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King Richard III's involvement in one of the most notorious and emotive mysteries in English history may be a step closer to being confirmed following a new study by Professor Tim Thornton of the University of Huddersfield.

Richard has long been held responsible of the murder of his nephews King Edward V and his brother, Richard, duke of York - dubbed 'the Princes in the Tower' - in a dispute about succession to the throne. The pair were held in the Tower of London, but disappeared from public view in 1483 with Richard taking the blame following his death two years later.

It has become of the most enduring unsolved mysteries of all, stoked by references in Shakespeare's play about the doomed Yorkist king and influenced by subsequent monarchs who were keen to paint their predecessor as a monster.

Evidence points to Richard's guilt

Defenders of Richard III have pointed to a lack of hard evidence to connect the king to the disappearance of the princes, who were aged just 12 and 9 when Richard took the throne in June 1483. But in 'More on a Murder' for History, the Journal of the Historical Association, Professor Thornton says that there is now clear evidence to substantiate the allegations against the men identified as the boys' murderers, and to connect them to Richard III.

Integral to this is the 'History of King Richard III' by Sir Thomas More, the first detailed account of the deaths of the princes. More named two men, Miles Forest and John Dighton, as the murderers. More claimed that they were recruited by Sir James Tyrell, a servant of Richard III at his orders.

Until now, many people have questioned this story as being written long after the event, as 'Tudor propaganda' to blacken the name of a dead king, and even suggested that the names of the alleged murderers were made up by More.

More's conclusions were reliable

But Professor Thornton believes that More came to the right conclusion due to some inside knowledge. Two of the famed politician and philosopher's fellow courtiers were the sons of Miles Forest, one of the men More named as having killed the princes.

"This has been the greatest murder mystery in British history, because we couldn't really rely on More as an account of what happened - until now," says Professor Thornton.

"But I have shown that the sons of the chief alleged murderer were at court in Henry VIII's England, and that they were living and working alongside Sir Thomas More. He wasn't writing about imaginary people. We now have substantial grounds for believing that the detail of More's account of a murder is credible."

The mystery surrounding the princes has resonated for centuries, being revived in the 1670s when the bones of two boys were rediscovered in the Tower of London, and again in the 1930s when the remains, which had been reburied in Westminster Abbey, were scientifically reexamined.

The discovery of Richard III's body under a car park in Leicester in 2012 also reignited interest in the controversial monarch, with some historians questioning whether he has deserved his notoriety. And the recent announcement of a new film about the rediscovery of Richard, written by Steve Coogan and Stephen Frears, shows that interest in the controversial monarch is as strong as ever.

Amsterdam, December 29, 2020 - This new pioneering study by Prof. Ricardo Maccioni and coworkers of the International Center for Biomedicine, "New Frontiers in the prevention, diagnosis and treatment of Alzheimer´s disease" was published in the special issue of Latin American investigators of the Journal of Alzheimer's Disease(JAD). This supports a growing body of research on the Alzheimer's prevention value of an integrated approach using daily exercise, nutraceuticals, oriental practices such as QiGong along with meditation, and social life. These elements of a healthy style of life are supplemented with the use of reliable biomarkers for early detection of this disease that allows the detection of Alzheimer up to 20 years before symptomatic phase of the disease.

One of the major puzzles in medical research and public health systems worldwide is Alzheimer's disease (AD), reaching nowadays a prevalence of nearly 50 million people. AD is a multifactorial brain disorder characterized by progressive cognitive impairment, apathy, and mood disorders. The main risk of AD is aging. Studies suggest that AD is a break from normal aging with changes in the powerful functional capacities of neurons as well as in the mechanisms of neuronal protection. There are factors that are determinants of the functional losses during aging, an important part is played by epigenetic components. Thus, the action of genes that confer susceptibility to AD can be mitigated with healthy lifestyles, physical exercise, balanced nutrition, avoiding molecules harmful to health and drugs. An active social life and practicing activity during the latter years of aging, to achieve health in advanced age.

In this context, an important path has been opened towards AD prevention considering the factors mentioned above and the control of neuroinflammatoy events (Figure 1). On the basis of medical evidence we conclude that a rational integration of all these factor exert a preventive action against neuronal degeneration in AD providing a better quality of life. Prevention as well as innovative screening programs for an early detection of the disease using reliable biomarkers are becoming critical to control the disease. Our own data suggest that AD is a clear break with normal aging; understanding that this process requires a systems of a biology-based approach. In addition, the failure of traditional pharmacological treatments and search for new drugs has stimulated the emergence of nutraceutical compounds in the context of a "multitarget" therapy, as well as non-pharmacological approaches shown to be effective in aging, and applied to AD control. An integrated approach involving all these preventive factors combined with novel multitarget therapeutic approaches should pave the way for the future control of the disease.

Researchers at the National Institutes of Health and their collaborators found that inhaling unfragmented hyaluronan improves lung function in patients suffering from severe exacerbation of chronic obstructive pulmonary disease (COPD). Hyaluronan, a sugar secreted by living tissue that acts as a scaffold for cells, is also used in cosmetics as a skin moisturizer and as a nasal spray to moisturize lung airways. Utilized as a treatment, hyaluronan shortened the amount of time COPD patients in intensive care needed breathing support, decreased their number of days in the hospital, and saved money by reducing their hospital stay.

The study, published online in Respiratory Research, is a good example of how examining the impacts of environmental pollution on the lungs can lead to viable treatments. Several years ago, co-senior author Stavros Garantziotis, M.D., medical director of the Clinical Research Unit at the National Institute of Environmental Health Sciences (NIEHS), part of NIH, showed that exposure to pollution causes hyaluronan in the lungs to break down into smaller fragments. These fragments irritate lung tissue and activate the immune system, leading to constriction and inflammation of the airways. He determined that inhalation of healthy, unfragmented hyaluronan reduces inflammation by outcompeting the smaller hyaluronan fragments.

Garantziotis offered an analogy for how the inflammation occurs. He said hyaluronan surrounds cells like mortar surrounds bricks. Introducing pollution causes cracks in the mortar, breaking it into smaller chunks.

