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GALVESTON, Texas - A multidisciplinary team from The University of Texas Medical Branch at Galveston has uncovered a Zika virus mutation that may be responsible for the explosive viral transmission in 2015/2016 and for the cause of microcephaly (babies with small heads) born to infected pregnant women. The study is currently available in Proceedings of National Academy of Sciences.

The Zika virus caused a global epidemic in 2015 and 2016. Like West Nile, dengue, yellow fever, and chikungunya viruses, the Zika virus is primarily transmitted by mosquitoes. These viruses pose constant threats to populations living in areas with mosquitoes. Dengue virus alone causes 390 million human infections each year. Because these viruses circulate between mosquitoes and animals/humans, they are prone to genetic mutations, making them highly capable of emerging and causing epidemics.

In this study, the UTMB team has identified a mutation in the Zika envelope protein that can enhance mother-to-baby transmission in pregnant mice, increase neurological disease and lethality in newborn mice and elevate virus levels in the blood of infected non-human primates. When a mosquito bites an individual with the Zika virus, the elevated virus level in the blood increases the potential of transmitting the virus to mosquitoes, consequently promoting the establishment of urban transmission of the virus between mosquitoes and humans.

"Our study demonstrates that the Zika envelope mutation V473M, which just occurred before the 2015 epidemic in the Americas, enhances Zika virus particle assembly in infected cells. The enhanced virus assembly leads to increased human disease and maternal transmission," said Pei-Yong Shi, I.H. Kempner professor of Human Genetics at UTMB. "The viral genetic change reported here, combined with the naïve herd immunity, may have accounted for the Zika epidemic and severe diseases in 2015 and 2016."

"There are over 500 known arboviruses, among which 100 of these can cause human diseases," said Chao Shan, a former UTMB Research Scientist who co-senior authored the study. "Because arbovirus polymerase - an enzyme responsible for amplifying the viral genetic footprint - lacks proofreading capability, these viruses are prone to high mutation frequencies. So, these viruses often emerge and reemerge. During the past two decades, we have witnessed the emergence of West Nile, dengue, yellow fever, chikungunya viruses, and Zika viruses."

"RNA viruses are the pathogens most often responsible for outbreaks and epidemics, including Ebola virus and SARS-CoV-2, the virus causing COVID-19" said Shi. "Understanding the mechanisms of viral emergence and transmission is essential to detect and respond to future outbreaks. Although the world is currently focusing on COVID-19, I am certain that COVID-19 will not be the last emerging virus we face. Moving forward, building public health capacity and countermeasure technology are the only effective means to overcome these threats."

PHILADELPHIA - A new Penn Medicine study sheds light on yet another reason why the coronavirus pandemic is disproportionately killing the poor: Residents in low-income neighborhoods lack access to intensive care unit (ICU) beds.

While the shortage of ICU beds in the United States has been documented since the pandemic began, the new report, published Monday in the August issue of Health Affairs, is the first to show how starkly a person's ZIP code affects access to COVID-19 care. Most dramatically, approximately half of communities with the lowest median household incomes (less than $35,000) have zero ICU beds per ten thousand residents age fifty or older, compared with just 3 percent of communities with household incomes of at least $90,000.

ICU, or critical care units, provide life support and high-tech equipment for patients with serious, life-threatening illnesses who require continuous care and monitoring. In the case of COVID-19, patients who are unable to breathe on their own require the ventilator support offered by an ICU to survive. For seriously ill patients, having access to an ICU is the difference between life and death.

The findings suggest that policymakers must take action, such as facilitating hospital sharing and publicly financing specialized resources, said study principal investigator Genevieve P. Kanter, PhD, an assistant professor of Medicine, Medical Ethics, and Health Policy in the Perelman School of Medicine at the University of Pennsylvania.

"Because low-income communities face higher infection rates of the virus, as well as a higher prevalence of comorbidities -- which increases the risk of death from the disease -- the low supply of ICU beds compounds the impact COVID-19 will have on these communities," Kanter said. "Plans should be made for coordinating how hospitals can share these burdens."

The study sample consisted of the ICU bed capacity of 4,518 short-term and critical access hospitals in the 50 states and Washington, D.C., obtained from the Centers for Medicare and Medicaid Services' Healthcare Provider Cost Reporting Information System. The researchers used 2018 five-year American Community Survey estimates to gather information about population, age distribution, racial distribution, and median household income. Rather than comparing ICU bed capacity by county or ZIP code, the researchers instead aggregated their data by hospital service area (HSA), which is defined as a set of ZIP codes corresponding to the area in which residents receive most of their hospital care.

