Body

DALLAS, Jan. 6, 2021 -- Statins, common cholesterol-lowering medications, may protect women's hearts from damage caused during chemotherapy for early-stage breast cancer, according to new research published today in the Journal of the American Heart Association, an open access journal of the American Heart Association.

"Two types of cancer medications, anthracyclines and trastuzumab, are effective treatments for many women with breast cancer, however, the risk of heart muscle damage has limited their use, particularly in women who are at higher risk for heart problems because of their age or other medical issues," said Husam Abdel-Qadir, M.D., Ph.D., lead author of the study, assistant professor of medicine at the University of Toronto's Institute of Health Policy, Management and Evaluation, and a cardiologist at Women's College Hospital and the Peter Munk Cardiac Centre, part of the University Health Network in Toronto.

"The mechanisms for these medications are essential to kill breast cancer cells, however, these processes can also damage the cells of the heart muscle, leading to weakening of the heart," he said.

Previous small studies have suggested that women taking statins may have less heart muscle damage from these types of chemotherapy. The exact mechanisms of how statins protect against the cardiac cell damage remains unknown. It is believed that statins have antioxidative and anti-inflammatory actions.

For the current study, researchers used several administrative health databases in Ontario, Canada, to review the occurrence of heart failure in women ages 66 and older who received anthracyclines or trastuzumab for newly diagnosed early-stage breast cancer between 2007 and 2017. Each woman already taking statins was matched with a peer who was not taking statins as well as a variety of medical and social background factors. The two groups were compared to understand how many required hospitalizations or an emergency room visit for heart failure within the five years after chemotherapy. None had previously been diagnosed with heart failure.

Researchers found:

In the 666 pairs of women (median age 69) treated with anthracyclines, those taking statins were 55% less likely to be treated at the hospital for heart failure (1.2% vs. 2.9%).
In the 390 pairs of women (median age 71) treated with trastuzumab, those taking statins were 54% less likely to be treated at the hospital for heart failure (2.7% vs. 3.7%), a trend that did not reach statistical significance.
"Our findings support the idea that statins may be a potential intervention for preventing heart failure in patients receiving chemotherapy with anthracyclines and potentially trastuzumab," Abdel-Qadir said.

This observational study found an association but cannot conclude that there is a cause-and-effect relationship between taking statins and a lower risk of heart failure.

"This study does not conclusively prove statins are protective," Abdel-Qadir said. "However, this study builds on the body of evidence suggesting that they may have benefits. For women with breast cancer who meet established indications for taking a statin, they should ideally continue taking it throughout their chemotherapy treatment. Women who do not have an indication for a statin should ask their health care team if they can join a clinical trial studying the benefits of statins in protecting against heart muscle damage during chemotherapy. Otherwise, they should focus on measures to optimize their cardiovascular health before, during and after chemotherapy."

Findings from this study in older women may not be generalizable to younger women or to those at low cardiovascular risk who do not meet current indications for a statin. Because the populations are similar in terms of demographics, these results from Canada are likely generalizable to women in the United States. Other limitations include that the study is a retrospective analysis that relied on administrative data, and the researchers could not account for potentially important factors that were not available, including the heart's pumping ability and heart biomarkers.

A new advanced computing technique using routine medical scans to enable doctors to take fewer, more accurate tumour biopsies, has been developed by cancer researchers at the University of Cambridge.

This is an important step towards precision tissue sampling for cancer patients to help select the best treatment. In future the technique could even replace clinical biopsies with 'virtual biopsies', sparing patients invasive procedures.

The research published in European Radiology shows that combining computed tomography (CT) scans with ultrasound images creates a visual guide for doctors to ensure they sample the full complexity of a tumour with fewer targeted biopsies.

Capturing the patchwork of different types of cancer cell within a tumour - known as tumour heterogeneity - is critical for selecting the best treatment because genetically-different cells may respond differently to treatment.

Most cancer patients undergo one or several biopsies to confirm diagnosis and plan their treatment. But because this is an invasive clinical procedure, there is an urgent need to reduce the number of biopsies taken and to make sure biopsies accurately sample the genetically-different cells in the tumour, particularly for ovarian cancer patients.

High grade serous ovarian (HGSO) cancer, the most common type of ovarian cancer, is referred to as a 'silent killer' because early symptoms can be difficult to pick up. By the time the cancer is diagnosed, it is often at an advanced stage, and survival rates have not changed much over the last 20 years.

But late diagnosis isn't the only problem. HGSO tumours tend to have a high level of tumour heterogeneity and patients with more genetically-different patches of cancer cells tend to have a poorer response to treatment.

Professor Evis Sala from the Department of Radiology, co-lead CRUK Cambridge Centre Advanced Cancer Imaging Programme, leads a multi-disciplinary team of radiologists, physicists, oncologists and computational scientists using innovative computing techniques to reveal tumour heterogeneity from standard medical images. This new study, led by Professor Sala, involved a small group of patients with advanced ovarian cancer who were due to have ultrasound-guided biopsies prior to starting chemotherapy.

For the study, the patients first had a standard-of-care CT scan. A CT scanner uses x-rays and computing to create a 3D image of the tumour from multiple image 'slices' through the body.

The researchers then used a process called radiomics - using high-powered computing methods to analyse and extract additional information from the data-rich images created by the CT scanner - to identify and map distinct areas and features of the tumour. The tumour map was then superimposed on the ultrasound image of the tumour and the combined image used to guide the biopsy procedure.

By taking targeted biopsies using this method, the research team reported that the diversity of cancer cells within the tumour was successfully captured.

Co-first author Dr Lucian Beer, from the Department of Radiology and CRUK Cambridge Centre Ovarian Cancer Programme, said of the results: "Our study is a step forward to non-invasively unravel tumour heterogeneity by using standard-of-care CT-based radiomic tumour habitats for ultrasound-guided targeted biopsies."

Co-first author Paula Martin-Gonzalez, from the Cancer Research UK Cambridge Institute and CRUK Cambridge Centre Ovarian Cancer Programme, added: "We will now be applying this method in a larger clinical study."

Professor Sala said: "This study provides an important milestone towards precision tissue sampling. We are truly pushing the boundaries in translating cutting edge research to routine clinical care."