"These smaller chunks irritate the body and activate the immune system, leading to inflammation," Garantziotis said. "Reintroducing the full-length hyaluronan, like a fresh coat of mortar, means it is less irritating and reduces the amount of inflammation."

Since hyaluronan was approved in Italy for airway moisturization, Garantziotis worked with colleagues in Rome to see if inhalation of full-size hyaluronan could improve lung function in critically ill COPD patients. He explained that the patients were using a breathing apparatus similar to a continuous positive airway pressure (CPAP) machine to treat their acute exacerbation of COPD. This apparatus provided breathing support by blowing air into the airways through a mask.

"Inhaled hyaluronan qualifies as a stimulating aid for patients with exacerbated COPD, as it is safe and easy to administer," said co-senior author Raffaele Incalzi, M.D., Department of Medicine, Campus Bio-Medico University and Teaching Hospital, Rome. "Furthermore, it acts locally, only in the bronchial tree, and, thus, cannot interfere with any systemic drug."

Garantziotis also wanted to know what was producing airway constriction in the lungs of COPD patients. He theorized that thick mucus may be involved. Collaborating with scientists at the University of Alabama at Birmingham (UAB), they grew airway cells from emphysema patients in culture and looked at how mucus moved in the cells. They saw that mucus flowed more easily after administering hyaluronan.

Co-author Steven Rowe, M.D., director of the Gregory Fleming James Cystic Fibrosis Research Center at UAB, said if patients with severe COPD took hyaluronan, the treatment would improve mucus transport and aid their recovery.

Current treatments for lung disease include inhaled steroids, antibiotics, and bronchodilators, so using a molecule that is already found in the body is a new concept. The goal now for Garantziotis is to study this treatment in more patients in the U.S., so he can understand the optimal conditions and dosing that will produce the most benefit.

As the numbers of those infected with COVID-19 has continued to climb, the desperate need for a vaccine was apparent. Even now with the invention and administration of several COVID-19 vaccinations, the question remains: How effective are these vaccines? HMNTL students Congnyu Che, Weijing Wang, and Nantao Li, also members of the ECE Nanosensors Group, along with Postdoctoral Researcher Bin Zhao and Professor Brian Cunningham have recently been published in Talanta journal for the development of a cost efficient COVID-19 antibody test.

"Compared with other detection methods, our method is a simple, 15-minute sample-to-answer test," says Zhao, a postdoctoral research associate and IGB Fellow. "It costs less than $2 per test and is used with a desktop detection system that is suitable for point-of-care situations like clinics and physician offices."

When COVID-19 began developing into a global crisis in early 2020, this research group was already working on an NIH-funded project to develop a "flu chip" that would rapidly determine the most likely cause of a fever by measuring several proteins within a droplet of blood. They decided to pivot their efforts to detect COVID-19 antibodies instead.

"We made an important breakthrough at the end of May and our method started working," says Congnyu Che, a BioE and Holonyak Lab graduate student. "After that, it took only a couple of months for us to complete all the experiments that measured detection limits, selectivity against other proteins, and the minimum time needed to get a result."

Serological (detected by blood sample) antibody testing is an important diagnostic tool for combating the COVID-19 pandemic. Studies have shown that measurement of SARS-CoV-2 specific antibodies may be helpful for the diagnosis of suspected patients with negative RT-PCR results and for the identification of asymptomatic infections - a cause for concern as vaccinations may lessen or eliminate symptoms as well as prevent infection. Quantitative measurement of COVID-19 antibody titer is also vital for blood transfusion therapy, which has shown promising results for treating patients with severe symptoms.

"Quantitative assessment of COVID-19 antibody titer is especially important as clinicians and researchers more fully understand the patient-to-patient variability of immune response, in terms of the onset time for post-infection antibody production, and the post-recovery time that antibodies continue to be present," says Weijing Wang, a BioE and Holonyak Lab graduate student. "As vaccines become available, it will be urgent for patients to know the extent to which their immune response has been stimulated."

This highly sensitive, fast, and low-cost test demonstrates great potential for wide applications in diverse working environments. COVID antibody testing could become routine and simple as a variety of vaccines are deployed whose long-term protection is not yet fully known. The test is simple enough to be performed at schools, health clinics, pharmacies, and parts of the world where diagnostic laboratories are not available.

"Our developed method is not only rapid and simple, but also highly sensitive and quantitative. It also requires only a fingerstick quantity of blood (~ 4 μL)," says Nantao Li, an ECE and Holonyak Lab graduate student. "The method that we used to detect COVID-19 antibody can also be adapted to detect other molecules, such as antibodies to other viral pathogens, biomarkers for cardiac disease, and biomarkers for cancer."

Members of the research group say that, as researchers in the field of disease diagnostics, their mission is to develop innovative analytical methods and tools to provide potentially effective solutions for global public health. They are eager to contribute their expertise to combat the COVID-19 pandemic.

"We are very glad we did it," says Zhao. "Without any one of us, this group couldn't have finished the work so quickly and efficiently. We all put forward many great ideas and were all very active during the experimental process."

The team says they also want to encourage everyone to continue social distancing and mask wearing even as vaccines are distributed.

Taking a particular type of medication to treat enlarged prostate is associated with a reduced risk of developing Parkinson's disease, according to a large observational study led by researchers at the University of Iowa, with colleagues in Denmark and China.

The findings, published Feb. 1 in JAMA Neurology, provide compelling evidence that terazosin, and similar medications, might have the potential to prevent or delay the development of Parkinson's disease.

The new study used data on almost 300,000 older men from two large, independent patient datasets--the Truven Health Analytics MarketScan database in the United States and national health registries in Denmark--to investigate whether taking terazosin is associated with the development of Parkinson's disease.

The findings build on previous preclinical research by the team, which showed that terazosin enhances cellular energy levels and can prevent or slow the progression of Parkinson's disease in animal models. In this earlier study, the team also used the Truven database to show that men with Parkinson's disease who were also taking terazosin and related drugs had reduced signs, symptoms, and complications of Parkinson's disease.