The study found that ICU availability varied considerably across the country. More than one third of American communities had zero ICU beds. Geographically, half of hospital service areas in the Midwest census region and 34 percent in the West had zero ICU beds per then thousand residents age fifty or older. By contrast, 52 percent of hospital service areas in the Northeast and 54 percent in the South had more than four ICU beds per ten thousand residents age fifty or older

The researchers also found a large gap in access by income: 49 percent of the lowest-income communities had no ICU beds in their communities, compared to only 3 percent of the highest income areas. Conversely, 46 percent of the lowest-income communities had an ICU bed supply of more than four beds per ten thousand residents age fifty or older, while a total of 59 percent of the highest-income places had more than four beds per ten thousand.

These differences were most pronounced in rural areas. Similar proportions of low-, middle-, and high-income communities in cities had access to more than seven ICU beds per ten thousand residents age fifty or older, compared with communities in less urban areas.

In response to these disparities, the study's authors suggest several steps that policymakers might take to mitigate further harms of COVID-19 in these regions. First, they point out that individual hospitals facing severe COVID-19-related financial losses have little incentive to attract critically-ill patients from underserved areas, as these patients often lack extensive insurance coverage, and the costs of their care often exceed reimbursement rates. Therefore, the authors recommend that higher-level coordination is needed at the county, state, and federal levels to facilitate hospital sharing of the demand for care and to publicly finance specialized resources, such as ventilators and critical care doctors.

Second, the researchers say that the typical emergency medical system guideline to "transport to the nearest hospital" should be revisited under these new pandemic conditions. Local emergency medical services agencies should develop plans for how and under what conditions patients can be transported to hospitals outside their immediate communities and how these transport protocols will be communicated to the public.

And lastly, the study's authors argue that emergency funds need to be directed toward hospitals lacking sufficient ICU resources, especially those caring for large older populations that are more likely to be hospitalized for COVID-19.

"I hope our study provides policymakers with information on which communities will be in greatest need, as well as guidance in the steps required to meet those needs," Kanter said.

New Rochelle, NY, August 3, 2020--Despite recent reports of lower COVID-19 incidence among high-altitude populations, current data is insufficient to conclude that high altitude is protective against the SARS-CoV-2 virus, as reported in the peer-reviewed journal High Altitude Medicine & Biology. Click here to read the article.

"The reported lower incidence of COVID-19 among high-altitude residents is quite intriguing, but epidemiological observations presented so far from high-altitude regions are preliminary," state Matiram Pun, MBBS, MSc, University of Calgary, Erik Swenson, MD, University of Washington and Editor-in-Chief of High Altitude Medicine & Biology, and coauthors

The authors also conclude that there is currently little supporting evidence for any protective benefit of genetic or nongenomic adaptation to high-altitude hypoxia.

"We should avoid reaching the conclusion that any community has an innate protection from COVID-19 in the absence of robust evidence," state the authors

The death rate for patients who experienced what is normally a lower-risk heart attack rose sharply during the peak of the COVID-19 pandemic in England, according to an analysis of NHS data.

In comparison, the death rate for people who had a more severe heart attack fell.

It also revealed a substantial drop in the number of people who were arriving at hospital with a heart attack. At its lowest point, hospitals were treating just over half the cases they would normally expect to see.

Although the number of people seeking medical help did rebound, they had not returned to their pre COVID-19 levels by 22 May, when the study period ended.

The reduction in patients seeking timely help is likely to have resulted in people dying at home or developing chronic heart problems.

Despite the pressures on the NHS from COVID-19, the study showed that hospitals were able to maintain their emergency cardiac services in the vast majority of cases and adhere to best-practice clinical guidelines.

The study is the first detailed insight into what happened to heart attack patients as the NHS reorganised services to focus on COVID-19. The investigation was only possible after Ministers sanctioned access to anonymised patient data.

It was led by the University of Leeds in collaboration with Leeds Teaching Hospitals NHS Trust, the University of Keele, Imperial College, Barts Health NHS Trust, University College, London and Glangwili General Hospital, Carmarthen, Wales.

Researchers analysed admission data for 50,689 patients who had a heart attack and were treated at 99 acute NHS hospitals in England over the 14 months prior to UK lockdown on 23 March, and the first two months of lockdown.

The study was endorsed by Sir Patrick Vallance, the Government's Chief Scientific Advisor. He wanted scientists to investigate how patients and healthcare providers responded during the peak of the pandemic to help inform future NHS planning.

The findings are published in the European Heart Journal - Quality of Care and Clinical Outcomes.

