Body

Scientists have found a switch which is associated with prostate cancers spreading or forming metastases (secondary tumours). The researchers caution that this work is still at an early stage, and needs further investigation to see if it applies to all prostate cancers. Up to 15% of patients have high risk prostate cancers, potentially leading to significantly increased mortality over time. The work is presented at the virtual European Association of Urology congress.

The researchers, from the University of Leuven in Belgium, worked with a group of 44 patients who had high-risk prostate cancer (see notes for definition). Twenty-five of the patients were cured after treatment, but 19 went on to develop metastatic prostate cancer. The scientists then compared differences in the number of copies of DNA segments in the two groups. They found that these patients who went on to develop metastatic disease had many more copies of the AZIN1 gene, indicating that it was associated with a more aggressive disease.

To test this, the team changed the activity of the AZIN1 gene, found on chromosome 8, in both cell culture and a mouse model. They found that reducing the activity (expression) of the gene resulted in reduced metastases.

Lead researcher, Dr Lisa Moris (Molecular Endocrinology Laboratory, Leuven, Belgium) said:

"We were able to show that the regulation of the AZIN1 gene is closely associated with the risk of the tumour spreading. We need to do a lot more research on AZIN1 to see if the relation with metastases is generally applicable to prostate cancers; there are many different types and causes of prostate cancer, so this finding is still a long way from any clinical application. What we can say is that this finding applies to the patients we tested, who were followed up over a period of 10 years, as well as our mouse and in-vitro models. There are also some initial findings that this gene may have an effect in other cancers.

We are currently looking at what exactly this gene does, to see if we can find a way of regulating it in real-life cancers. This is still a long way from any clinical application, but opening a way to controlling whether tumours risk spread would be a significant step towards controlling prostate cancer"

Commenting, the EAU's Adjunct Secretary General responsible for Science, Professor Arnulf Stenzl (Tübingen, Germany) said:

"More than 10 years ago the influence of Antizyme Inhibitor 1 as a small protein for cell transformation and promotion of tumour growth was discovered. Recently a role in the progression and metastasis of a variety of tumours including breast, colorectal, lung and gastric cancer has been suggested. Some of this interest has arisen because of the role of AZIN1 in the methylation of HPV warts and a possible connection to HPV-associated malignancies.

The study by Moris et al. looks like a promising clue for those prostate cancers which are aggressive and metastasizing. At a time when more than 80% of all newly diagnosed prostate cancers are diagnosed in a localized stage, and the value of any treatment may be arguable in some patients, studies like this are important. They may clarify which patients will benefit from immediate and directed treatment, and which will benefit from active surveillance. The results of this study may also give us a clue for targeting AZIN1 to prevent metastasis".

Professor Stenzl was not involved in this work, this is an independent comment.

Prostate cancer is the most common male cancer, with around 400,000 new cases every year in Europe, with 76,000 deaths in the EU. In the UK, there are over 46,000 new cases of prostate cancer every year, leading to more than 11,000 deaths. Germany has 14,434 annual deaths, France 9041, Italy 7523 (see https://ec.europa.eu/eurostat/statistics-explained/pdfscache/39738.pdf, page 13). More than a million European men undergo prostate cancer biopsies every year.

Chronic kidney disease (CKD) affects approximately 37 million U.S. adults and less than 25% are aware of their disease. CKD is readily identified with simple blood and urine tests that are often in a patient's health record yet providers usually do not diagnose the CKD and inform the patient. In a randomized clinical trial, Dr. Peralta and colleagues at the University of California in San Francisco randomized 80 primary care providers to an electronic decision support system with or without follow-up by a pharmacist and tested whether the support system improves processes of care including blood pressure management, medication prescribing and patient education. Patients with CKD were identified from electronic health record data and primary care providers in the intervention arm received guidance on lab testing, medication prescribing, patient education and blood pressure management. A total of 80 providers caring for 524 patients with CKD were enrolled in the trial. After a total of 12 months of follow-up, there was no differences in processes of care by implementation of the electronic decision support system with or without a pharmacist. However, awareness of CKD was two-fold higher among the providers randomized to the electronic decision support system with a pharmacist compared to usual care (16% without support system vs. 32% with the support system and pharmacist follow-up). This study demonstrates that implementation of a decision support system within the electronic health records system can increase provider awareness of CKD.

CHAPEL HILL, N.C.--The onset of the COVID-19 pandemic has broadly affected how health care is provided in the United States. One notable change is the expanded use of telehealth services, which have been quickly adopted by many health care providers and payers, including Medicare, to ensure patients' access to care while reducing their risk of exposure to the coronavirus.

In an article published in JAMA Oncology, Trevor Royce, MD, MS, MPH, an assistant professor of radiation oncology at the University of North Carolina Lineberger Comprehensive Cancer Center and UNC School of Medicine, said the routine use of telehealth for patients with cancer could have long-lasting and unforeseen effects on the provision and quality of care.

"The COVID-19 pandemic has resulted in the rapid deregulation of telehealth services. This was done in part by lifting geographical restrictions, broadening patient, health care professional, and services eligibility," said Royce, the article's corresponding author. "It is likely aspects of telehealth continue to be part of the health care delivery system, beyond the pandemic."

The article's other authors are UNC Lineberger's Hanna K. Sanoff, MD, MPH, clinical medical director of the North Carolina Cancer Hospital and associate professor in the UNC School of Medicine Division of Hematology, and Amar Rewari, MD, MBA, from the Associates in Radiation Medicine, Adventist HealthCare Radiation Oncology Center in Rockville, Maryland.

Royce said the widespread shift to telehealth was made possible, in part, by three federal economic stimulus packages and the Centers for Medicare and Medicaid Services making several policy changes in March that expanded Medicare recipients' access to telehealth services.

The policy changes included allowing telehealth services to be provided in a patient's home. Medicare previously only paid for telehealth services in a facility in nonurban areas or areas with a health professional shortage. Medicare also approved payment for new patient appointments, expanded telehealth coverage to include 80 additional services, allowed for services to be carried out on a wider assortment of telecommunication systems - including remote video communications platforms, such as Zoom - and modified the restrictions of who can provide and supervise care.