Importantly, the researchers had a good control group for this earlier database study. Tamsulosin is another drug commonly used to treat enlarged prostate, but unlike terazosin, tamsulosin has no effect on cellular energy production, which the team's lab studies suggest is important in terazosin's protective effect.

The new study extends these findings to investigate whether terazosin, and related drugs that can also enhance cellular energy production, are associated with a reduced risk of developing Parkinson's disease.

Using the U.S. and Danish databases, the team identified 150,000 men newly started on terazosin or similar medications and matched them, based on age and clinical history to 150,000 men newly started on tamsulosin.

"We then tracked the health data on these men to determine how many in each group developed Parkinson's disease," explains Jacob Simmering, PhD, UI assistant professor of internal medicine and corresponding author of the study. "Men taking terazosin were 12 to 37% less likely to develop Parkinson's disease during follow-up than men taking tamsulosin."

Additionally, the study found that longer duration of use of the energy-enhancing prostate drugs was associated with increased protective effects.

"Despite the relative differences in population and health care system structure, we found a similar protective effect in both countries," Simmering adds. "The replication of the finding in an international cohort is powerful evidence suggesting a causal effect. If these results are confirmed through further investigation, especially a randomized clinical trial, terazosin may provide neuroprotection and potentially prevent--and not just manage--Parkinson's disease."

A new kind of wearable health device would deliver real-time medical data to those with eye or mouth diseases, according to Huanyu 'Larry' Cheng, Dorothy Quiggle Career Development Professor in the Penn State Department of Engineering Science and Mechanics (ESM).

Cheng recently published a paper in Microsystems & Nanoengineering on new micro- and nano-device technology that could revolutionize how certain health conditions are monitored and treated.

"We sought to create a device that collects both small and large substances of biofluids such as tears and saliva, which can be analyzed for certain conditions on a rapid, continuous basis, rather than waiting on test results from samples in a lab," he said.

The sensors would be placed near the tear duct or mouth to collect samples, which would then produce data viewable on a user's smartphone or sent to their doctor, according to Cheng.

"But a device like this would have to be discreet, soft and comfortable for a patient to agree to wear it," he said. "And it would have to be a low-cost option for patients."

The tears- and saliva-sensing technology can help manage diseases like oral ulcers, oral cancer, eye wrinkles and oral or eye infections like keratitis, which is inflammation of the clear tissue on the front of the eye.

Last year, Cheng published on a similar wearable skin patch that collects sweat and tests for pH, sodium and glucose levels -- most helpful for those with hypoglycemia or diabetes.

This new device not only collects data but also administers medicine with a microneedle through the skin around the eye, mouth or tongue.

"Through nano- to micro-steel ports on the device, we can probe the cell to deliver molecular drugs for treatment in a very efficient process at the cellular level," Cheng said. "Conversely, the ports can allow us to get access to the gene and coding information on the cell."

The researchers are developing working prototypes and are in talks with local manufacturers as well as the National Institutes of Health and Amazon for manufacturing the device on a large scale.

"This is a mature technology with a lot of interest behind it," Cheng said. "There are many possible uses for the device if it makes it to the commercial marketplace."

With future support from the National Science Foundation, Cheng hopes to extend the technology to other applications as well.

"There is strong motivation for us to apply this technology to similar sensing devices in the future," he said.

HOUSTON-(Feb. 1, 2021) - Houston Methodist researchers have developed a mathematical model to predict how specific cancers will respond to immunotherapy treatments, thus enhancing chances for successful treatments from a wide variety of cancer-immunotherapy drug combinations. The results were published last month in Nature Biomedical Engineering in collaboration with researchers at MD Anderson Cancer Center.

Immunotherapy activates patients' immune systems to recognize and attack their cancers, leading to higher, more targeted kill rates and fewer side effects than chemotherapy, radiation and other therapies. While this technology is a significant advance in fighting cancer, it works only with some cancer types, and only in a subset of patients with these cancers.

The mathematical model uses a system of mathematical equations based on laws of physics and chemistry to describe the complex biological systems involved in immunotherapy treatment and the associated immune response. Often, the important players or processes involved in cancer therapy (for example, immune cells or drugs that penetrate into the tumor) cannot be measured in patients. Mathematical modeling overcomes this limitation by discovering ways these can be calculated from other quantities that can be measured. Houston Methodist's Dr. Zhihui Wang and Dr. Vittorio Cristini and colleagues have designed this model to predict the strength of immune response using only inputs that are already measured in cancer patients. The model establishes a framework for engineering individual treatment strategies in a step toward the future of personalized medicine.

To test their model's ability to accurately and reliably characterize the specific strength of a cancer type to a specific immunotherapy treatment, they obtained CT or MRI scan data of tumors from before, during and after immunotherapy in 124 patients treated with checkpoint inhibitor immunotherapy in one of four in-house clinical trials. These were then analyzed using the model to obtain specific numeric measures of the therapeutic response. They found that two model-derived measures that quantify (1) the presence and health of the immune presence within the tumor and (2) the resulting kill rate of cancer cells by immunotherapy-activated immune cells were able to be combined into a single measure that was highly correlated with long-term tumor burden, thus providing a unique numerical score of the strength of response of that cancer to the specific drug. These results were further validated with data from 177 additional patients treated with one of the most common checkpoint inhibitor immunotherapies (anti-CTLA4 or anti-PD1/PDL1 monotherapies).

The mathematical model can be immediately implemented in the clinic, without the need for new technology, personnel or extensive training. Furthermore, methods to use other clinical measures to improve the accuracy and precision of model-based predictions, such as data from blood samples or tumor biopsies, are currently under investigation.

This collaborative effort between researchers and clinicians at Houston Methodist and MD Anderson Cancer Center is ongoing, with the long-term goal of clinical translation of this predictive model. MD Anderson collaborators include: Dr. James Welsh; Dr. Eugene J. Koay; Dr. Caroline Chung; and Dr. David S. Hong.