Fiona Barve (56) is a science teacher who lives near Cambridge. She was diagnosed with ovarian cancer in 2017 after visiting her doctor with abdominal pain. She was diagnosed with stage 4 ovarian cancer and immediately underwent surgery and a course of chemotherapy. Since March 2019 she has been cancer free and is now back to teaching three days a week.

"I was diagnosed at a late stage and I was fortunate my surgery, which I received within four weeks of being diagnosed, and chemotherapy worked for me. I feel lucky to be around," said Barve.

"When you are first undergoing the diagnosis of cancer, you feel as if you are on a conveyor belt, every part of the journey being extremely stressful. This new enhanced technique will reduce the need for several procedures and allow patients more time to adjust to their circumstances. It will enable more accurate diagnosis with less invasion of the body and mind. This can only be seen as positive progress."

Analysis from a workshop convened by the National Institute of Neurological Disorders and Stroke (NINDS) in 2017 reveals gaps in and opportunities for research to improve understanding of the effects of traumatic brain injury (TBI) in women. A new paper in the Journal of Head Trauma Rehabilitation summarizes and updates the findings presented during the "Understanding Traumatic Brain Injury in Women" workshop and provides strategies for advancing research efforts in this area. NINDS is part of the National Institutes of Health.

"We are making advances in understanding the effects of head injury on the brain, but many of these studies have been done in males," said Patrick Bellgowan, Ph.D., program director at NINDS. "There is evidence that traumatic brain injury affects women differently, but we need focused research efforts to get a full understanding of those differences to help improve prevention and treatment strategies."

There are sex-based differences in TBI across the lifespan. For example, in children ages 0-4, boys are two times more likely to have a TBI than girls, but during the adolescent years, female athletes are likelier to experience concussions than male athletes. Among older populations, women who are 65 and older are most likely to experience mild TBI, and the majority of those result from falls.

Studies suggest that women may have different outcomes, depending on when during their menstrual cycle they were injured. For example, there is evidence that head injuries occurring during the luteal phase of the menstrual cycle, when levels of progesterone are high, may be associated with worse outcomes and decreased quality of life. Additional research on reproductive hormones, such as progesterone or estrogen, may provide important clues to recovery from head injury.

The report, written by Eva Valera, Ph.D., professor of psychiatry at the Harvard Medical School Boston, and her colleagues, highlights several opportunities for research looking at the biological effects of TBI, including imaging studies and examination of brain tissue for evidence of neuroinflammation and damage to neurons. Many preclinical studies have relied on male animals but including female animals will help inform researchers about sex differences in immediate response and recovery to TBI.

Not much is known about military-related TBI in female servicemembers, although studies have reported sex-based differences in symptoms as well as functional connectivity, which is the activity between brain regions. Increasing the number of female veterans in longitudinal research studies would increase knowledge about acute and long-term recovery of TBI in women.

"Discussions at the workshop identified a large gap in research efforts aimed at understanding the effects of violence-related TBI in women, in particular intimate partner violence," said Diana Cummings, Ph.D., NINDS scientific review officer.

Studies looking at the prevalence of brain injuries resulting from intimate partner violence are needed to understand how often they occur and could lead to identifying prevention strategies. More information about outcomes may result in improved treatment options.

A reduced sense of smell, or olfactory dysfunction, is one of the most common symptoms of COVID-19. A recent study published the Journal of Internal Medicine has examined it prevalence and recovery in patients with varying degrees of severity of COVID-19.

In the study of 2,581 patients from 18 European hospitals, the patient-reported prevalence of olfactory dysfunction was 85.9% in mild cases of COVID-19, 4.5% in moderate cases, and 6.9% in severe-to-critical cases. The average duration of olfactory dysfunction reported by patients was 21.6 days, but nearly one-quarter of affected patients reported that they did not recover their sense of smell 60 days after losing it.

Objective clinical evaluations identified olfactory dysfunction in 54.7% of mild cases of COVID-19 and 36.6% of moderate-to-critical cases of COVID-19. At 60 days and 6 months, 15.3% and 4.7% of these patients did not objectively recover their sense of smell, respectively.

"Olfactory dysfunction is more prevalent in mild COVID-19 forms than in moderate-to-critical forms, and 95% of patients recover their sense of smell at 6-months post-infection," said lead author Jerome R. Lechien, MD, PhD, MS, of Paris Saclay University.

Australian research has identified a new mechanism in which prostate cancer cells can 'switch' character and become resistant to therapy.

These findings, just published in Cell Reports, are an important development in unravelling how an aggressive subtype of prostate cancer, neuroendocrine prostate cancer (NEPC), develops after hormonal therapies.

It is well established that some tumours show increased cellular 'plasticity' in response to new or stressful conditions, such as cancer therapy, says lead researcher Associate Professor Luke Selth, from the Flinders Health and Medical Research Institute.

This plasticity allows the cancer cells to adapt and continue to grow by evolving into different cell types that no longer respond to the therapy.

"Increased cellular plasticity is increasingly recognised as a key feature by which prostate cancers become resistant to therapy and progress to a lethal stage," he says.

"Our new study reveals that a particular molecule, the microRNA 'miR-194', can enhance this plasticity in prostate cancer, leading to the emergence of NEPC.

"By targeting miR-194, we were able to slow down and inhibit the growth of prostate cancer models with neuroendocrine features."

Associate Professor Selth says while this study is a long way from clinical application, it "nevertheless provides us with important new insights into how prostate cancers 'evolve' in response to therapy".

There are currently no effective treatments for NEPC, with estimates up to 15% of men may develop this aggressive subtype of prostate cancer after hormonal treatment - a major problem because these men face "very poor outcomes".

"By revealing another regulator of prostate cancer cell plasticity that can promote evolution of tumours, our study highlights why prostate cancer is so difficult to cure.

"While this reality is sobering, we hope that our study and lots of other research going on around the world will eventually lead to smarter, more targeted ways to treat NEPC or even prevent its emergence," Associate Professor Selth says.

What The Study Did: Data from public health surveillance of reported COVID-19 cases and seroprevalence surveys were used in this observational study that reports an estimated 46.9 million SARS-CoV-2 infections, 28.1 million symptomatic infections, 956,174 hospitalizations and 304,915 deaths occurred in the U.S. through November 15, 2020.