While the potential benefits of telehealth have been demonstrated during the pandemic, Royce said they must be balanced with concerns about care quality and safety.

"There is a lot we don't know about telehealth, and how its rapid adoption will impact our patients," Royce said. "How will the safety and quality of care be impacted? How will we integrate essential components of the traditional doctor visit, including physical exam, lab work, scans and imaging? Will patients and doctors be more or less satisfied with their care? These are all potential downsides if we are not thoughtful with our adoption."

He said appropriate oversight of care is critical. There will be a continued need for objective patient assessments, such as patient-reported outcomes, physical examinations and laboratory tests, and to measure care quality and monitor for fraud. There are also a number of standard measures of care quality that can be implemented during the transition to telehealth, including tracking emergency room visits, hospitalizations and adverse events.

Telehealth presents other challenges, as well. Though technology and internet access are now more widely available, they are not universally accessible. Where one lives, their socioeconomic status and comfort level with technology can be barriers to using telehealth services. A reliance on telehealth might lower participation in clinical trials, which can require regular in-person appointments.

"Telehealth can be used to improve access to care in traditionally hard-to-reach populations. However, it is important to acknowledge that if we are not thoughtful in its adoption, the opposite could be true," Royce said. "For example, will lower socioeconomic groups have the same level of access to an adequate internet connection or cellular services that make a virtual video visit possible? Telehealth needs to be adopted with equity in mind."

Sophia Antipolis, 17 July 2020: The largest study on opium use and outcomes after bypass surgery has found that - in contrast to widely held beliefs - it is linked with more deaths and heart attacks. The research is published today in the European Journal of Preventive Cardiology, a journal of the European Society of Cardiology (ESC).1

The United Nations Office on Drugs and Crime estimates that in 2015, 17.7 million people used opiates (opium, heroin, and morphine) illicitly worldwide.2,3 Opium is the most commonly used substance after tobacco in the Middle East and many Asian countries. The two major ways of using the drug are smoking and dissolving it in tea and other drinks.

"Afghanistan, Pakistan and Iran have the highest prevalence of opium abuse due to their proximity to production," said study author Dr. Farzad Masoudkabir of Tehran University of Medical Sciences, Iran. "In Iran it is estimated that 8-16% of the public use opium, but given the sensitivities around reporting, the true prevalence may be even higher."

Another reason for opium's popularity is the perception that it has health benefits. "There are traditional beliefs among the public and medical staff that opium lowers blood glucose, blood lipids and blood pressure and prevents heart attacks and diabetes," said Dr. Masoudkabir. "The result is that heart patients often use opium. In our study, nearly one in five (18%) were users."

Cardiac surgeons and cardiologists are concerned about advising patients to stop using opium after bypass surgery because of fears that withdrawal could induce heart attacks. Until now there was no evidence that discontinuation of opium consumption after surgery was safe.

This was the largest study to investigate the impact of continuing or stopping opium use after coronary artery bypass graft surgery. The study included 28,691 patients who underwent bypass surgery between 2007 and 2016. The average age was 61 years and 73% were men. Patients were divided into three groups according to opium use: never-users (82%), continued use after surgery (13%), and stopped after surgery (5%).

Patients were followed-up for five years. The researchers examined the association of post-operative opium use and the risks of death, heart attack, stroke, and repeat heart procedures.

Patients who continued their opium habit after bypass graft surgery had a 28% higher risk of death and a 34% raised likelihood of heart attack compared to never-users. They also had a 25% higher risk of a combined endpoint of adverse events (death, heart attack, stroke, and repeat procedures) compared to never-users.

"In contrast to the worry that opium cessation could trigger heart attacks in patients undergoing cardiac surgery, we found that stopping the drug was safe and even beneficial," said Dr. Masoudkabir. "In fact, the risks of death, heart attacks and other adverse events in those who stopped using opium after surgery were similar to those who had never used the drug."

Regarding when to start opium cessation, he said: "The first outpatient visit after bypass surgery is a sensible time to start talking about stopping the use of opium. This gives patients about one month to recover from the physical stress of the operation before commencing withdrawal."

Dr. Masoudkabir noted that the study findings cannot be extrapolated to other opiates like heroine and morphine.

He concluded: "Taking our findings together with those of previous studies, there is now sufficient evidence to conclude that it's a falsehood that opium protects against heart disease and its risk factors."

Screening entire populations for breast and ovarian cancer gene mutations could prevent millions more breast and ovarian cancer cases across the world compared to current clinical practice, according to an international study led by Queen Mary University of London. The research also shows that it is cost effective in high and upper-middle income countries.

The most well-known breast and ovarian cancer causing genes are BRCA1 and BRCA2. These gene mutations cause around 10-20 per cent of ovarian and 6 per cent of breast cancers. If mutation carriers could be identified before they develop disease, most of these cancers could be prevented by drugs, increased screening or surgery.

Current clinical guidelines globally only recommend genetic testing for high-risk women, for example, if they fulfil certain clinical criteria or if there is a strong family history of breast or ovarian cancer. However, over 50 per cent of BRCA carriers do not meet these criteria so are not tested, and over 97 per cent of BRCA carriers in the UK population remain unidentified.

This new study was supported by the NHS Innovation Accelerator Fellowship and women's cancer charity The Eve Appeal and published in the journal Cancers. The researchers estimated the cost-effectiveness and health impact of BRCA testing in the general population, compared with current standard clinical testing of women designated as high risk, in countries considered high income (UK/USA/Netherlands), upper-middle income (China/Brazil), and low-middle income (India).

The researchers modelled a number of scenarios of population based BRCA-testing and compared the costs and health impact to the current family history based policy. Cost effectiveness was calculated from both a societal and a payer perspective. A payer perspective only includes medical costs incurred by the health system or health providers (such as costs of genetic testing, screening, prevention and cancer treatment). A societal perspective also takes into account costs such as the impact of income lost from inability to work and shorter life spans due to cancer.