Below please find a summary and link(s) of new coronavirus-related content published today in Annals of Internal Medicine. The summary below is not intended to substitute for the full article as a source of information. A collection of coronavirus-related content is free to the public at http://go.annals.org/coronavirus.

1. Taiwan finds decreased overall death rate in 2020 compared to 2019
Findings suggests mask wearing, physical distancing, and restricting large social events may have had a positive spillover effect

Researchers from Taipei Medical University and Menzies School of Health Research, Australia found lower mortality rates for all-causes, pneumonia, and influenza in 2020 compared to 2019. Traffic deaths were up slightly. These finding suggest that mask-wearing, physical distancing, and restricting large social events may have had a positive spillover effect on population health. A brief research report is published in Annals of Internal Medicine. Read the full text: https://www.acpjournals.org/doi/10.7326/M20-7788.

A team of researchers in Taipei, Taiwan and Darwin, Australia sought to assess the possibility of undocumented COVID-19 deaths in Taiwan and whether nonpharmaceutical interventions and behavior changes affected all-cause, pneumonia and influenza, and road traffic deaths in 2020. They collected government data from 2008 to 2020 for yearly population deaths in those areas and looked at monthly road traffic deaths for January to October 2020. Using midyear population and World Health Organization (WHO) standard population data, they calculated the corresponding adjusted mortality rates per 100,000 persons for each year.

The data showed that the age- and sex-adjusted all-cause mortality rate per 100,000 persons in 2020 was 399.8, which the authors say is in line with the decreasing trend seen in recent years and notably lower than the 2019 rate. The adjusted pneumonia and influenza mortality rate in 2020 was 48.7, which is significantly lower than the 2019 rate and a deviation from the overall increasing trend. Finally, the adjusted road traffic mortality rate in 2020 was 8.8, which is higher than the 2019 rate but in line with the increasing trend in the past 3 years.

According to the researchers, these findings suggest that Taiwan’s rapid, coordinated, and early response should be an example for other countries.

Media contacts: A PDF for this article is not yet available. Please click the link to read full text. The lead authors can be contacted directly. Wayne Gao, PhD, can be reached at waynegao@tmu.edu.tw. Marita Hefler, PhD, can be reached at marita.hefler@menzies.edu.au.

2. Immunization experts call on clinicians to utilize immunization information systems to facilitate fair and equitable COVID-19 vaccine distribution

Immunization information systems (IISs) play a central role in coordinating distribution, administration, documentation, and monitoring of COVID-19 vaccination by confidentially collecting and consolidating vaccination data from multiple providers within a geographic area. Among other tools, IISs are critical to ensuring adequate vaccination across targeted populations and geographic areas. The United States has an independent network of 61 IISs in 49 states, the District of Columbia, 3 cities, and 8 territories.

Immunization experts from the University of Illinois College of Medicine, the American Immunization Registry, and the Immunization Action Committee call on clinicians to familiarize themselves with their IIS to maximize their COVID-19 vaccination campaigns. They say that the more clinicians are aware of and connected to their IISs, the better they will be able to address equitable vaccine distribution, manage vaccine uptake, and monitor vaccination series completion.

Read the full text: https://www.acpjournals.org/doi/10.7326/M20-7725.

Media contacts: A PDF for this article is not yet available. Please click the link to read full text.

The lead author, Andrew B. Trotter, MD, MPH, can be reached through Lori Botterman at lbott@uic.edu.

3. Experts discuss principles for clinical decision making when science is uncertain

In a new commentary published in Annals of Internal Medicine, authors from Massachusetts General Hospital and Harvard Medical School apply principles for translating imprecision in diagnostic and therapeutic information into clinical decisions to address 3 ongoing areas of uncertainty related to diagnosis, treatment, and prevention of COVID-19. For each case, the authors briefly review the current state of knowledge, highlight the level of uncertainty, and then suggest a pathway forward for clinical decision making during the pandemic.

According to the authors, clinicians can only make decisions based on the information that is available at the time. Due to the nature of the pandemic, the advice provided may change as the science advances. Their goal is to illustrate how one could use available strategies to evaluate new information as it emerges and incorporate evidence into clinical decisions at the individual and hospital levels.

Read the full text: https://www.acpjournals.org/doi/10.7326/M20-8179.

Media contacts: A PDF for this article is not yet available. Please click the link to read full text.

The lead author, Joshua P. Metlay, MD, PhD can be reached through Michelle Tagerman at MTAGERMAN1@mgh.harvard.edu.

An underused type of knee surgery in younger patients, called high tibial osteotomy, shows considerable success in reducing the need for total knee replacement, according to new research in CMAJ (Canadian Medical Association Journal).

"High tibial osteotomy is a knee surgery aimed at younger patients in the earlier stages of knee osteoarthritis. One of its goals is to prevent or delay the need for knee replacement," says coauthor Dr. Trevor Birmingham, Canada Research Chair in the Faculty of Health Sciences and the Bone and Joint Institute at Western University, London, Ontario. "In some ways, it's like performing a front-end alignment on your car to stop asymmetric wear on your tires and increase their longevity."

Knee osteoarthritis is a common cause of pain and disability and puts tremendous burden on health care systems. Total knee replacement is frequently performed on older patients with end-stage disease and limited mobility.

In Canada, rates of total knee replacement are high and increasing, while rates of high tibial osteotomy are low and decreasing. One reason for this is the perception that high tibial osteotomy is not warranted if the joint is going to be replaced soon afterwards. The findings of this new study contradict this perception.

Of the patients in this study getting high tibial osteotomy in London, Ontario (643 knees in 556 patients), 95% did not need a total knee replacement within 5 years, and 79% did not get a total knee replacement within 10 years. Even in patients traditionally not considered ideal candidates for high tibial osteotomy (e.g., women and patients with later-stage disease), about 70% did not get a knee replacement within 10 years.

The procedure is particularly suitable for people who are younger, have less severe joint damage and who may be more physically active. "Those patients especially contribute to the burden of knee osteoarthritis," says Mr. Codie Primeau, lead author. "There is a treatment gap between exhausting nonoperative treatments and appropriateness for joint replacement, resulting in many years of pain, lost productivity and associated costs."