Authors: Frederick J. Angulo, D.V.M., Ph.D., of  Medical Development and Scientific/Clinical Affairs of Pfizer Vaccines, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2020.33706)

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

BOSTON - Findings from the Nurses' Health Study, one of the longest running studies of women's health, show that five diet and lifestyle factors, including regular exercise, can make a significant impact on gastroesophageal reflux (GERD) or heartburn symptoms. GERD is a common condition, affecting about a third of the U.S. population; the main symptom is heartburn and it is often managed with medications. This new study suggests, however, that following diet and lifestyle guidelines may reduce symptoms substantially and could make medication unnecessary for some patients. It was published as a letter in JAMA Internal Medicine.

The five factors include normal weight, never smoking, moderate-to-vigorous physical activity for at least 30 minutes daily, restricting coffee, tea and sodas to two cups daily, and a "prudent" diet.

"This study provides evidence that common and debilitating gastrointestinal symptoms could be well controlled in many cases with diet and lifestyle modifications alone," says Andrew T. Chan, MD, MPH, the study's senior author. "Given that there are long-term health effects of GERD and lingering concerns about the side effects of medications used to treat it, lifestyle should be considered the best option for controlling symptoms." Chan is a gastroenterologist, chief of the Clinical and Translational Epidemiology Unit at MGH, and professor of medicine at Harvard Medical School. The lead author of the research letter is Raaj S. Mehta, MD, gastroenterology fellow at MGH and Harvard Medical School.

The Nurses' Health Study II is a nationwide study established in 1989 whose participants return a detailed health questionnaire twice a year. It began with 116,671 participants and has had follow-up that exceeds 90%. This study included data from almost 43,000 women aged 42 to 62 who were questioned about GERD or heartburn symptoms from 2005 to 2017 -- which represents approximately 390,000 person-years.

The researchers created a statistical model that allowed them to calculate the "population-attributable risk" for GERD symptoms associated with each of the five anti-reflux lifestyle factors -- in other words, they estimated how likely it was that each lifestyle factor lowered risk of experiencing symptoms. They found that following all these guidelines could reduce GERD symptoms overall by 37%. The more of the specific guidelines a woman followed, the lower her risk of symptoms. Among women using common heartburn treatments (proton pump inhibitors and H2 receptor antagonists), adhering to the guidelines also reduced symptoms.

"We were particularly interested in the effectiveness of physical activity," says Chan. "This is one of the first studies that has demonstrated its effectiveness in controlling GERD." This effect, he suggests, could be due in part to exercise's effect on the motility of the digestive tract. "Being physically active may help with the clearance of stomach acid which causes heartburn symptoms," he says.

SAN ANTONIO and CHICAGO - An article published Jan. 5 in Alzheimer's & Dementia: The Journal of the Alzheimer's Association cites decades of published scientific evidence to make a compelling case for SARS-CoV-2's expected long-term effects on the brain and nervous system.

Dementia researchers from The University of Texas Health Science Center at San Antonio (UT Health San Antonio) are the first and senior authors of the report and are joined by coauthors from the Alzheimer's Association and Nottingham and Leicester universities in England.

"Since the flu pandemic of 1917 and 1918, many of the flulike diseases have been associated with brain disorders," said lead author Gabriel A. de Erausquin, MD, PhD, Msc, professor of neurology in the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio. "Those respiratory viruses included H1N1 and SARS-CoV. The SARS-CoV-2 virus, which causes COVID-19, is also known to impact the brain and nervous system."

Dr. de Erausquin, an investigator with the Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases at UT Health San Antonio, said it is becoming clear that the damage done by the pandemic will not be limited to acute effects, such as delirium in the hospital, but will have chronic consequences that impact many individuals' quality of life and independence.

The question is to what degree and under what form. Even mild COVID-19 infections may have negative effects on the brain long term, Dr. de Erausquin said.

"As the Alzheimer's & Dementia article points out, the under-recognized medical history of these viruses over the last century suggests a strong link to brain diseases that affect memory and behavior," said Maria C. Carrillo, PhD, Alzheimer's Association chief science officer and a coauthor on the paper. "In this difficult time, we can create a 'silver lining' by capitalizing on the Alzheimer's Association's global reach and reputation to bring the research community together to illuminate COVID-19's long-term impact on the brain."

Urgently needed international study

The Alzheimer's Association is funding the initial work of a consortium of experts from more than 30 countries to understand how COVID-19 increases the risk, severity, pace and progression of neurodegenerative diseases such as Alzheimer's and psychiatric diseases including depression. Consortium members will enroll study participants selected from a pool of millions of confirmed COVID-19 cases documented in hospitals worldwide. A second group of enrollees will consist of people participating in existing international research studies. Participants will be evaluated on a host of measures at their initial appointment and again at six, nine and 18 months. These measures include cognition, behavior and, when possible, brain volumes measured by magnetic resonance imaging.

Infiltrating the brain

The coronavirus is known to enter cells via receptors called ACE2. The highest concentration of ACE2 receptors is in the olfactory bulb, the brain structure involved in the sense of smell.

"The basic idea of our study is that some of the respiratory viruses have affinity for nervous system cells," said senior author Sudha Seshadri, MD, professor of neurology in the Long School of Medicine at UT Health San Antonio and director of the Glenn Biggs Institute. "Olfactory cells are very susceptible to viral invasion and are particularly targeted by SARS-CoV-2, and that's why one of the prominent symptoms of COVID-19 is loss of smell."

The olfactory bulb connects with the hippocampus, a brain structure primarily responsible for short-term memory.

"The trail of the virus, when it invades the brain, leads almost straight to the hippocampus," Dr. de Erausquin said. "That is believed to be one of the sources of the cognitive impairment observed in COVID-19 patients. We suspect it may also be part of the reason why there will be an accelerated cognitive decline over time in susceptible individuals."

The authors point out that:

Intranasal administration of SARS-CoV-2 in mice results in rapid invasion of the brain.

Headache, hypogeusia (reduced ability to taste) and anosmia (loss of smell) appear to precede the onset of respiratory symptoms in the majority of affected patients.

SARS-CoV-2 can be found in the brain post-mortem.

Abnormal brain imaging that may be characterized by the appearance of lesions in different brain regions - and the appearance of other abnormal brain changes that may influence clinical presentation - has emerged as a major feature of COVID-19 from all parts of the world.