The research team found that population based testing was extremely cost effective in high and upper middle income countries from a payer perspective. From a societal perspective it was cost saving in high income countries and cost effective in middle income countries like China and Brazil. Costs of BRCA testing would need to fall to around USD $172 to become cost effective in low income countries like India.

Findings suggest that population based BRCA testing can prevent an additional 2,319-2,666 breast cancer and 327-449 ovarian cancer cases per million women than the current clinical strategy. Over the course of a lifetime, this translates to preventing around an additional 57,700 breast cancer and 9,700 ovarian cancer cases in the UK; 269,000 breast cancer and 43,800 ovarian cancer cases in the USA; 15,000 breast cancer and 2,500 ovarian cancer cases in the Netherlands; 1,050,300 breast cancer and 154,700 ovarian cancer cases in China; 156,300 breast cancer and 25,170 ovarian cancer cases in Brazil; and 692,570 breast cancer and 97,650 ovarian cancer cases in India.

Lead researcher Professor Ranjit Manchanda from Queen Mary University of London said: "General population BRCA testing can bring about a new paradigm for improving global cancer prevention. Why do we need to wait for people to develop a preventable cancer to identify others in whom we can prevent cancer? Strategies and pathways for population testing must be developed to enable population genomics to achieve its potential for maximising early detection and cancer prevention.

"With the costs of testing falling this can provide huge new opportunities for cancer prevention and changes in the way we deliver cancer genetic testing. This approach can ensure that more women can take preventative action to reduce their cancer risk or undertake regular screening."

Dr Rosa Legood, Associate Professor at the London School of Hygiene & Tropical Medicine added: "Our analysis shows that testing all women for BRCA mutations is a more cost-effective strategy which can prevent these cancers in high risk women and save lives. This approach has important implications given the effective options that are available for breast and ovarian cancer risk management and prevention for women at increased risk."

Athena Lamnisos, CEO, Eve Appeal said: "We must invest in cancer prevention - this is what will save most lives and also be cost effective within cash-strapped healthcare systems. The evidence emerging from this study is an exciting step forward: we can stop cancer before it has a chance to start through broadening a simple genetic test to a wider population. At The Eve Appeal we work with women given a heart-breaking diagnosis of cancer, this is really hard news to process when they find out they carry a mutation which could have been identified at an early stage and their cancer prevented. For those women and their loved ones, this research provides hope."

This research was led by Prof Ranjit Manchanda (Queen Mary University of London) and supported by Dr Rosa Legood (London School of Hygiene & Tropical Medicine). This research was an international collaboration involving research teams from Queen Mary University of London, London School of Hygiene & Tropical Medicine, and involved Amsterdam UMC, Vrije Universiteit Amsterdam (Netherlands); Universidade de Sao Paulo, Sao Paulo (Brazil); Peking University, Beijing (China); Indian Institute of Technology, Kharagpur (India); Presidency University, Kolkata (India); Tata Medical Centre, Kolkata (India); University of Melbourne, Victoria (Australia); Newcastle University (UK).

For more information, please contact:

Joel Winston
Communications Manager (School of Medicine and Dentistry)
Queen Mary University of London
j.winston@qmul.ac.uk
Tel: +44 (0)7968 267 064

Notes to the editor

* Research paper: 'Economic Evaluation of Population-based BRCA1/BRCA2 Mutation Testing across multiple countries and Health systems'. Ranjit Manchanda, Li Sun, Shreeya Patel, Olivia Evans, Janneke Wilschut, Ana Carolina de Freitas Lopes, Faiza Gaba, Adam Brentnall, Stephen Duffy, Bin Cui8, Patricia Coelho de Soarez, Zakir Husain, John Hopper, Zia Sadique, Asima Mukopadhyay, Li Yang, Johannes Berkhof and Rosa Legood. Cancers.

About Queen Mary University of London

At Queen Mary University of London, we believe that a diversity of ideas helps us achieve the previously unthinkable.

In 1785, Sir William Blizard established England's first medical school, The London Hospital Medical College, to improve the health of east London's inhabitants. Together with St Bartholomew's Medical College, founded by John Abernethy in 1843 to help those living in the City of London, these two historic institutions are the bedrock of Barts and The London School of Medicine and Dentistry.

Today, Barts and The London continues to uphold this commitment to pioneering medical education and research. Being firmly embedded within our east London community, and with an approach that is driven by the specific health needs of our diverse population, is what makes Barts and The London truly distinctive.

Our local community offer to us a window to the world, ensuring that our ground-breaking research in cancer, cardiovascular and inflammatory diseases, and population health not only dramatically improves the outcomes for patients in London, but also has a far-reaching global impact.

This is just one of the many ways in which Queen Mary is continuing to push the boundaries of teaching, research and clinical practice, and helping us to achieve the previously unthinkable.

Adults with type 2 diabetes that have no history, signs or symptoms of heart problems have been shown to have severely limited exercise capacity, according to researchers at the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre. Such limitations place them at impending risk of developing heart failure, according to the team who led the study.

Researchers studied the hearts of 247 people who had been diagnosed with type 2 diabetes between 2.5 and 10 years ago. A control group of 78 people without type 2 diabetes was also recruited to act as a comparison. Over one third of volunteers were from a black or South Asian background, making the sample representative of the local community.

Using state-of-the art cardiac magnetic resonance imaging (MRI) and ultrasound the researchers spotted subtle impairments in the blood flow to the heart muscle and in the ability of the heart to fill with, and circulate blood around, the body of those volunteers with type 2 diabetes.

Participants also had their fitness levels measured using cardiopulmonary exercise testing - a non-invasive method used to assess the performance of the heart and lungs during exercise, usually carried out on an exercise bike.

Dr Gaurav Gulsin, BHF Clinical Research Training Fellow at the University of Leicester and lead for the study, said: "Our results showed that even when factoring in age, sex, ethnicity and smoking status, subtle heart impairments contributed to strikingly poor fitness in the volunteers with type 2 diabetes. This suggests that early heart disease is already present in this population, despite the absence of clinical indicators, such as angina and shortness of breath."