"Given these findings, high tibial osteotomy may be underused in Canada and could be performed more often to delay or prevent the need for total knee replacement," says coauthor Dr. Robert Giffin, professor of surgery at Western University's Schulich School of Medicine & Dentistry and the Bone and Joint Institute.

"Total knee replacement after high tibial osteotomy: time-to-event analysis and predictors" is published February 1, 2021.

DALLAS, Feb. 1, 2021 -- Women with a history of diabetes during pregnancy (gestational diabetes) are twice as likely by mid-life to develop calcium in heart arteries - a strong predictor of heart disease - even if healthy blood sugar levels were attained many years after pregnancy, according to new research published today in the American Heart Association's flagship journal Circulation.

Gestational diabetes, which is high blood sugar levels (glucose intolerance) first recognized during pregnancy, affects approximately 9% of U.S. pregnancies and up to 20% worldwide. After pregnancy, women who had gestational diabetes are at higher risk of developing prediabetes or Type 2 diabetes, conditions that are risk factors for cardiovascular disease.

Previous studies found a much higher risk of heart disease in women with a history of gestational diabetes who later developed Type 2 diabetes. However, it remained unclear whether heart disease risk among women with a history of gestational diabetes was lower for women who attained healthy glucose levels or who developed prediabetes in mid-life.

In 2018, the American College of Cardiology/American Heart Association Cholesterol Clinical Practice Guidelines specified that a history of gestational diabetes enhances women's risk for artery build-up that leads to cardiovascular disease.

Using data from the multicenter, 30-year prospective Coronary Artery Risk Development in Young Adult (CARDIA) study, researchers investigated whether attaining healthy blood sugar levels after pregnancy would mitigate the increased risk of cardiovascular disease that is associated with a history of gestational diabetes.

"CARDIA is the first study to assess heart disease risk in women with a history of gestational diabetes compared to those without gestational diabetes according their blood sugar levels many years later. Women with previous gestational diabetes had a twofold higher risk of coronary artery calcium if they maintained normal blood sugar levels, later developed prediabetes, or later were diagnosed with Type 2 diabetes many years after pregnancy compared to women without previous gestational diabetes who had normal blood sugar levels," said Erica P. Gunderson, Ph.D., M.S., M.P.H., epidemiologist and senior research scientist in the Cardiovascular and Metabolic Conditions Section at Kaiser Permanente's Division of Research in Oakland, California.

The CARDIA study enrolled more than 5,100 U.S. men and women who were aged 18-30 years at the beginning of the study in 1985. The new analysis includes approximately 1,100 women (49% Black women and 51% white women) without Type 1 or Type 2 diabetes who subsequently gave birth at least once during the 25-year study period, which ended in 2011. Blood tests were performed from before to after pregnancies at five-year intervals to determine if women had normal blood sugar levels, intermediate elevations in blood sugar levels (prediabetes) or they had developed overt Type 2 diabetes. Heart scans were performed to measure coronary artery calcium, a strong predictor for heart disease, at exams 15, 20 and 25 years after the baseline, the first exam of the study.

At the 25-year follow-up, the participants' median age was 48 years old, and 12% of the women in the study had a pregnancy complicated by gestational diabetes. The prospective analysis found:

Women with a history of gestational diabetes had a two-fold higher risk of coronary artery calcification whether they had healthy blood sugar levels, prediabetes or Type 2 diabetes.

Attaining healthy blood sugar levels after pregnancy did not decrease the risk of developing cardiovascular disease in mid-life for women with previous gestational diabetes.

Of women with previous gestational diabetes, 36% developed prediabetes and 26% developed Type 2 diabetes, compared to 35% and 9% of women with no history of gestational diabetes.

25% of women with a history of gestational diabetes had some level of coronary artery calcium vs. 15% of women who never had gestational diabetes.

"We were surprised to discover that women with a history of gestational diabetes are at a significantly greater risk of heart artery calcification, even if they maintain normal blood sugar levels after pregnancy," Gunderson said.

"Our findings represent a shift in this paradigm by showing that normal blood glucose after gestational diabetes is still related to higher coronary artery calcium risk," the authors note.

"Risk assessment for heart disease should not wait until a woman has developed prediabetes or Type 2 diabetes," Gunderson said. "Diabetes and other health problems that develop during pregnancy serve as early harbingers of future chronic disease risk, particularly heart disease. Health care systems need to integrate the individual's history of gestational diabetes into health records and monitor risk factors for heart disease, as well as the recommended testing for Type 2 diabetes in these women at regular intervals, which is critical to target prevention efforts."

Limitations of the study include that researchers had no measurement of coronary artery calcium levels prior to pregnancy, and coronary artery calcium scores were used as a surrogate marker for heart disease risk not cardiovascular events.

The American College of Cardiology's Cardiovascular Summit will feature several poster presentations on care delivery, cost reduction and quality improvement that offer innovative concepts to combat access to care, especially during the ongoing COVID-19 pandemic and as the broader health care system works to improve health equity. Research examines the rapid adoption of virtual outpatient care, enabling rural primary care teams to improve cardiovascular health and optimizing emergency room use after clinic hours.

Summaries of embargoed abstracts are below. For access to the full abstracts or to register for media access to the conference, contact Katie Glenn at kglenn@acc.org.

Rapid Adoption of Virtual Outpatient Cardiology Care During COVID-19

Following stay-at-home orders in March 2020 in Oregon, a large, integrated cardiology practice with 22 sites moved to implement virtual (telephone and video) platforms while providing patient, provider and staff education. After the stay-at-home order was lifted in June 2020, the institution continued to provide hybrid care to accommodate patients' needs. In a retrospective review of changes from January - October 2020, the institution saw a slight decline in total encounter volumes in March, which recovered in April. Virtual visits went from 0% prior to March to 98% in April, allowing the institution to mitigate care disruption that would have otherwise occurred. In subsequent months the hybrid model stabilized with more than 30% virtual care after the stay-at-home order lifted. According to the researchers, a hybrid model adoption is a potential long-term option to ensure access and efficiency of cardiology care.