Abnormal imaging was seen in an individual whose only symptom was loss of smell.

The study will collect information over the next two to three years. Initial results are expected in early 2022 for the first set of evaluations. The consortium is aided by technical guidance from the World Health Organization.

NEW YORK, NY (1/5/2021) - Subtle changes in speech and language can be an early warning sign of Alzheimer's -- sometimes appearing long before other more serious symptoms. The challenge is recognizing these changes and determining what may signal Alzheimer's or other neurodegenerative disorders. In a commentary in Exploration in Medicine (November 24, 2020), Alzheimer's experts lay out a vision for a worldwide research consortium that can give clinicians - and patients - these answers in the form of digital biomarkers.

"Rapidly expanding use of smart devices, such as smart phones and digital wearables, is making it easier than ever to collect large amounts of speech and language data," says lead author Nicole Bjorklund, Ph.D., of the Alzheimer's Drug Discovery Foundation (ADDF). "What we need now is a unified approach for collecting, analyzing and sharing this information to create algorithms that can predict who will go on to develop Alzheimer's."

Dr. Bjorklund and Shobha Purushothama, Ph.D., a commentary co-author, are manager and senior director, respectively, of the ADDF's Diagnostics Accelerator. The Diagnostics Accelerator invests in research into the development of minimally invasive, low-cost and reliable biomarkers, such as measuring changes in speech and language, blood tests, and eye scans that can be used to diagnose Alzheimer's, track its progression, and improve design of clinical trials for treatments.

The commentary lays out a plan for creating a comprehensive, harmonized, open-access speech and language sample repository. To maximize its usefulness, this repository needs to include a diverse cohort of subjects representing different accents, languages, and verbal communication components. It should also include samples from people at different disease stages and include healthy controls with and without dementia risk factors for comparison. Samples also need to be collected from the same patients over time so researchers can develop biomarkers that can monitor disease progression.

"By combining the strength of experts in dementia research, linguistics, data analytics, and clinical trials, we can generate a gold standard data set," says co-author Lampros Kourtis, Ph.D., adjunct assistant professor at Tufts University and managing director of Circadic. "We can then comb through this data to find the patterns consistent with early signs of disease."

Co-author Kristina Malzbender, associate director of Health and Life Sciences at Gates Ventures, which partners with the ADDF on the Diagnostics Accelerator, says another key to the repository's usefulness depends on researchers' ability to access and analyze the data while maintaining patient privacy and data security. "We are optimistic that generating this type of high-quality data would be incredibly enabling for the field. In particular, approaches to data privacy are continually evolving and best practices should be implemented, revisited and refined when appropriate as the repository takes shape."

"Lightning-fast advances in data science, coupled with a greater understanding than ever about dementia, are opening up new and exciting avenues of research," says Howard Fillit, M.D., ADDF founding executive director and chief science officer. "The ADDF knows the value of partnerships--we employ them in our funding model and they're just as valuable in research. Alone, researchers have not been able to take full advantage of the opportunities digital technology afford, but together we can facilitate truly seismic shifts in neurodegeneration research."

Heating up cancer cells while targeting them with chemotherapy is a highly effective way of killing them, according to a new study led by UCL researchers.

The study, published in the Journal of Materials Chemistry B, found that "loading" a chemotherapy drug on to tiny magnetic particles that can heat up the cancer cells at the same time as delivering the drug to them was up to 34% more effective at destroying the cancer cells than the chemotherapy drug without added heat.

The magnetic iron oxide nanoparticles that carry the chemotherapy drug shed heat when exposed to an alternating magnetic field. This means that, once the nanoparticles have accumulated in the tumour area, an alternating magnetic field can be applied from outside the body, allowing heat and chemotherapy to be delivered simultaneously.

The effects of the two treatments were synergistic - that is, each treatment enhanced the effectiveness of the other, meaning they were more potent when combined than when separate. The study was carried out on cells in a lab and further research is needed ahead of clinical trials involving patients.

Senior author Professor Nguyen T. K. Thanh (Biophysics Group, UCL Physics & Astronomy) said: "Our study shows the enormous potential of combining chemotherapy with heat treatment delivered via magnetic nanoparticles.

"While this combination of therapy is already approved for the treatment of fast-growing glioblastomas, our results suggest it has potential to be used more widely as a broad anti-cancer therapy.

"This therapy also has potential to reduce the side effects of chemotherapy, by ensuring it is more highly targeted on cancer cells rather than healthy tissue. This needs to be explored in further pre-clinical tests."

In the study, researchers combined the magnetic nanoparticles with a commonly used chemotherapy drug, doxorubicin, and compared the effects of this composite in various scenarios on human breast cancer cells, glioblastoma (brain cancer) cells, and mouse prostate cancer cells.

In the most successful scenario, they found that heat and doxorubicin together killed 98% of brain cancer cells after 48 hours, when doxorubicin without heat killed 73%. Meanwhile, for the breast cancer cells, 89% were killed by heat and doxorubicin together, while 77% were killed after 48 hours by doxorubicin alone.

Cancer cells are more susceptible to heat than healthy cells - they undergo a slow death (apoptosis) once the temperature reaches 42 degrees Celsius, whereas healthy cells are able to withstand temperatures up to 45 degrees Celsius.

The researchers found that heating cancer cells by only a few degrees, to 40 degrees Celsius, enhanced the effectiveness of the chemotherapy, meaning the treatment could be effective with lower doses of nanoparticles.

They found the combination of therapies was most effective when the nanoparticles were absorbed, or internalized, by the cancer cells, but they found the chemotherapy was also enhanced when the nanoparticles shed heat while remaining outside the cancer cells (which would be an easier form of treatment to deliver). However, the effects at lower temperatures only occurred when the iron oxide nanoparticles were internalized or tightly deposited on to the surface of the cancer cells.

The nanoparticles also have a polymer coating that prevents the chemotherapy drug from leaching out into healthy tissue. The coating is heat and pH-sensitive, and is designed to release the drug when temperature rises and the nanoparticles are internalized within tiny pockets in cells called "lysosomes", which have a lower pH than the rest of the cell medium. This intracellular delivery of the drug was particularly effective for the mouse prostate cancer cells, which showed superior and synergetic cell death effect, especially when the temperature reached 42°C.