Professor Gerry McCann, Professor of Cardiac Imaging at the University of Leicester and co-lead for the study, said: "If we can target these subtle heart impairments with treatments to increase blood supply to the heart, we may help to improve fitness levels and reduce the risk of heart failure in people with type 2 diabetes.

"We're now keen to explore such different treatment options to see which, if any, provide the best health outcomes for patients."

While a close association has been found between changes in the heart's blood supply and filling ability with exercise capacity, more research is needed to understand whether one causes the other.

Cannabidiol, or CBD, may help reduce the cytokine storm and excessive lung inflammation that is killing many patients with COVID-19, researchers say.

While more work, including clinical trials to determine optimal dosage and timing, is needed before CBD becomes part of the treatment for COVID-19, researchers at the Dental College of Georgia and Medical College of Georgia have early evidence it could help patients showing signs of respiratory distress avoid extreme interventions like mechanical ventilation as well as death from acute respiratory distress syndrome.

"ARDS is a major killer in severe cases of some respiratory viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and we have an urgent need for better intervention and treatment strategies," says Dr. Babak Baban, immunologist and interim associate dean for research at DCG and corresponding author of the study in the journal Cannabis and Cannabinoid Research.

Our laboratory studies indicate pure CBD can help the lungs recover from the overwhelming inflammation, or cytokine storm, caused by the COVID-19 virus, and restore healthier oxygen levels in the body, says co-author Dr. Jack Yu, physician-scientist and chief of pediatric plastic surgery at MCG.

Their CBD findings were enabled by their additional finding of a safe and relatively inexpensive model to duplicate the lung damage caused by ARDS. Work on the virus itself is limited to a handful of labs in the nation that can safely manage the highly contagious virus, and their newly reported approach opens more doors for studying SARS-CoV-2, COVID-19 and similar virus-induced conditions, they say.

Their model, which takes advantage of the large, unique genetic structure of the novel coronavirus, produced classic symptoms of ARDS like the overwhelming, destructive immune response, then CBD significantly downregulated classic indicators of the excess, like inflammation-promoting cytokines as it improved oxygen levels in the blood and enabled the lungs to recover from the structural damage.

A major problem with SARS-CoV-2 is instead of just killing the virus, the over-the-top immune response can quickly disable the lungs, transforming them to a place where virus is replicated, rather than a place that makes oxygen available for our bodies and eliminates potentially harmful gases like carbon dioxide.

Mechanical ventilators can take over these vital functions for a while, and enable critically ill people to use less energy to just breathe and have more energy to fight infection, while ideally the lungs recover from the assault. However evidence suggests 30-50% of patients who get to the point of mechanical ventilation, don't survive.

The cytokines in these now famous "storms" are a class of molecules like interferon and interleukin, secreted by immune cells and other cells like endothelial cells that line blood vessels, which impact cell communication and can both promote and deter inflammation. In the case of COVID-19, there is excessive production of inflammation-promoting molecules like the interleukins IL-6 and IL-1β, as well as immune cells like neutrophils and monocytes, the researchers say.

They looked at objective measures of lung function in mice like levels of proinflammatory cytokines, oxygen levels in the blood before and after treatment, as well as temperature, an indicator of inflammation. Oxygen levels went up, while temperatures and cytokine levels went down with CBD therapy. Days later, a more detailed analysis of the lungs, reinforced reduction of key indicators of destructive inflammation, which their model, like the virus, drove way up including reduced levels of IL-6 and infiltrating neutrophils.

In fact, both clinical symptoms and physical lung changes resulting from ARDS were reversed with CBD treatment, they say.

Their model was created with the help of a synthetic analog of double-stranded RNA called POLY (I:C). In humans, our double-stranded DNA contains our genetic information and our single-stranded RNA carries out the instruction of our DNA to make certain proteins. In the family of coronaviruses, the double-stranded RNA carries the genetic material needed to reproduce the viruses and hijacks the cell machinery of our body to do that, Baban says.

"The natural instinct of the virus is to make more of itself," Baban says. "It weaves with our DNA to make the cell produce food and everything it needs." Viruses also tend to have a tissue or tissues they prefer -- some can and do go anywhere -- and for SARS-CoV-2, the lungs are high on the list, he says.

Our bodies aren't used to this double-stranded RNA so, like the virus, POLY (I:C) gets the immediate and extreme attention of toll-like receptor 3, a family of receptors that help our body recognize invaders like a virus and activate our frontline, innate immune response.

"The toll-like receptors 3 see this and just go nuts," Yu says. The fact that the coronaviruses are literally big and have the largest known viral RNA genome make such a vigorous cytokine and immune response both plausible and probable, adds Baban.

Mice received three, once-a-day doses of POLY (I:C) in the nasal passageway. CBD was given by a shot in the abdomen, the first dose two hours after the second POLY (I:C) treatment, then every other day for a total of three days in a process that sought to mimic mice getting treatment about the time a human would begin to experience trouble breathing and likely seek medical care. Given too early, CBD might actually interfere with a proper immune response against the virus, Yu says.

CBD quickly improved the clinical symptoms, then later detailed studies of the lungs showed damage to their structure, like tissue overgrowth, scarring and swelling, also had totally or partially resolved. Their next steps include doing similar studies on other organs impacted by COVID-19 including the gut, heart and brain, Baban says.

At least one way CBD is thought to calm the immune response is because it looks similar to endocannabinoids, a natural cell signaling system in our bodies believed to be involved in a wide variety of functions from sleep to reproduction to inflammation and immune response. CB1 and CB2, the main receptors for this system, are found extensively throughout the body including the brain and respiratory system, where we breathe in manmade and natural irritants in the air -- as well as viruses and bacteria -- that might inflame. While understanding the workings of the natural endocannabinoid system is still very much a work in progress, it's thought that one way CBD works to reduce seizures, for example, is indirectly through the large number of CB1 receptors in the brain, says Yu.

CBD is available without a prescription, and is used to treat problems like seizures as well as Parkinson's, Crohn's and other conditions where pain and/or inflammation are a major factor. It's derived from the hemp and cannabis plant, which are essentially the same although hemp has a much lower concentration of the "high" producing THC. Other investigators have shown the calming effect of CBD, for example, can block IL-6 in other models of inflammatory disease.