Co-Designing an Intervention for Transformation of Cardiovascular Care Delivery in Rural Settings

The needs and resources available to rural patients with heart disease are different than their urban and suburban counterparts. A multidisciplinary team in Minnesota developed an intervention to enable rural primary care teams to improve the cardiovascular health of patients with atherosclerotic cardiovascular disease (ASCVD). The team designed an intervention that included adapting existing technology to deliver guideline recommendations to primary care practices and also observed clinical encounters, interviewed patients and conducted workshops with rural care team members to develop feasible intervention concepts. The collaboration resulted in workflows and a clinical decision support tool that identifies patients with ASCVD who would benefit from additional care touchpoints, aggregates crucial medical information for clinical decision-making and assigns the appropriate care team role to determine care plans. The process developed an intervention that combines novel responsibilities, workflows and technology while recognizing capacities and limitations of rural clinics.

Optimizing Emergency Room Use During After Hour Triage Calls

After hour triage calls at an ambulatory clinic are managed by a telehealth service of Registered Nurses (RN). The RNs follow an accepted protocol for each patient interaction leading to many of these patients being directed to the emergency room, often for an unwarranted visit. However, in an effort to reduce unnecessary utilization of health care resources in response to COVID-19 the clinic sought to improve this process. Starting on April 1, 2020, if the standing protocol suggested a referral to the emergency room, the RN instead connected with the on-call physician or advanced practice provider for further recommendations. The RN would then direct the patient to seek emergency services or an alternative level of care. The clinic compared calls and referrals from April - October 2019 to April - October 2020 to assess the effectiveness of the new protocol. From April to October 2019, 1,150 patients were referred to the emergency room based on the existing process. From April to October 2020, 332 patients were referred to the emergency room. The new care coordination process reduced emergency room referrals by 55.7% and of those patients 35% were admitted to the hospital. According to the researchers, in addition to better utilizing health care resources, the program showed that of patients sent to the ER by the on-call provider, a higher percentage was admitted, which suggests the clinic was doing a better job of sending the appropriate patients to be evaluated in the emergency room.

Irvine, Calif. -- Researchers from the University of California, Irvine and the University of Minnesota have found that an enriched diet and companionship can reduce pain in mice with sickle cell disease by increasing serotonin. They also discovered that duloxetine, an antidepressant that boosts serotonin levels, could be an alternative to opioids in treating chronic pain.

"Finding safe and effective alternatives to opioids is a research priority, especially for patients with sickle cell disease," said Dr. Keith Hoots, director of the Division of Blood Diseases and Resources at the National Heart, Lung, and Blood Institute. "It's encouraging to see a dose-response relationship to nutrients and companions in mice, which guides future research about the role foods and friends may have in helping humans manage chronic pain."

Scientists have long suspected that feeling pain is connected to a person's mood or state of mind, but the link has never been proven beyond doubt. This study, published Feb. 1 in Scientific Reports, supports that connection.

"Part of pain is perception," said Kalpna Gupta, a visiting professor of medicine at UCI and the study's lead author. "For instance, if I start watching a comedy, suddenly I might forget that I was hurting; mood and a feeling of well-being block pain from being perceived."

Sickle cell disease is a painful, lifelong condition that affects about 100,000 Americans, according to the Centers for Disease Control and Prevention, the majority of whom are African American. Opioids are the most common method of treating their pain. But because they're addictive, and overdoses are a leading cause of death in the United States, Gupta's team has been investigating alternatives.

"By suggesting a safe alternative to opioids for pain control, the findings of this study have the potential to change the practice of pain management and save lives," said study co-author Dr. Rajendra Badgaiyan, a professor of psychiatry at the University of Minnesota at the time who's now at the University of Texas Health Science Center in San Antonio.

Love conquers pain

The researchers found that mouse models of sickle cell disease in a "happy environment" experienced less pain from the disorder. Over a four-week period, pain was reduced for male mice that were placed with female companions and received a diet rich in protein, fatty acids and amino acids.

Their pain decreased as the diet and companionship caused their brains to secrete serotonin. Researchers quantified the mice's pain according to the frequency with which they lifted their paws in response to stimuli and by their ability to exert force.

To confirm that serotonin caused the reduction in pain, the mice were given duloxetine, an antidepressant that works by raising the amount of serotonin in the brain. The drug decreased pain levels for both male and female mice.

The researchers believe that adapting these conditions for humans would produce the same results. Gupta is recommending that duloxetine be used in clinical trials for sickle cell patients as an alternative to opioids for pain relief.

Combating pain and prejudice

In the United States, the stigma associated with opioids can make it difficult for sickle cell patients to lessen their pain.

"Patients with sickle cell disease often have to navigate the complex social prejudices of the healthcare system in addition to dealing with severe pain," said Varun Sagi, a medical student at the University of Minnesota and a contributing author on the study. "Finding alternatives to opioids could help alleviate this burden."

Duloxetine could provide an easier-to-obtain alternative. Likewise, as in the mice, building strong relationships and improving nutrition might also stimulate serotonin production in humans and thus reduce their pain.

As the COVID-19 pandemic persists, social isolation can make relationship-building a challenge, and as unemployment continues to hover around 7 percent, many Americans lack food security. As the study suggests, this can impact pain for sickle cell patients and others, so Gupta stressed the importance of developing strategies to enhance social interaction and nutrition for those affected.

ROCHESTER, Minn. -- Researchers from Mayo Clinic and AliveCor Inc. have been using artificial intelligence (AI) to develop a mobile device that can identify certain patients at risk of sudden cardiac death. This research has yielded a breakthrough in determining the health of the electrical recharging system in a patient's heart. The researchers determined that a smartphone-enabled mobile EKG device can rapidly and accurately determine a patient's QTc, thereby identifying patients at risk of sudden cardiac death from congenital long QT syndrome (LQTS) or drug-induced QT prolongation.