Co-author Dr Olivier Sandre, of the University of Bordeaux, said: "Since heat can be generated through the alternating magnetic field, the release of the drug can be highly localised to cancer cells, potentially reducing side effects."

OBESITY WEAKENS HEART MUSCLE IN PATIENTS WITH A COMMON TYPE OF HEART FAILURE

Media Contact: Vanessa McMains, Ph.D., vmcmain1@jhmi.edu

For decades, physicians have known that about half of all patients with heart failure appear to have hearts that contract normally -- a syndrome now known as heart failure with a preserved ejection fraction (or HFpEF, pronounced hef-pef). This type of heart failure was first seen primarily in slim, elderly women with high blood pressures and thicker heart muscle. But as the incidence of obesity and diabetes has increased, many patients with HFpEF are now found to be severely obese with blood pressures not as high and heart muscle not as thick as seen in previous patients.

New research from Johns Hopkins Medicine has uncovered that greater obesity seems to make muscle contraction much weaker in this very common form of heart failure.
In their study, published Dec. 2, 2020, in Circulation, the researchers say "the surprising findings upends the field," as it challenges the view that the disease is all about having a stiff heart that cannot relax.

"Obesity would seem to have changed the heart muscle," says senior study author David Kass, M.D., the Abraham and Virginia Weiss Professor of Cardiology at the Johns Hopkins University School of Medicine. "The "p" in HFpEF stands for preserved, and that's what contraction was supposed to be, and what HFpEF used to be. But, as more patients are obese and our results show this reduces contraction strength, we will need to rethink our concepts and along with it, our treatments."

Traditionally, this form of heart failure has been treated with medicines that often reduce contraction strength while improving the heart's relaxation. Further research, Kass says, will need to determine if this approach needs to be modified.

Johns Hopkins Medicine has one of the few dedicated HFpEF clinics in the country, run by study co-author Kavita Sharma, M.D., associate professor of medicine and director of the heart failure transplant program at the Johns Hopkins University School of Medicine.

As part of the evaluation of patients with HFpEF, a tiny piece of heart muscle is collected using a standard heart biopsy procedure. The biopsy samples taken from patients who were less obese (a body mass index, or BMI, averaging 30) but had high blood pressure and thick heart muscle were compared with those with severe obesity (BMI averaging 40) but lower blood pressure and less thick heart muscle. The investigators teased out single muscle cells from these samples and studied their function. When the researchers added calcium to stimulate the cells to contract, those from the less-obese group responded normally.

However, the force response to high calcium was reduced by 40% in cells from patients with obesity. In a third group of patients who had both high blood pressure and thicker hearts, as well as severe obesity, the force response in the cells given calcium was similarly reduced as in the mostly obese group. Kass and his colleagues believe this points to obesity as the key factor.

HFpEF was previously called diastolic heart failure, emphasizing the idea that although the heart could contract normally, it didn't properly fill with blood when the heart relaxed in preparation for the next beat (called diastole). While preserved contraction appears still true for less obese patients with high blood pressure and thick heart muscle, it doesn't appear to hold true when they also have severe obesity.

Severe obesity alters underlying human biology -- most recently brought in focus with the COVID-19 pandemic as obesity has been shown to be an independent risk factor for more severe disease and worse outcome. Many of COVID-19's effects on artery function, the immune system and inflammation, and metabolism and heart stress may also be relevant to HFpEF, the researchers say.

"We do not yet know why this reduced force happens," says Kass. "But, we are trying to figure it out with the goal of testing new and different drugs to improve contraction and personalize treatment for our patients with HFpEF and obesity."

Kass is available for interviews.

ARTIFICIAL ENZYME MAY BE FIRST STEP TOWARD TREATMENT FOR PARKINSON'S DISEASE

Media Contact: Ayanna Tucker, atucke25@jhmi.edu

A growing body of research has shown that misshapen and misfolded alpha-synuclein, the protein culprit behind Parkinson's disease and its characteristics, travels from the gut to the brain, where it spreads and sticks together in lethal clumps known as Lewy bodies. As these clumps accumulate, they cause brain cell death.

Now, Johns Hopkins Medicine researchers have created an artificial enzyme that stops misfolded alpha-synuclein from spreading and could become the basis for a new treatment for Parkinson's disease.

The results were announced in a study published online Nov. 20, 2020, in the journal Nano Today.

The artificial enzymes, nanosized (a nanometer is a billionth of a meter) combinations of platinum and copper called PtCu bimetallic nanoalloys, were created by the research team for their strong antioxidant properties. The antioxidant capability is dependent largely on the alloy composition.

"Oxidative stress caused by reactive oxygen species is inescapable, and increases with age due to mechanistic slowdowns in processes such as protein degradation," says senior study researcher Xiaobo Mao, Ph.D., assistant professor of neurology at the Johns Hopkins University School of Medicine. "This indicates the importance of antioxidants, because in Parkinson's disease, roaming reactive oxygen species promote the spread of misfolded alpha-synuclein, leading to worse symptoms."

When injected into the brain, the nanozymes scavenge for reactive oxygen species, gobbling them up and preventing them from causing damage to neurons in the brain. The nanozymes mimic catalase and superoxide dismutase, two enzymes found in our bodies that break down reactive oxygen species. Adding the nanozymes strengthens our body's response to them.

The study used a research method known as the alpha-synuclein preformed fibril model, which replicates the pathology, spreading and neurodegeneration resulting from Lewy bodies. The nanozyme was found to decrease alpha-synuclein induced pathology and inhibit neurotoxicity, in addition to decreasing reactive oxygen species. The nanozyme also prevented alpha-synuclein from passing from cell to cell, and from the substantia nigra to the dorsal striatum, two areas in the midbrain that influence movement and cognition.

Mao has long collaborated with fellow Parkinson's disease expert Ted Dawson, M.D., Ph.D., professor of neurology and director of the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. Dawson recently added to evidence that misfolded alpha-synuclein travels along the vagus nerve from the gut to the brain. Mao hopes that further research can connect the two findings and lead to a Parkinson's disease treatment that targets the gut.

"We know that the nanoenzymes work when injected directly into the brain," says Mao. "Now, we'd like to see if the nanoenzymes can block the disease progression induced by pathogenic alpha-synuclein traveling from the gut, across the blood-brain barrier and into the brain."