ARDS is a rapid, severe infection of the lungs that results in widespread inflammation, shortness of breath, rapid breathing and the inability to sustain adequate oxygen levels to the body and brain. Shortness of breath or difficulty breathing are some of the early signs of COVID-19. ARDS is a major cause of death in patients who are critically ill for a variety of reasons, including common sepsis.

Biomedical experts believe that half of heart failure patients likely have low levels of the thyroid hormone T3 in their cardiac tissue. While heart failure symptoms are commonly attributed to cardiovascular conditions like coronary artery disease and high blood pressure, a growing number of studies suggest that low cardiac T3 may significantly contribute to a patient's symptoms and underlying heart dysfunction. Now, researchers at New York Institute of Technology College of Osteopathic Medicine (NYITCOM) and FuWai Heart Hospital (Beijing, China) have developed a new use for a common blood test, which could provide a potentially life-saving treatment for heart failure.

Heart failure occurs when the heart cannot keep up with its workload, causing symptoms such as shortness of breath, fatigue, swollen legs, and rapid heartbeat. In recent years, scientists have actively researched the connection between thyroid hormones and cardiac function, with clinical studies suggesting that borderline-low thyroid hormone levels may increase risk of death in heart failure patients, and animal studies indicating that restored cardiac thyroid levels can dramatically improve heart function.

The symptoms of low cardiac T3 are also virtually indistinguishable from other conditions that lead to heart failure, suggesting that a significant number of underlying heart dysfunction and heart failure symptoms may actually be caused by a treatable T3 hormone imbalance. Despite this treatability, clinicians are hesitant to prescribe T3 to heart patients, as too much of the hormone could accidentally trigger irregular heartbeat. In addition, no method has yet been identified to titrate, or continually measure and adjust, for the dosage of T3 needed to safely restore the heart's thyroid hormone function.

Now, as seen in Frontiers, an existing biomarker called brain natriuretic peptide (BNP) may provide the much-needed solution. In medicine, biomarkers are biological molecules found in patient's blood, fluid, or tissue sample that can indicate whether a disease or condition is present. They can also be used to see how well the body responds to treatments. During heart failure, the heart will secrete higher levels of the biomarker BNP into blood, a key indication that the heart disease is worsening.

"I have been rather obsessed with the need for a serum biomarker for cardiac tissue T3 levels for many years," says Martin Gerdes, Ph.D., chair and professor of biomedical sciences at NYITCOM, who was one of the study's researchers. "It dawned on me that the clinical literature showed a very consistent inverse relationship between serum T3 and BNP levels."

The researchers hypothesized that by analyzing a patient's BNP levels in response to added T3, clinicians could titrate for just the right dosage required. Using rat models of heart failure caused by low T3 and heart attack, the researchers tested their theory, examining changes in BNP, cardiac function, and heart failure genes after T3 treatment. For the first time, they discovered through a simple blood test, not an extensive, invasive procedure, that T3 could be adjusted to safely restore cardiac hormone balance. In addition, because heart patients routinely undergo BNP and thyroid hormone testing, these widely used biomarkers could be easily monitored from blood tests.

"The results were remarkable, suggesting that serum BNP levels can be used to titrate the volume of T3 required," says Gerdes. "When T3 treatment led to a reduction in serum BNP levels, this was associated with improved cardiac function and reversal of these heart failure genes."

Gerdes and the team are hopeful that future investigations will confirm BNP's powerful new purpose in the very near future. "The beauty of this biomarker is that it is already in widespread use, so efficacy could be shown quickly," he notes.

New Haven, Conn. -- Yale pharmacology professor Barbara Ehrlich and her team have uncovered a mechanism driving a rare, lethal disease called Wolfram Syndrome and also a potential treatment. Their findings appear in the July 6 edition of Proceedings of the National Academy of Sciences.

Wolfram Syndrome -- a progressive degenerative disease that affects about one in 500,000 people worldwide -- is characterized by the onset of diabetes in childhood, and, in teen years, psychiatric symptoms, loss of vision, deafness, and incontinence. Most patients die in their 30s. There are no treatments.

The new study confirms that calcium inside the body's cells play a key role, and proposes a potential treatment involving two existing drugs.

Specifically, Ehrlich's team confirmed that when the protein Wolframin is lost in cells in the pancreas -- the organ that produces insulin, which regulates blood sugar -- "calcium signaling goes awry," Ehrlich said. This, the team found, results in reduced cell viability and lower insulin secretion, which, in turn, triggers the debilitating symptoms of the disease.

The researchers tested a number of compounds for their effectiveness in restoring calcium signaling and improving cell functions, and found two drugs that worked -- ibudilast and a calpain inhibitor. Ibudilast has been approved for nearly 20 years to treat asthma in South Korea and Japan. It is now being tested in a number of clinical trials in the U.S., including for possible treatment of multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), and, in a trial underway at Yale, for COVID-19.

Some 99% of the body's calcium can be found in the bones and teeth. The other 1% -- found in solution inside cells and bodily fluids -- supports a variety of critical biological functions, said Ehrlich. It is this latter form of calcium that her lab has scrutinized in relation to Wolfram Syndrome. This fluid-based calcium is necessary for muscle contraction, nerve function, and insulin secretion, she said.

"Calcium is a signaling molecule," Ehrlich said. "It will signal, for instance, when insulin should be secreted."

Calcium signaling, in turn, is regulated by calcium-binding proteins, including neuronal calcium sensor-1 (NCS-1), a protein Ehrlich's lab has studied for the past 20 years. When a research group from Europe proposed that NCS-1 was involved in Wolfram Syndrome pathology, Ehrlich started investigating the disease.

"The first step was to better understand what the protein Wolframin does," said Tom T. Fischer, a medical student from Germany working in Ehrlich's lab. "In our cell model that is lacking Wolframin, we measured intracellular calcium and found that calcium signaling as well as calcium-dependent cell functions, particularly insulin secretion and cell viability, were disrupted."