The heart beats by a complex system of electrical signals triggering regular and necessary contractions. Clinicians evaluate the heart's rate-corrected QT interval, or QTc, as a vital health barometer of the heart's electrical recharging system. A potentially dangerous prolonged QTc, which is equal to or longer than 50 milliseconds, can be caused by:

More than 100 drugs approved by the Food and Drug Administration (FDA).

Genetics, including congenital long QT syndrome.

Many systemic diseases, including even SARS-CoV-2-mediated COVID-19.

Such a prolonged QTc can predispose people to dangerously fast and chaotic heartbeats, and even sudden cardiac death. For over 100 years, QTc assessment and monitoring has relied heavily on the 12-lead electrocardiogram (EKG). But that could be about to change, according to this research.

Under the direction of Michael Ackerman, M.D., Ph.D., a genetic cardiologist at Mayo Clinic, researchers trained and validated an AI-based deep neural network to detect QTc prolongation using AliveCor's KardiaMobile 6L EKG device. The findings, which were published in Circulation, compared the ability of an AI-enabled mobile EKG to a traditional 12-lead EKG in detecting QT prolongation.

"This collaborative effort with investigators from academia and industry has yielded what I call a 'pivot' discovery," says Dr. Ackerman, who is director of Mayo Clinic's Windland Smith Rice Comprehensive Sudden Cardiac Death Program. "Whereby, we will pivot from the old way that we have been obtaining the QTc to this new way. Since Einthoven's first major EKG paper in 1903, 2021 will mark the new beginning for the QT interval."

The team used more than 1.6 million 12-lead EKGs from over a half-million patients to train and validate an AI-based deep neural network to recognize and accurately measure the QTc. Next this newly developed AI-based QTc assessment ?the "QT meter" ? was tested prospectively on nearly 700 patients evaluated by Dr. Ackerman in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic. Half of these patients had congenital long QT syndrome.

The object was to compare the QTc values from a 12-lead EKG to those from the prototype hand-held EKG device used with a smartphone. Both sets of EKGs were given at the same clinical visit, typically within five minutes of each other.

The AI algorithm's ability to recognize clinically meaningful QTc prolongation on a mobile EKG device was similar to the EKG assessments made by a trained QT expert and a commercial laboratory specializing in QTc measurements for drug studies. The mobile device effectively detected a QTc value of greater than or equal to 500 milliseconds, performing with:

80% sensitivity
This means that fewer cases of QTc prolongation were missed.

94.4% specificity

This means that it was highly accurate in predicting who did not have a prolonged QTc.

"The ability to equip mobile EKG devices with accurate AI-powered approaches capable of calculating accurately the QTc represents a potential paradigm shift regarding how and where the QT interval can be assessed," says John Giudicessi, M.D., Ph.D., a Mayo Clinic cardiology fellow and first author of the study.

"Currently, AliveCor's KardiaMobile 6L EKG device is FDA-cleared for detection of atrial fibrillation, bradycardia, and tachycardia. Once FDA clearance is received for this AI-based QTc assessment, we will have a true QT meter that can enable this emerging vital sign to be obtained easily and accurately," says Dr. Ackerman. "Akin to a glucose meter for diabetics, for example, this QT meter will provide an early warning system, enabling patients with congenital or acquired LQTS to be identified and potentially lifesaving adjustments to their medications and electrolytes to be made."

"This point-of-care application of artificial intelligence is massively scalable, since it is linked to a smartphone. It can save lives by telling a person that a specific medication may be harmful before he or she takes the first pill," says Paul Friedman, M.D., chair of the Department of Cardiovascular Medicine at Mayo Clinic in Rochester. "This allows a potentially life threatening condition to be detected before symptoms are manifest."

"Regularly monitoring for LQTS using KardiaMobile 6L allows for accurate, real-time data collection outside the walls of a hospital," says David Albert, M.D., founder and chief medical officer at AliveCor Inc. "Because LQTS can be intermittent and elusive, the ability to detect this rhythm abnormality without a 12-lead EKG -- which requires the patient be in-hospital -- can improve patient outcomes and save on hospital resources, while still providing the reliable and timely data physicians and their patients need."

AUGUSTA, Ga. (Feb. 1, 2020) - A gene panel that looks for about 10 times the number of cancer-causing genes as panels currently used to diagnose and fine tune treatment for a variety of cancers is effective at identifying problematic genes in the most common leukemia, investigators report.

The 523-gene panel, developed by San Diego-based biotech company Illumina, which includes all genes known to potentially cause cancer, can be readily adopted for use in clinical laboratories to diagnose acute myeloid leukemia, or AML, the investigators report in the journal PLOS ONE.

Identifying more genetic mutations in an individual's cancer also enables more targeted treatment for that patient, they say. That includes finding mutations not previously associated with their cancer type, which opens the door to using drugs targeting those mutations that have traditionally been used against other cancers.

"Having a bigger panel gives us more targets," says Dr. Ravindra Kolhe, vice chair for translational research in the Department of Pathology at the Medical College of Georgia at Augusta University.

"Part of what we found here is this 523-panel works for leukemia and that it's a practical and clinically relevant tool for clinical laboratories for routine molecular profiling of blood cancer," says Kolhe, the study's corresponding author.

AML is a distinct disease in every patient because, as investigators are increasingly learning, the gene mutations involved may not be the same in any two patients, says Dr. Vamsi Kota, MCG hematologist/oncologist who directs the Bone Marrow and Stem Cell Transplant Program at the Georgia Cancer Center and AU Health.

"The term 'leukemia' is broad and we should not be treating everyone the same," says Kota, a study coauthor. "That is one of the reasons you see the same treatment working for some and not working for others."

The MCG investigators retrospectively analyzed 61 bone marrow samples, which included samples from 40 patients with confirmed leukemia and detailed clinical information on 27 of those patients.

The larger panel identified 880 variants in 292 genes, and only 14.8% of the variants were in genes included in the smaller 54-gene panel currently in use by many labs, they write. The remaining 749 variants are not typically assessed in a leukemia diagnosis or detected by the 54-gene panel, they note.

When they looked at the information available on those 749 variants in follow up, they found at least 14 of the variants in 10 genes likely could contribute to AML and 96.2% of the patients had at least one of the 14 novel variants. They also found 22 variants in five other genes associated with other tumor types in the vast majority of the patients with AML.

