking to replace the trainings public health organizations are already offering; rather, we were hoping to offer an alternative for folks who can't get to an in-person training, but still want the knowledge. And we're excited to be able to do that."

In addition to continuing to test their VR training, the researchers plan to begin making it available to the general public through partnerships with libraries, public health organizations, and other local stakeholders. With grant support from the Independence Blue Cross Foundation, the team will be disseminating and promoting the VR training throughout the Greater Philadelphia Area. Now, more than ever, the portability and immersive aspects of this VR raining can be leveraged to expand access to overdose training. For more information on how to experience the VR training, which can be used at home through Google Cardboard or other VR viewers, visit their website: https://www.virtualinnovation.org.

Launching a dual-pronged attack on tumours using a combination of two innovative precision medicines could treat patients with multiple common cancers, a new clinical trial shows.

It is the first trial to use the pioneering genetically targeted drug olaparib - already licensed for ovarian, breast and prostate cancer - together with a promising new medicine, called capivasertib.

The researchers used the drug combination to target two fundamental weaknesses in cancer at the same time - a damaged system for repairing DNA, and 'addiction' to a molecule called AKT which fuels tumour growth.

The early-stage trial, led by a team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, found that the drug combination was safe, successfully hit its targets, and was effective against a variety of advanced cancers - including those that had stopped responding to chemotherapy.

This combination is now planned to move forward into larger-scale trials. The study was published in the prestigious journal Cancer Discovery.

The Institute of Cancer Research (ICR) played a key role in pioneering both of the two precision medicines in the combination - discovering how to genetically target olaparib, and collaborating to create a precursor to capivasertib before the drug's ultimate formulation by AstraZeneca.

The new study is an exemplar of the research the ICR will be doing in its revolutionary new Centre for Cancer Drug Discovery, which aims to use combination treatments to cut off cancer's evolutionary pathways and overcome drug resistance.

In the phase I trial, researchers gave 64 patients with advanced solid tumours - including those with breast cancer, ovarian cancer and prostate cancers -combinations of olaparib and capivasertib.

The combination was well tolerated, and 25 of the 56 patients whose response could be assessed - or 45 per cent - benefited from treatment, with their tumours either shrinking or stopping growing.

Some of these patients had previously stopped responding to chemotherapy and other targeted treatments as their cancers became drug resistant.

Many of the patients who responded to the treatment had mutations to genes involved in repairing DNA, including to the BRCA genes.

The trial was funded by the pharmaceutical company AstraZeneca, under the auspices of the Cancer Research UK Experimental Cancer Medicine Centre Combinations Alliance.

The findings provide early clinical evidence that olaparib and capivasertib have the potential to work well as a combination treatment and could improve outcomes for some patients with drug-resistant cancer.

The team are now planning further, later-stage clinical trials to assess the drug combination's benefit and to study its effect in patients whose tumours do not have faults in the AKT gene or related to DNA repair.

The ICR is the most successful academic institution in the world at discovering cancer drugs - having discovered 20 new drug candidates since 2005. The ICR is nearing completion of a new Centre for Cancer Drug Discovery, and is now raising money for the state-of-the-art equipment its scientists will need to get their work in the building off to the strongest possible start.

Study leader Professor Johann de Bono, Professor of Experimental Cancer Medicine at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said:

"Our study establishes the potential of a combination of two precision medicines for patients whose tumours have stopped responding to existing drugs. The combination of olaparib and capivasertib works by attacking two fundamental weaknesses in cancer, and could potentially be used to treat patients with several common tumours. I look forward to seeing the possible benefit of the combination tested in later-stage trials."

Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said:

"This new clinical trial is a terrific example of how we can now translate scientific discoveries about the biology of cancer cells into innovative new cancer treatments with real benefits for patients. It's also an example of the pioneering strategy we have adopted at the ICR of targeting cancer evolution and drug resistance - often through the use of combination treatments to hit multiple targets at once and block off escape routes, just as is done with diseases like HIV.

"It's very exciting to see two drugs pioneered thanks to the ICR's research now being used together in patients, with the real possibility that they could offer an urgently needed new treatment option for patients whose cancers have become resistant to current treatments."

Staying close to home and avoiding crowded places can help older adults reduce their risk of COVID-19. But a new national poll suggests it comes with a cost, especially for those with health challenges.