They then tested a number of drug compounds and found that ibudilast and the calpain inhibitor restored intracellular calcium and cell functions, Fischer said.

With support from the Blavantik Fund for Innovation at Yale, Ehrlich's team will begin a mouse study within the next six months to further confirm the effectiveness of the drugs in correcting calcium signaling and preventing the progression of Wolfram Syndrome. If the results of the animal study show promise, the researchers said, they could move quickly into human trials.

Although Wolfram Syndrome is a rare disease caused by genetic mutations in a single gene, it is tied to a number of other diseases that could be viable targets for this treatment, including diabetes and bipolar disorder, the researchers said.

"Some people with bipolar disorder also have mutations in Wolframin," Ehrlich said. "This might be one of the first genetically identified mood disorders -- and we will definitely be exploring this more."

In the largest international study of its kind, researchers at the University of Alberta and Toronto's St. Michael's Hospital found that an accelerated renal-replacement therapy strategy did not reduce mortality after three months, compared to a standard strategy for critically ill patients with acute kidney injury.

The Standard vs. Accelerated Initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial was co-led by Sean Bagshaw, professor and chair of the University of Alberta's Department of Critical Care Medicine, and Ron Wald, nephrologist and medical director of hemodialysis at St. Michael's and associate professor of medicine at the University of Toronto. STARRT-AKI enrolled 3,019 patients across 168 hospitals in 15 countries.

"This is the largest trial to tackle a question that has been vexing clinicians for more than 30 years," said Bagshaw. "The critical care and nephrology communities have been eagerly awaiting further information to guide the question, 'When is the ideal time to start dialysis therapy in critically ill patients admitted to Intensive Care Unit (ICU) with acute kidney injury?'"

A sudden loss of kidney function--a condition known as acute kidney injury--frequently affects patients who are admitted to the intensive care unit. When acute kidney injury is severe, kidney function may be replaced by dialysis machines that remove toxins and excess fluid and salts that accumulate in the bloodstream. There is no universal consensus on the optimal time to start such therapy.

In STARRT-AKI, patients admitted to the ICU who experienced severe acute kidney injury were randomly assigned to one of two treatment strategies. One strategy looked at pre-emptive or accelerated initiation of renal replacement therapy, in which patients received renal-replacement therapy almost immediately upon fulfilling eligibility. The second treatment strategy used a more conservative approach, which entailed observing the patient and initiating renal-replacement therapy only if the patient developed complications or had persistence of acute kidney injury beyond three days.

The team found that 43.9 per cent of patients in the accelerated strategy and 43.7 per cent of patients in the standard strategy died by 90 days, showing that there was no significant difference in survival between the two treatment strategies.

"Because little evidence existed previously, clinicians around the world were approaching the initiation of dialysis very differently," said Wald. "We hope that this definitive evidence can help clinicians make more informed decisions."

"Dialysis is life-saving, but it has potential harms. By initiating it more judiciously, it will expose patients to less risk and potentially reduce health-care costs without any negative impact on patient survival," Wald said.

The study also looked at several subgroups of patients--including their sex, where they live, presence of chronic kidney disease, whether they had sepsis and the severity of illness at presentation--to try to understand whether there was evidence that any patient group benefited from the accelerated strategy versus the standard strategy. Again, they did not find any substantial difference in survival between the two approaches. They did, however, find that at the 90-day endpoint, patients who had received the accelerated strategy were slightly more likely to remain dependent on dialysis than patients who received the standard strategy.

"About 10 per cent of patients in the accelerated strategy remained dialysis-dependent versus six per cent who received the standard strategy," Bagshaw said.

The trial was one of the largest coordinated by the Applied Health Research Centre at St. Michael's, an organization that helps design, coordinate and manage large clinical trials around the world.

The team said they hope to do further research with this data to better understand how different factors impact outcomes in this population and develop further insights about how to best deliver dialysis to this high-risk population.

"Ultimately what is most important is how we can use these results to improve the care of critically ill patients with acute kidney injury at the bedside," Bagshaw said.

New insights into Ewing sarcoma, an aggressive childhood cancer, were published July 15 in the prestigious journal Nature. Researchers from the Long School of Medicine at The University of Texas Health Science Center at San Antonio contributed to the study.

Ewing sarcoma is a bone and soft tissue cancer that primarily affects children and adolescents. The discovery, made by scientists at the University of Toronto, relates to cell structures called nucleoli and a physical change they undergo called phase separation.

The Toronto team observed that to form normal nucleoli, a structure must be made in the DNA. This is accomplished by the delicate balance of two different, but opposing, genetic code-reading machines. If these systems are not in balance, nucleoli lose their form and break up into smaller entities, the team found.

Study author Alexander Bishop, DPhil, of UT Health San Antonio, with team members at the Greehey Children’s Cancer Research Institute, previously showed that one of the genetic code-reading machines is overactive in Ewing sarcoma. In the newly published study, they confirmed that, in Ewing sarcoma, this overactivity causes the nucleoli to break up into smaller entities.

“We are working now to better understand the impacts of this biology in Ewing sarcoma and how we can take advantage of it therapeutically,” Dr. Bishop said.

Dr. Bishop joined UT Health San Antonio in 2005. He is an associate professor in the Department of Cell Systems and Anatomy of the Long School of Medicine, is a researcher in the university’s Greehey Institute, and is a member of the Mays Cancer Center, home to UT Health San Antonio MD Anderson.

Funding for the UT Health San Antonio investigators is from the U.S. National Institutes of Health and the Cancer Prevention and Research Institute of Texas.