Novel variants identified in the patients might be significant in providing a more complete diagnosis and prognosis for patients and in better identifying treatment that more directly targets their cancer-associated mutations, they say.

There is often overlap in the mutations that contributes to different types of cancer and the broader assessment of mutations present should help identify those.

"The more we know, the more it expands our knowledge of leukemia and expands our ways to treat it," Kota says. "If you find something abnormal in the genes, which is there in other cancers, then we can use those drugs in these patients," Kolhe adds.

"The hope is by finding more of these mutations, we no longer call the cancer by a name but we call it-- and treat it -- by the mutations," says Kota.

The Georgia Esoteric and Molecular Laboratory, which Kolhe directs, was the first in the nation to validate the 523-gene panel by comparing results to established but less comprehensive methods, like polymerase chain reaction used to amplify small segments of DNA to look for suspect changes. For this study, they also ran the same bone marrow samples multiple times on the 523-gene panel and found essentially 100% consistency each time. They also did individual tests looking for specific mutations identified by the panel, and those were consistently on par with the panel's findings as well. They found the larger panel nearly 100% effective in clinical sensitivity, specificity, precision and accuracy.

"It's a panel we can consistently do in a lab on a routine basis in a cost- effective way that increases our understanding of the gene mutations contributing to an individual patient's cancer," Kota says.

While noting their sample size was small, there were interesting clinical correlations, like finding seven mutations in a 23-year-old male who had been diagnosed with two mutations. The new mutations they found included two novel variants now associated with leukemia and other cancers, they say. The patient, who had the highest number of gene mutations identified by the larger panel, only survived four months and two days.

Kota notes that decades have passed without any real advancements in AML treatment, but in the past year six new drugs, which target six mutations identified by the smaller gene panels, have been approved. Kolhe hopes the new panel will help expand that new drug number at least 10 times as well.

"The idea of having a bigger panel is not only confirming what we already know about which mutations are associated with a cancer but identifying new ones," Kolhe says.

"What we are doing is taking that 50-gene panel and going to the next level with a 523- gene panel and one of our goals includes identifying 60 new targets within the next five years," Kolhe says.

Most patients with AML relapse within three years of diagnosis, and broader identification of treatment targets should improve those percentages, they say.

The National Comprehensive Cancer Network recommends that testing for AML include molecular analysis for at least those six genes now known to be causative for AML.

Current guidelines also suggest the use of the multi-gene panels and next-generation sequencing for a comprehensive prognostic assessment. Next generation sequencing is a high-throughput approach, like the 523-gene panel, that enables investigators to efficiently sequence a large number of genes at one time, even the entire genome in a day's time. Sequencing means looking at the order of the four base pairs of DNA -- A, T, C and G -- to find changes that cause disease.

Kota and Kolhe say that while the smaller gene panels are cost and time efficient, they provide an incomplete mutational profile, including omissions of several known hotspot mutations. The increased understanding of the molecular heterogeneity of blood cancer, and other cancers as well, make the broader assessment logical, they say. They note that the cost of the broader panel is no higher than testing for the six AML- associated genes.

Blood stem cells from the bone marrow produce both white blood cells that help us fight infection and blood-forming cells called myeloid cells, and AML may affect both.

(Singapore--January 31, 2021 2:40 p.m. SPT 1:40 a.m. EST)--Patient-reported outcomes from the phase III CROWN study showed that time to treatment deterioration (TTD) in pain in chest, dyspnea, and cough was comparable between those who received lorlatinib and patients who took crizotinib. The research was presented today at the International Association for the Study of Lung Cancer's 2020 World Conference on Lung Cancer Singapore.

Lorlatinib, a third-generation ALK inhibitor, significantly improved progression-free survival compared to crizotinib in patients with previously untreated advanced ALK-positive NSCLC.

Dr. Julien Mazieres, Toulouse University Hospital, in Toulouse, France presented the detailed results of patient reported outcomes (PROs) from his same study.

CROWN enrolled 296 patients with ALK+ NSCLC and randomly assigned each to receive either lorlatinib or crizotinib. PROs were assessed using the EORTC QLQ-C30 and QLQ-LC13, and the EQ-5D-5L--assessments used to rate the health-related quality of life (QOL) of patients with cancer participating in international clinical trials. Each patient completed an assessment on the first day of each cycle (28 days) through end of treatment. Dr. Mazieres and her team measured time to treatment deterioration (TTD) in pain in chest, dyspnea, and cough and compared these results between the two treatment arms.

Completion rates were 100% at baseline and remained high (? 96%) through cycle 18 in both treatment arms. There were no clinically meaningful or statistically significant differences between treatment arms in any functioning domain, with numerical improvements favoring lorlatinib in physical, role, emotional, and social functioning scales, and a numerical improvement favoring crizotinib for cognitive functioning.

According to Dr. Mazieres, there were statistically significant, but not clinically meaningful differences favoring lorlatinib in symptoms of fatigue, nausea and vomiting, insomnia, appetite loss, and constipation. For diarrhea there was both a clinically meaningful and statistically significant difference favoring lorlatinib.

Lung cancer symptoms improved from baseline in both treatment arms, with clinically meaningful improvements in cough as early as Cycle 2 and maintained through Cycle 18. TTD in the composite endpoint of lung cancer symptoms (cough, dyspnea, or pain in chest) was similar between treatment arms (HR 1.09; 95% CI: 0.82-1.44; 2-sided p = 0.5415). Median time to worsening of global QOL was 24.0 months for lorlatinib and 12.0 months for crizotinib (HR 0.92; 95% CI 0.65-1.29).

"Time to treatment deterioration for lung cancer symptoms was comparable between treatment arms. Improvements in lung cancer symptoms were seen early and clinically meaningful improvements in cough were detected in [patients who received] lorlatinib," Dr. Mazieres reported.

"Patient-reported outcomes in phase III CROWN support the improved PFS and are consistent with safety/tolerability of lorlatinib relative to crizotinib."