In June of this year, 56% of people over the age of 50 said they sometimes or often felt isolated from others - more than double the 27% who felt that way in a similar poll in 2018. Nearly half of those polled in June of this year also said they felt more isolated than they had just before the pandemic arrived in the United States, and a third said they felt they had less companionship than before.

Social contacts suffered too, with 46% of older adults reporting in June that they infrequently interacted with friends, neighbors or family outside their household - doing so once a week or less -- compared with 28% who said this in 2018.

The new findings come from the National Poll on Healthy Aging, which is done for the University of Michigan's Institute for Healthcare Policy and Innovation with support from AARP and Michigan Medicine, U-M's academic medical center. Both the 2020 and 2018 polls on loneliness involved a national sample of more than 2,000 adults aged 50 to 80.

The poll points to some bright spots, too. For instance, the 46% of older adults who said they interacted with people in their neighborhood at least once a week were less likely to say they'd experienced forms of loneliness. Technology also helped many people over 50 connect with others, including the 59% who reported using social media at least once a week, and the 31% who used video chat at least once a week.

And many older adults said they engaged in healthy behaviors despite the pandemic -- including 75% who said they were getting outdoors or interacting with nature, and 62% who said they got exercise several times a week. But those experiencing loneliness were less likely to engage in these healthy behaviors.

"As the pandemic continues, it will be critical to pay attention to how well we as a society support the social and emotional needs of older adults," says John Piette, Ph.D., a professor at the U-M School of Public Health who worked with the poll team. "The intersection of loneliness and health still needs much study, but even as we gather new evidence, all of us can take time to reach out to older neighbors, friends and relatives in safe ways as they try to avoid the coronavirus."

"The change we see in these measures in less than two years is truly remarkable," says Preeti Malani, M.D., the U-M Medical School professor who directs the poll and has training in geriatrics and infectious diseases. "The use of technology to bridge the gap, and the importance of keeping up healthy routines like exercise, sleep, a balanced diet and getting outside, will no doubt continue to be important in the months ahead."

Interactions with health and lifestyle

Malani notes that 80% of those polled in June said they were eating a healthy diet, and 81% said they got enough sleep - almost exactly the same as in the 2018 poll.

The poll also found that half of those who live alone, and just over half (52%) of those who are unemployed or disabled, said they felt a lack of companionship, compared with 39% of those who live with others, work or are retired.

Similarly, just over half of those who said their physical health was fair or poor, and two-thirds of those who said the same about their mental health, said they lacked compantionship. Nearly three-quarters of those who said their mental health was fair or poor said they felt isolated, compared with 55% of those reporting better mental health.

The use of technology to connect appears to be a double-edged sword, with those who use social media and video chat being more likely to say they felt isolated.

Moving forward

As the pandemic continues, and older adults try to avoid coronavirus infection and the outsize risk to their health, AARP is offering resources, including tips for older adults to avoid feeling isolated despite the pandemic. AARP Foundation's Connect2Affect website includes a tool that can help older adults assess their level of isolation, and connect them to resources and opportunities in their area.

"Past studies have shown that prolonged isolation has a profound negative effect on health and wellbeing -- as much as smoking 15 cigarettes a day," says Alison Bryant, Ph.D., senior vice president of research for AARP. "It's not surprising that older adults reported more loneliness since the pandemic began, particularly those who live alone. We need to continue finding ways to connect and engage with one another throughout this public health crisis."

The National Academies of Sciences, Engineering and Medicine issued a report in February 2020 about the need for the health care system to help in preventing, identifying and addressing loneliness in people over 50.

The National Poll on Healthy Aging results are based on responses from a nationally representative sample of 2,074 adults aged 50 to 80 who answered a wide range of questions online. Questions were written, and data interpreted and compiled, by the IHPI team. Laptops and Internet access were provided to poll respondents who did not already have them.

Why does exercise training make you more fit? It's well established that exercising enhances insulin sensitivity and improves our metabolism that, in turn, increases exercise performance. But the biological mechanisms underlying this adaptation are not fully understood.

New research published in the journal PNAS suggests that part of the explanation rests on how skeletal muscle and fat tissue communicate with each other. The research was led by CBMR's Associate Professor Jonas Treebak from the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) at the University of Copenhagen, together with Assistant Professor Marcelo A. Mori from the University of Campinas.

DICER primes fat to help muscles

In experiments in both mice and humans, they found that short-term exercise training increases levels of the enzyme DICER in fat cells. DICER in fat helps muscles adapt to exercise and increase performance because it primes fat cells to release fatty acids into the bloodstream that muscles need.