Mao is available for interviews.

GENETIC MARKER FOR PROSTATE CANCER FOUND TO BE COMMON AMONG BLACK MALES

Media Contact: Brian Waters, bwaters3@jhmi.edu

Johns Hopkins Medicine and University of Southern California researchers have announced that a genetic marker tied to prostate cancer -- previously seen in a significant number of Ugandan men with the disease -- also could be found in larger populations of Black males with prostate cancer, including African Americans.

The finding was reported in the Sept. 2020 issue of the journal European Urology. The collaborative study was led by Christopher Haiman, Sc.D., professor of preventive medicine at the Keck School of Medicine of USC.

The biological marker that the researchers studied is a single variation in the DNA of chromosome 8 of the human genome. Known as a single nucleotide polymorphism (SNP), such variants can help scientists identify the connections between genes and specific diseases. Carrying the chromosome 8 SNP marker has been linked to a twofold increase in a man's risk for prostate cancer, going to threefold or higher in men with a family history of the disease.

The research team examined the DNA of prostate cancer patients of African descent across the United States and found results similar to those observed in previous studies in Ugandan men. As this SNP is not found in Americans of European descent, the researchers say this finding may partly explain why African American men are significantly more likely to be diagnosed with prostate cancer and die from the disease.

This information opens an important door for future genetic testing. Study co-author William Isaacs, Ph.D., professor of urology and oncology at the Johns Hopkins University School of Medicine, says that a set of these SNP markers is being developed as a diagnostic tool for determining an individual's prostate cancer risk level.

"We have to get these tests into the general practitioner's office," he says.

Having an SNP diagnostic test for prostate cancer, Isaacs explains, would enable clinicians to screen patients who they believe may be at highest risk for developing the disease, so they can be monitored for it and treated at an early stage if diagnosed.

Isaacs is available for interviews.

SCIENTISTS FIND HINTS FOR HOW A FATTY COMPOUND FUNCTIONS IN THE CELL'S POWERHOUSE

Media Contact: Rachel Butch, rbutch1@jhmi.edu

In a study of yeast, Johns Hopkins Medicine researchers say they have found how a fatty compound called cardiolipin helps create cellular energy. The researchers say their findings will help shed light on conditions that impact human metabolism, such as heart disease, diabetes and Barth syndrome, a rare genetic disorder that weakens the heart.

Cardiolipin is found in almost every one of the body's cells and resides within the labyrinth of membranes that make up mitochondria. It's thought to help mitochondria create adenosine triphosphate (ATP), the molecule that fuels cell metabolism. Cardiolipin has been implicated in a number of metabolic and immune diseases, including blood clotting disorders caused by an abnormal immune reaction to the fatty molecule.

In its study published Aug. 28, 2020, in Science Advances, the Johns Hopkins Medicine team found how cardiolipin helps stabilize other structures within mitochondrial membranes.

"Mitochondrial membranes are some of the busiest structures in the body, packed with fats and proteins that give our cells the energy they need to keep us alive," says Steven Claypool, Ph.D., professor of physiology at the Johns Hopkins University School of Medicine.

Within this membrane matrix is an important transport protein called Aac2 that ships the building blocks of ATP into the mitochondria and then moves activated ATP out into the cell. Previous studies hinted that cardiolipin was important in helping Aac2 transport proteins do their job. However, not much was known about this process.

Claypool and his colleagues found that three areas on Aac2 where cardiolipin binds help Aac2 stay in the right shape to transport ATP. They found that yeast cells engineered to lack cardiolipin did not produce cellular energy as efficiently as yeast cells with abundant cardiolipin levels.

In further experiments analyzing how proteins interacted in the membrane, the researchers found that links between Aac2 and the rest of the ATP production line -- known as respiratory supercomplexes -- also are dependent on the presence of cardiolipin.

The researchers speculate that cardiolipin-protein interactions in mitochondrial membranes evolved as a way to streamline energy production. They believe this occurs by connecting Aac2 with the respiratory supercomplexes that supply ATP materials or by using cardiolipin to protect the membrane proteins from being jostled out of place.

Overall, these results suggest that changes in cardiolipin structure or production could be linked with diseases, say the researchers.

"We may need to look closer at cardiolipin structure or production in diseases or conditions in which cardiolipin metabolism has been implicated," says Claypool.

Claypool and his colleagues are developing new tools to analyze the fats in mitochondrial membranes to study protein-cardiolipin interactions.

Claypool is available for interviews.

MINOR STROKES LEAD TO GLOBAL DISRUPTIONS IN BRAIN SIGNALING AND COGNITIVE DYSFUNCTION

Media Contact: Vanessa McMains, Ph.D.; vmcmain1@jhmi.edu

When most people think about stroke, they picture someone who can't move an entire side of their body or speak. Minor strokes on the surface appear far less disabling, and often people are able to walk and talk normally. However, people who've had minor strokes anecdotally report difficulty in thinking, focusing their attention on more than one task or following conversations.

Now, Johns Hopkins Medicine researchers and colleagues at the University of Maryland have found what is believed to be the first measurable physical evidence of diminished brain processing after a minor stroke.

Minor strokes occur when a small blood clot lodges in one of the tiny blood vessels deep in the brain. They are typically less devastating than a major stroke that blocks a major artery, but still damage tissue needed for the brain to properly function.

In their study published in the Dec. 29, 2020, issue of the Proceedings of the National Academy of Sciences of the United States of America (PNAS), the researchers say that their findings are not only the first step toward better understanding the cause of post-stroke cognitive dysfunction, but they will ultimately enable clinicians to design more effective treatments. Additionally, they say, these therapies may be useful for other neurologic conditions that result in small regions of damaged brain tissue with similar symptoms, such as multiple sclerosis.

"We tend to think that certain parts of the brain are responsible for specific functions but in reality, you need your entire brain to think clearly and complete tasks," says Elisabeth Marsh, M.D., associate professor of neurology at the Johns Hopkins University School of Medicine. "In this study, we show how minor damage anywhere in the brain can disrupt the entire cognitive network and result in a global dysfunction."