Nucleolar RNA polymerase II drives ribosome biogenesis

Karim Mekhail, Karan Abraham, Negin Khosraviani, Janet Chan, Aparna Gorthi, Anas Samman, Dorothy Zhao, Miling Wang, Michael Bokros, Elva Vidya, Lauren Ostrowski, Roxanne Oshidari, Violena Pietrobon, Parasvi Patel, Arash Algouneh, Rajat Singhania, Yupeng Liu, V Yerlici, Daniel de Carvalho, Michael Ohh, Brendan Dickson, Razq Hakem, Jack Greenblatt, Stephen Lee, Alexander Bishop

First published: July 15, 2020, Nature

https://doi.org/10.1038/s41586-020-2497-0

# # #

The Long School of Medicine at The University of Texas Health Science Center at San Antonio is named for Texas philanthropists Joe R. and Teresa Lozano Long. The school is the largest educator of physicians in South Texas, many of whom remain in San Antonio and the region to practice medicine. The school teaches more than 900 students and trains 800 residents each year. As a beacon of multicultural sensitivity, the school annually exceeds the national medical school average of Hispanic students enrolled. The school’s clinical practice is the largest multidisciplinary medical group in South Texas with 850 physicians in more than 100 specialties. The school has a highly productive research enterprise where world leaders in Alzheimer’s disease, diabetes, cancer, aging, heart disease, kidney disease and many other fields are translating molecular discoveries into new therapies. The Long School of Medicine is home to a National Cancer Institute-designated cancer center known for prolific clinical trials and drug development programs, as well as a world-renowned center for aging and related diseases.

The University of Texas Health Science Center at San Antonio, also referred to as UT Health San Antonio, is one of the country’s leading health sciences universities and is designated as a Hispanic-Serving Institution by the U.S. Department of Education. With missions of teaching, research, patient care and community engagement, its schools of medicine, nursing, dentistry, health professions and graduate biomedical sciences have graduated more than 37,000 alumni who are leading change, advancing their fields, and renewing hope for patients and their families throughout South Texas and the world. To learn about the many ways “We make lives better®,” visit www.uthscsa.edu.

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Journal

Nature

DOI

10.1038/s41586-020-2497-0

ITHACA, N.Y. - Infertility affects 10% to 15% of couples globally, and while often viewed as a women's health problem, men contribute to around half of the cases.

Now, a male fertility test based on Cornell research could help predict which men might need treatment and which couples might have success with different forms of assisted reproduction.

"The 'Cap-Score' test is designed to provide information on the man's fertility that they never had before," said Dr. Alexander Travis, professor of reproductive biology at the Baker Institute for Animal Health and the test's inventor. "Now the doctors can discuss these results with the couple, and help them choose the personalized treatment pathway that is right for them to try to get pregnant, including how to improve the man's fertility."

The research was published in Reproductive BioMedicine Online. Travis is senior author.

The Cap-Score is a diagnostic test approved for use by medical doctors in all 50 states; the technology has been licensed to Androvia LifeSciences, LLC, a fertility research company co-founded by Travis, its chief science officer, in 2015. Travis holds equity in the company.

Cap-Score quantifies the ability of sperm to undergo a process called "capacitation," which enables the sperm to fertilize an egg. Only sperm that capacitate are capable of fertilizing. By contrast, traditional male fertility exams rely primarily on semen analysis, which counts sperm and assesses whether they swim and look normal.

"Fertility exists in degrees; as long as a man produces some sperm that swim, he has some level of fertility," Travis said. "But it is the functional ability of those sperm to fertilize an egg that influences the odds that a couple will become pregnant."

The new research included prospective clinical pregnancy outcomes data from six fertility clinics. Prospective tests are important when evaluating a new diagnostic procedure because they show the ability to predict what will happen for patients.

Travis said Cap-Score's predictive ability "held true across different age ranges for the female partner." This is important because there are many well-known impacts of maternal age on a couple's fertility. The new data shows that the man's fertility plays a key role in whether a couple will be able to conceive, even if they might have delayed having children and are older.

The researchers also compared Cap-Score results from more than 2,000 men having fertility exams at 22 clinics against results from a control group of fertile men with a pregnant partner or young baby. Cap-Scores from the fertile men showed an expected bell-shaped curve. In contrast, the vast majority of men questioning their fertility had scores below the mean of the fertile population.

Additionally, the researchers examined the relationship between traditional semen analysis results and impaired capacitation. "Men are often assumed to be fertile if they have enough normal-looking sperm that swim," Travis said, "but we found that almost two-thirds of the men who had low Cap-Scores passed the traditional semen analysis."

Infertility and most male infertility cases remain unexplained due to a lack of diagnostic testing. Not only does this place the onus of expensive and often invasive testing on women, it also may prompt couples to try expensive procedures that might be inappropriate for their situation. The Cap-Score can now provide crucial missing information to help guide their choices.

"Couples and doctors have had to make important decisions about their fertility without all the information they needed. This has caused a lot of anxiety and pain - physically, financially and emotionally," Travis said.

Using the Cap-Score, doctors and couples can make informed decisions about whether to try to conceive unassisted or choose one of several medical approaches. The results can also be used to identify which men might benefit from treatment to improve their fertility, including changes in lifestyle, nutritional supplements or surgery.

The increased severity and mortality of SARS-CoV-2 infections in older individuals may be related to inflammageing - an age-associated phenomenon of increased general inflammation. In this Perspective, Arne Akbar and Derek Gilroy discuss this possibility as well as strategies to mitigate related effects. Inflammageing is thought to be caused, at least partially, by deterioration of aged cells (senescence) in tissues of the body that release inflammatory molecules. A growing number of studies show that excessive inflammation due to inflammageing combined with an aged immune system can inhibit overall immunity, which can also reduce vaccination efficacy in older people. According to Akbar and Gilroy, reducing the numbers of senescent cells with senolytic drugs or reducing inflammageing with anti-inflammatory drugs may be a beneficial strategy for improving COVID-19 outcomes in older patients. They also raise the question of whether vaccines can even be effective within these inflammatory environments. "The search for an effective vaccine for COVID-19 has also to consider the decreased vaccination efficacy in older subjects that may be associated with inflammageing. Therefore, the effective treatment of COVID-19 in older patients may require a combination of anti-inflammatory, anti-viral regimes to compliment vaccination against the virus," write Akbar and Gilroy.

Certain methods of decontaminating medical face masks for repeated use during the COVID-19 pandemic appear to damage the masks' integrity and protective function, according to research by a University of Massachusetts Amherst environmental health scientist.