The scientists argue that DICER works by regulating a microRNA molecule that stops fat from utilizing glucose from the bloodstream. Their study shows that mice, which cannot produce DICER, do not get more fit from exercising, and even develop obesity.

However, if you transfer blood from previously exercised mice into non-exercised mice, it increased levels of DICER in the fat of non-exercised mice. This suggests that exercise training causes muscles to release a molecule that causes fat cells to produce more DICER.

An unknown circulating factor

Associate Professor Jonas Treebak says: "The idea that skeletal muscle signals to other tissues in response to exercise is not new, and although the specific signal from muscle remains elusive, we have identified a signalling axis between muscle and fat that is central for the adaptive response in muscle to exercise training."

He adds: "The next steps are obviously to identify the circulating factor from skeletal muscle as well as to identify the target(s) of the specific microRNA."

Following a large-scale clinical trial, researchers have found that lanthanum carbonate does not reduce the risk of cardiovascular disease developing in patients with chronic kidney disease.

The drug is routinely prescribed to patients with chronic kidney disease to help reduce the risk of both bone disease and cardiovascular disease, with cardiovascular disease the most common complication and cause of death for this group.

The new findings follow a seven-year clinical trial led by a collaboration of kidney disease specialists from Australia, New Zealand and Malaysia as well as The University of Queensland's Australasian Kidney Trials Network, which is based at the Translational Research Institute.

Co-Principal Investigator, Associate Professor Nigel Toussaint from The Royal Melbourne Hospital, says high phosphate levels are a common problem in kidney disease and are linked to the onset and degree of cardiovascular disease.

"Phosphate binder medication has long been a treatment for high phosphate levels in people with kidney disease, especially those on dialysis," said A/Prof Toussaint.

"There was some evidence that phosphate lowering may be effective in reducing risk factors for cardiovascular disease, but there were no adequate studies looking at the effect of lanthanum carbonate on cardiovascular risk factors in people with chronic kidney disease not on dialysis.

"In our clinical trial involving more than 270 patients from 18 hospitals, we found that lanthanum carbonate did not have a beneficial effect on cardiovascular disease indicators such as arterial stiffness or aortic calcification when compared to placebo."

The study was the largest trial of its kind to look at the effect of lanthanum carbonate, a phosphate binder medication, in people with chronic kidney disease.

The results will be critical for Nephrologists to determine the best treatment pathways for patients and provide high value care, according to lead New Zealand Investigator, Professor Rob Walker from Dunedin Hospital.

"The pill and symptom burden along with the economic impact for people with chronic diseases is very high, and if we can determine that certain treatments provide limited benefit then that is just as important as finding something that works," said Prof Walker.

Australasian Kidney Trials Network Chair of the Executive Operations Secretariat, Professor Carmel Hawley said that while further trials were needed to ensure consistency of the findings and generalizability of the results, in relation to phosphate binders, the use of these medications was associated with significant side-effects, particularly gastrointestinal, and they were inconvenient as they have to be taken with meals.

Clinicians enrolled 278 adult participants who had stage 3 or 4 chronic kidney disease from 18 hospitals across Australia, New Zealand and Malaysia. Half the participants received lanthanum carbonate and the other half of participants received a placebo for 96 weeks.

During the trial, clinicians performed pulse wave velocity - a measure of stiffness of arteries - and CT scans looking at calcium build up in arteries. Medical information was collected and blood samples taken. This was the longest trial to date in this study population.

The main results for the IMPROVE-CKD trial were published in the Journal of the American Society of Nephrology, with an editorial also published in the journal.

Lanthanum carbonate reduces the absorption of dietary phosphate from the gut, and its ability to potentially lower phosphate balance in the body was thought to possibly prevent stiffening of blood vessels.

Approximately 1.7 million Australians and 400,000 New Zealanders aged 18 years and over have chronic kidney disease. Many people have a progressive decline in kidney function, also known as progression of chronic kidney disease, to the point of needing dialysis or kidney transplantation. In Australia and New Zealand, about 3600 individuals progress to end-stage kidney disease each year. There are more than 15,500 individuals receiving dialysis.

The IMPROVE-CKD study was sponsored by The University of Queensland, coordinated by the Australasian Kidney Trials Network and funded through research grants from the National Medical and Medical Research Council (NHMRC) and Shire International GmbH, a member of the Takeda group of companies, IST-AUS-000108.