As the medical director of the Comprehensive Stroke Center at Johns Hopkins Bayview Medical Center, Marsh implemented the Bayview Stroke Intervention Clinic, a program designed to promote patient follow-up, reduce hospital readmission rates and enhance post-stroke recovery.

For their recent study, the researchers used magnetoencephalography (MEG) to compare the brain function of nine patients who had experienced minor strokes with the mental processing of age-matched healthy controls. MEG is a noninvasive neuroimaging technique that, like an electroencephalogram (EEG), measures electrical activity within the brain in real time.

Once inside the scanner, the study participants had their brain function recorded as they completed word- and picture-matching tasks.

Brain signal strength for the patients with minor stroke was noticeably smaller than the controls, appearing more like rolling hills than the normal sharp mountain peaks. The researchers say this indicates that information isn't effectively traveling through the network and the brain is processing information less efficiently. Stroke patients took nearly twice as long (about a second) as the control group (about half a second) to complete the tasks, which the researchers say leads to a noticeable difference when trying to participate in a three-way conversation or follow complicated instructions.

After six months, six patients who had experienced minor strokes returned for reevaluation. They not only performed better on each task, but also anecdotally reported that their symptoms of impairment were much improved. However, their MEG scans showed only minimal improvement.

"Right now, we don't know the neural mechanisms that allowed the patients to improve," says study co-author Jonathan Simon, Ph.D., professor of electrical and computer engineering at University of Maryland, College Park. "It could be that new neural communication routes have formed to bypass the sluggish pathways. Or it could be that older, less used communication pathways have been repurposed."

He adds, "We hope by looking at the details of which neural connections are disrupted -- and how -- that it will not only be a next step in understanding this particular effect of a minor stroke, but also give us a new window into understanding how information is processed across the brain."

The team plans to bring participants back in early 2021 for further analysis and to begin treatment trials aimed at improving recovery from these minor strokes.

Marsh and Simon are available for interviews.

Diabetes continues to be the leading cause of new cases of blindness among adults in the United States. But the current shortage of eye-care providers would make it impossible to keep up with demand to provide the requisite annual screenings for this population. A new study looks at the effectiveness of seven artificial intelligence-based screening algorithms to diagnose diabetic retinopathy, the most common diabetic eye disease leading to vision loss.

In a paper published Jan. 5 in Diabetes Care, researchers compared the algorithms against the diagnostic expertise of retina specialists. Five companies produced the tested algorithms - two in the United States (Eyenuk, Retina-AI Health), one in China (Airdoc), one in Portugal (Retmarker), and one in France (OphtAI).

The researchers deployed the algorithm-based technologies on retinal images from nearly 24,000 veterans who sought diabetic retinopathy screening at the Veterans Affairs Puget Sound Health Care System and the Atlanta VA Health Care System from 2006 to 2018.

The researchers found that the algorithms don't perform as well as they claim. Many of these companies are reporting excellent results in clinical studies. But their performance in a real-world setting was unknown. Researchers conducted a test in which the performance of each algorithm and the performance of the human screeners who work in the VA teleretinal screening system were all compared to the diagnoses that expert ophthalmologists gave when looking at the same images. Three of the algorithms performed reasonably well when compared to the physicians' diagnoses and one did worse. But only one algorithm performed as well as the human screeners in the test.

"It's alarming that some of these algorithms are not performing consistently since they are being used somewhere in the world," said lead researcher Aaron Lee, assistant professor of ophthalmology at the University of Washington School of Medicine.

Differences in camera equipment and technique might be one explanation. Researchers said their trial shows how important it is for any practice that wants to use an AI screener to test it first and to follow the guidelines about how to properly obtain images of patients' eyes, because the algorithms are designed to work with a minimum quality of images.

The study also found that the algorithms' performance varied when analyzing images from patient populations in Seattle and Atlanta care settings. This was a surprising result and may indicate that the algorithms need to be trained with a wider variety of images.

The human papillomavirus infection, or HPV, is the most common sexually transmitted infection in the U.S., according to the Centers for Disease Control and Prevention. HPV is associated with health problems including genital warts and cancers, but a vaccine has been available since 2006 to help stop the virus. The CDC reports more than 12 years of data supports the HPV vaccine is safe and effective, yet HPV vaccination rates across the U.S. still remain low.

Social media has a history of being a popular place for sexual health discussions, and the HPV vaccine is one of the most discussed vaccines on the internet. Monique Luisi, an assistant professor in the University of Missouri School of Journalism, has studied more than 6,500 public HPV vaccine-related posts on Facebook from 2006 to 2016. In a previous study, Luisi used these Facebook posts to identify a negative trend on Facebook related to how people perceive the HPV vaccine.

Now, she suggests this negative trend on Facebook may also cause people to develop a false perception of the health risk of the vaccine. After looking at the percentage of posts that made the vaccine seem more dangerous, less dangerous or neither, Luisi found nearly 40% of Facebook posts about the HPV vaccine amplified a perceived risk, and the data suggests these posts had momentum over time.

"We should not assume that only the disease is perceived as a risk, but when research supports it, that medical treatments and interventions might unfortunately also be perceived as risks," she said. "It's more likely that people are going to see things on social media, particularly on Facebook, that are not only negative about the HPV vaccine, but will also suggest the HPV vaccine could be harmful. It amplifies the fear that people may have about the vaccine, and we see that posts that amplify fear are more likely to trend than those that don't."

Luisi suggests the spread of this negative information may lead people to have a false perception of the vaccine, so people should consult their doctor or health care provider before making an informed decision.

"Facebook remains a very popular social media platform for adult audiences, which necessitates action to address HPV vaccine risk messages," she said. "People are going to see what they are going to see on social media, so it's important to not only take what you see on social media, but also talk to a doctor or health care provider. Just because it's trending doesn't mean it's true."

Luisi notes research must continue to address the perception of vaccine safety where the vaccine is perceived as a greater health threat than the virus or disease it prevents, and her study could also inform officials for the ongoing COVID-19 vaccine roll out and distribution.

"As the COVID-19 vaccine is being rolled out, people are likely going to see a lot of negative information, and that negative information will be what trends on social media," she said. "But, if the public can anticipate this negative information, it will be interesting to see if that will that make them less sensitive to the perceived risk of the vaccine."

Trio of articles suggest that a single dose of vaccine, even if less effective than two doses, may have greater population benefit.