Dr Jianhua Wu, Associate Professor in Biostatistics at the University of Leeds and lead author of the study, said: "The data have given us a very detailed picture of the way patient behaviour changed as COVID-19 swept across Europe.

"It has revealed that although patients were able to get access to high levels of care, the study suggests a lot of very ill people were not seeking emergency treatment and that may have been an unintended consequence of the 'Stay at Home' messaging."

Chris Gale, Professor of Cardiovascular Medicine at the University of Leeds and senior author of the study, said: "This national picture provides evidence for the devastating impact that the COVID-19 pandemic has had on people's lives. The inflation in deaths among people attending hospital with heart attack is very likely an early signal of the mortality and morbidity that is yet to be observed.

"Notably, we have not seen a return to the normal rates of admissions with heart attack. This means that people may still be delaying seeking help."

Don't delay seeking help

Dr Sonya Babu-Narayan, Associate Medical Director at the British Heart Foundation, said: "We know that throughout lockdown fewer people were treated for a heart attack, risking death or long-term heart damage.

"If you experience chest pain or discomfort, which may feel like squeezing or heaviness or tightness not necessarily the chest-clutching agony that we see on TV and which may radiate to your jaw, arm, back or stomach, it's important to understand you could be having a heart attack.

"Thanks to decades of research, prompt treatment for your heart attack could save your life, so if you think you are experiencing symptoms call 999 immediately."

What the study found

The analysis looked at two types of heart attack - 17,246 people who had a STEMI heart attack and 33,443 who had a NSTEMI heart attack (total patients: 50,698).

An NSTEMI is the most common form of heart attack and usually happens when there is a partial blockage to one of the blood vessels supplying the heart.

A STEMI heart attack is where there is a complete blockage of one of the blood vessels that takes oxygen to the heart.

The statistical analysis revealed that significantly fewer people were attending hospital with a heart attack. NSTEMI cases were down by 49 percent - and STEMI by 29 percent on what hospitals were expecting to see.

The graph with this story shows the 7-day moving average for the number of people admitted to hospital for two types of heart attack: NSTEMI and STEMI. Key dates in the spread of the pandemic around the world are also highlighted.

If you re-produce the graph, please credit: University of Leeds

The decline in patients attending hospital started in early 2020 as China implemented lockdown measures and the World Health Organisation announced a public health emergency. And that decline continued through the early part of the lockdown in the UK.

The smallest number of cases was seen on 19 April where the 99 hospitals recorded 60 heart attack cases. They would normally expect to see around 104.

Professor Gale said: "It was not the case that people were not having heart attacks - they were deciding not to go to hospital. Some were undoubtedly heeding the message to stay at home, others might have been afraid of picking up the virus in hospital or were trying to shield because they had other conditions.

"The study has revealed that patient behaviour was beginning to shift as reports emerged of the pressure COVID-19 was having on other healthcare systems.

"But a heart attack is a medical emergency and if people do not seek help, they die or go on to develop heart failure. We need to make sure people are aware that emergency services continued to operate."

The analysis showed that by 22 May, the number of heart attack cases that hospitals were seeing had not returned to pre-lockdown levels.

For patients experiencing a STEMI heart attack, the preferred treatment is primary percutaneous coronary intervention, where a balloon inside a catheter is inserted into the artery to clear the blockage. The NHS was able to maintain the treatment in the vast majority of cases. A small number, 0.3 percent, were treated with clot-busting drugs instead.

Most of the patients having an NSTEMI heart attack were able to have coronary angiography, a technique that uses dyes and x-rays to pinpoint exactly where blood vessels are obstructed. But in an additional three percent of cases that did not happen.

People dying within a month of a heart attack

In the month after lockdown started, the proportion of patients who had an NSTEMI heart attack and died within a month went from 5.4 percent to 7.5 percent, an increase of 39 percent. It dropped back to 5 percent over the following four weeks.

During the same period, patients who had a STEMI heart attack, the 30-day mortality figure dropped from 10.2 percent to 7.7 percent, a 25 percent reduction. Over the subsequent four weeks, it increased slightly to 8.3 percent.

As a statistical analysis, the study cannot identify the precise reasons for the fluctuation in the death rates but it is believed to be linked to the fall in patients seeking help, particularly among NSTEMI patients who may not display the classic symptoms of a heart attack such as chest pain.

Professor Gale said: "We can only speculate as to why there has been an increase in deaths among patients with NSTEMI, despite good care in hospital. It is possible that these patients had the COVID19 infection which contributed to their death."