"Some treatments for decontamination had no impact on respirator performance, while other treatments resulted in substantial damage to masks," writes Richard Peltier, associate professor in the School of Public Health and Health Sciences and lead author of the paper published July 16 in the journal Infection Control and Hospital Epidemiology.

Peltier received a fast-track grant from the National Science Foundation in May to study the impact of various sterilization techniques authorized for emergency use by the Food and Drug Administration (FDA) in light of the shortage of medical face masks, also known as N95 respirators.

"Given the global N95 shortages, clinicians face a choice: wearing a used, and potentially infected respirator, or wearing one that was decontaminated through a process that may affect the integrity of the respirator," says Peltier, whose co-authors include doctors and researchers at New England Baptist Hospital in Boston and UMass Memorial Medical Center in Worcester.

Peltier uses state-of-the-art pollution detection instruments and a mannequin head in his lab to measure whether microscopic particles can pass through the masks after they are sterilized. "Respirators must be effective across a range of potential conditions to provide protection since droplets that contain virus particles immediately start to evaporate and shrink," he explains.

While the testing was limited by the availability of processed masks provided by hospitals in Massachusetts, the study draws several generalizable conclusions, Peltier says.

Respirators that were treated between one and 10 times with specific vaporized hydrogen peroxide (vHP) sterilizers or up to five times with shorter decontamination cycles of gas plasma hydrogen peroxide (gpHP) retain their original filtration capabilities. A decontamination process using ultraviolent germicidal irradiance (UVGI) slowly diminishes filtration efficiency, reaching a level "that warrants caution" after nine repeated treatments, the research found. "However, there are still a number of sterilizer systems that are being used on these masks which we don't have information about and therefore can't determine if they keep workers safe," Peltier says.

Treatments with high concentrations of gpHP or longer processing times degraded filtration performance below the requirement for N95 masks, which should be capable of filtering 95% of 300 nanometer (nm) particles.

For comparison, Peltier also tested a KN95 mask, some brands of which have been removed from the FDA's emergency-use list due to poor performance, and a four-ply polyester bandana. Neither had been treated with any decontamination technique, and both performed below N95 standards. Peltier also found that immersing an N95 mask in a 10% bleach solution degraded its performance.

Peltier notes that his study did not address the masks' fit or general integrity, including elastic function, corrosion on staples and compression of the respirator, all of which are important for proper functioning. His research highlights the importance of using decontamination techniques shown to be safe for the reuse of N95 masks.

"We hope this work supports good decision-making that protects those who are on the front lines of this pandemic keeping us all safe," Peltier says. "Without them, none of us are safe."

A new peer-reviewed study by researchers at NSF International and Novateur Ventures finds significant variability in the accuracy of currently available COVID-19 antibody tests. The study, "COVID-19 Serological Tests: How Well Do They Actually Perform?", appears in the latest issue of the journal Diagnostics, an international peer-reviewed open-access journal published monthly by the Multidisciplinary Publishing Institute (MDPI).

In the absence of vaccines and effective therapeutics for SARS-CoV-2 and the associated COVID-19 disease, reliable antibody testing can be a key element of public health policy to control further spread of the disease and gradually ease quarantine measures.

The study was coauthored by Robyn Meurant, Executive Director of Health Sciences for NSF International, Abdi Ghaffari, Advisor in Scientific affairs at Novateur Ventures and an Adjunct Associate Professor at the Department of Pathology and Molecular Medicine at Queen's University, and Ali Ardakani, Founder & Managing Director at Novateur Ventures.

The urgent need for the development of antibody diagnostic tests in response to the COVID-19 pandemic has compelled regulatory bodies to implement emergency use authorization programs to expedite the commercialization process of these tests. "Granting FDA Emergency Use Authorization to several companies to accelerate the manufacturing of diagnostic tests was a good move," said Ghaffari. "But it must be accompanied by informed and clear guidelines on preferred and minimally acceptable profiles of the COVID-19 antibody tests designed for a specific indication."

Published independent performance data of five CLIA (chemiluminescence immunoassay), 15 ELISA (enzyme-linked immunosorbent assay) and 42 RDT (rapid diagnostic test) antibody tests that are currently on the market were reviewed for this study to understand their limits and potential.

"No single assay can be used for all diagnostic use cases in the COVID-19 response for a country," said Meurant. "What works well in one setting may be inappropriate or not accessible for another. As such, access to information on test performance, that is generated independently, greatly assists countries in informed decision-making."

The findings show significant variability in the accuracy of marketed tests and highlight several lab-based and point-of-care rapid diagnostic tests with high performance levels in detecting SARS-CoV-2 specific antibodies. The findings of this review highlight the need for ongoing independent evaluations of commercialized COVID-19 diagnostic tests.

"Antibody testing is important to understanding the extent of exposure for COVID-19 so it can be effectively monitored and treated," said Ardakani. "It is important for regional and national governments to continue their coordinated efforts to independently validate antibody test performance and also partner with industry to scale up manufacturing and production capacity."

Thirteen top-performing COVID-19 antibody tests were identified in this study based on independent evaluations of their sensitivity (ability to correctly identify those with the disease) and specificity (ability to correctly identify those without the disease) data (>95% accuracy).

In any infectious disease outbreak, accurate and accessible diagnostic testing must be one of the pillars of control measure policies to understand and minimize the spread of disease. The epidemiological studies of the outbreak in China estimated the proportion of undetected COVID-19 cases to be as high as 86% . As asymptomatic or mild cases could play a significant role in the transmission and spread of the SARS-CoV-2 virus, symptoms alone are not reliable diagnostic markers.

There are two major types of diagnostic technologies available to address this: molecular and antibody (sometimes called serological) tests. Currently, much of the focus is on the SARS-CoV-2 molecular test, which can detect, with high accuracy, the viral-specific RNA molecules circulating in the host body. However, the molecular test is not useful in distinguishing between highly infective viruses versus ones that have been neutralized by the host, and it cannot assess immunity status against SARS-CoV-2. Antibody tests can complement molecular-based tests in providing a more accurate estimate of SARS-CoV-2 incidence and potentially detect individuals with immunity against the disease as these tests detect markers of the immune response.