Three articles published today in Annals of Internal Medicine discuss the most effective vaccination strategy for maximum impact against the COVID-19 pandemic. The articles are accompanied by an editorial from Thomas J. Bollyky, JD, Director of Global Health Program, Council on Foreign Relations. Mr. Bollyky can be reached through Lauran Potter at lpotter@cfr.org. The full text of his editorial is available here: https://www.acpjournals.org/doi/10.7326/M20-8280.

Speed Versus Efficacy: Quantifying Potential Tradeoffs in COVID-19 Vaccine Deployment https://www.acpjournals.org/doi/10.7326/M20-7866.

Researchers from Yale School of Public Health used a previously published model of a COVID-19 vaccination program to quantify the speed-versus-efficacy tradeoff of vaccination deployment. The model accounted for transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19 disease severity, and recovery or vaccination leading to protective immunity. According to the authors' analysis, a 2-dose vaccination strategy would impose steep clinical and epidemiologic costs in the context of ongoing pandemic response. Depending on the duration of protection conferred, a single-dose vaccine with 55% effectiveness may confer greater population benefit than a 95%-effective vaccine requiring two doses.

Media contacts: A PDF for this article is not yet available. Please click the link above to read the full text. The lead corresponding author, A. David Paltiel, PhD, can be reached through Michael Greenwood at michael.greenwood@yale.edu.

A Public Health COVID-19 Vaccination Strategy to Maximize the Health Gains for Every Single Vaccine Dose: https://www.acpjournals.org/doi/10.7326/M20-8060.

Authors from the University of Washington and Fred Hutchinson Cancer Research Center suggest that speed is essential for controlling the COVID-19 pandemic and offer four rationale supporting their conclusion:

Doubling the vaccine coverage with a single dose compared with a 2-dose regimen will accelerate pandemic control because even lack of complete protection on an individual level is likely to lower transmission rates enough to stop epidemic growth;

Providing effective protection for as many people as possible is more ethical because it distributes the scarce commodity more justly;

A single-dose vaccine approach could mitigate the higher incidence of many vaccine-associated adverse events seen with the second dose;

And administering a vaccine that is only partly protective may reduce risky behavior such as doffing masks or eliminating social distancing.

Media contacts: A PDF for this article is not yet available. Please click the link above to read the full text. The lead corresponding author, Ruanne V Barnabas, MBChB, MSc, DPhil, can be reached through Susan Gregg at sghanson@uw.edu.

Alternative Dose Allocation Strategies to Increase Benefits From Constrained COVID-19 Vaccine Supply: https://www.acpjournals.org/doi/10.7326/M20-8137.

Researchers from Stanford University developed a decision analytic cohort model to estimate direct benefits of vaccination against COVID-19 under alternative strategies for dose allocation. First, they analyzed a fixed strategy based on the current U.S. model of two doses, timed about one month apart. Second, they analyzed a flexible strategy that would reserve 10% of the supply for second doses during the first 3 weeks, 90% during each of the next 3 weeks, and 50% thereafter. They estimate that the flexible strategy would result in an additional 23% - 29% of COVID-19 cases averted compared with the fixed strategy. In both scenarios, 24 million people received at least one dose of the vaccine by week 8, whereas 2.4 million additional people received two doses of vaccine in the flexible strategy because million more received an initial dose during the first 3 weeks. According to the researchers, these findings suggest that vaccinating more people as soon as possible using a flexible approach could increase the benefits of vaccines while enabling most recipients to receive second doses on schedule.

Media contacts: A PDF for this article is not yet available. Please click the link above to read the full text. The lead corresponding author, Joshua A. Salomon, PhD, can be reached through Lisa Kim at LiKim@stanfordhealthcare.org.

The combination of ibrutinib plus rituximab is approved for the treatment of adults with previously untreated chronic lymphocytic leukaemia (CLL). In an early benefit assessment, the German Institute for Quality and Efficiency in Health Care (IQWiG) now examined which advantages and disadvantages this drug combination has for the patients. For patients who could also be treated with the chemo-immunotherapy FCR, the assessment found an indication of a major added benefit in comparison with this appropriate comparator therapy. No study data are available for patients for whom FCR or other chemo-immunotherapy is not an option due to their poorer general health. An added benefit is therefore not proven.

Study data on only one of three research questions

The Federal Joint Committee (G-BA) distinguished three groups of patients. For the first group, which was also the largest, the appropriate comparator therapy was fludarabine + cyclophosphamide + rituximab (FCR). This chemo-immunotherapy is usually only given if the patient is in good general health. For the second group, FCR is not an option, but another chemo-immunotherapy is. In the third group, chemo-immunotherapies are generally not indicated, for example because of the mutation status of the patients. Here, the appropriate comparator therapy is ibrutinib alone.

In its dossier, the drug manufacturer only presented data on the question of whether ibrutinib plus rituximab offers an added benefit in comparison with FCR for the patients in the first group. These data are from the ongoing ECOG-E1912 study, which is not conducted by the manufacturer, but which it also used already in its application for approval. Data from about 40 per cent of the study participants are relevant for the present assessment.

Prolonged overall survival

There was an indication of a major added benefit for overall survival in patients for whom FCR therapy is an option. In the outcome category of side effects, there was a hint of lesser harm for the overall rate of severe side effects and for discontinuations due to side effects, which were of minor and of considerable extent respectively. Predominantly positive effects were shown in severe and non-serious/non-severe side effects. No results were available on health-related quality of life.

Overall, there is an indication of a major added benefit of ibrutinib plus rituximab in comparison with FCR for patients with previously untreated CLL for whom FCR therapy is an option. Since no data were available for the other patients, an added benefit in comparison with the respective appropriate comparator therapy is not proven for them.

Promising therapeutic option

"This means that a relatively large group of people with chronic lymphocytic leukaemia now have a chemotherapy-free treatment alternative that has a clear survival advantage," says Volker Vervölgyi from IQWiG's Drug Assessment Department. "This is good news, as we have not seen an added benefit in comparison with FCR in the previous early benefit assessments for untreated CLL."

G-BA decides on the extent of added benefit

The dossier assessment is part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the G-BA. After publication of the dossier assessment, the G-BA conducts a commenting procedure and makes a final decision on the extent of the added benefit.