What the findings mean for healthcare planning

Professor Gale said the study showed that emergency cardiac services were able to maintain their effectiveness during the peak of the pandemic. But he warned: "There is little doubt that the substantial drop in admissions to hospital with heart attack will have had substantial repercussions on population health outcomes.

"People will have died or developed heart failure as a result of not seeking treatment for their heart attack. The NHS now needs to be ready to support those who did not attend hospital."

PHILADELPHIA (August 3, 2020) - The diverse situations experienced by health-care workers during the COVID-19 pandemic often present serious ethical challenges. From the allocation of resources and triage protocols to health-care worker and patient rights and the management of clinical trials, new ethical questions have come to the forefront of today's global public health emergency.

In an editorial in the journal AJOB Empirical Bioethics, three nurse researchers provide ideas for meaningful empirical bioethics research related to the COVID-19 pandemic to aid clinicians in ethical decision-making approaches.

"Empirical bioethics research on decision-making during this pandemic can contribute to a body of evidence describing these unique ethical challenges, as well as the failures and successes of the decisions made to address and resolve them," writes Connie Ulrich, PhD, RN, FAAN, Lillian S. Brunner Chair in Medical and Surgical Nursing and Professor of Nursing at the University of Pennsylvania School of Nursing (Penn Nursing), one of the co-authors.

The researchers outline a number of areas of opportunity in COVID-19-related bioethics studies, including:

Descriptive studies defining current practices, opinions, and policies to inform research and interventions.

Insight into sources and different constraints that lead to moral distress of health-care workers on the front lines of the pandemic.

Assessment of the extent of which clinical practice reflects purported ethical norms.

Development and testing of interventions aimed at closing the gap between reality and ethical ideals.

"Better understanding the experiences, views, values, and expectations of stakeholders across diverse communities can ensure that the bioethics community--along with policymakers, public health and health care systems, and research institutions--is better prepared during the months and years that lie ahead as we tackle the problems raised by COVID-19 and for future pandemics," the authors conclude.

What The Study Says: This study investigates the presence of SARS-CoV-2 on the environmental surfaces of an ophthalmology examination room after visits by patients who were asymptomatic and passed COVID-19 triage.

Authors: Hasan Ayto?an, M.D., of the ?zmir Tepecik Training and Research Hospital in ?zmir, Turkey, is the corresponding author.

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

(doi:10.1001/jamaophthalmol.2020.3154)

Editor's Note: Please see the articles for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

New Haven, Conn. -- A new study from researchers at Yale and the Mayo Clinic found that emergency department (ED) visits dropped significantly in March as the public responded to messages about staying home as a result of the pandemic.

The study, published in the Aug. 3 edition of JAMA Internal Medicine, looked at data from 24 emergency departments in five health-care systems: in Colorado, Connecticut, Massachusetts, New York, and North Carolina. Researchers analyzed daily emergency department visits and ED hospital admissions for four months, from January to April 2020.

As COVID-19 case rates increased nationally in March and April, along with public messaging about social distancing, emergency department visits plunged in all five states compared with visits in January and February 2020. Visits fell by 41.5% in Colorado, at the low end, and by 63.5% in New York, at the high end.

During the same period, hospital admissions via the emergency department spiked, corresponding to state-level COVID-19 cases: rising by 22% in North Carolina to a high of 149% in New York.

"This is a case where public messaging appears to have worked too well," said lead author Dr. Edward R. Melnick, associate professor of emergency medicine. "We said, 'stay home,' and what people heard was: 'Stay home at all costs to avoid COVID-19.'"

The researchers concluded that, across the states, public health officials need to provide more nuance in their messaging -- to make clear that, even during a pandemic, it's crucial for people to continue visiting the emergency department for serious injuries and illnesses.

"Our new rallying cry is that hospitals are safe," Melnick said. "Few hospitals outside of New York approached going over capacity during March and April 2020. That means a lot of people suffering from non-COVID illnesses and injuries may have stayed home and unnecessarily suffered or even died because they were too scared to come in."

The 24 emergency departments included in the study varied widely in size and location, serving from small rural to large urban populations, with annual emergency department volume ranging from 12,500 to 115,000 patients per year. All five states experienced decline in ED visits beginning the week of March 11, with the greatest decline in New York (63.5%), followed by Massachusetts (57.4%), Connecticut (48.9%), North Carolina (46.5%), and Colorado (41.5%).

These declines tracked closely with the spike in COVID-19 cases in each state. The trend lasted until mid-April.

Melnick said they are continuing to expand the scope of their observations to include more states and to drill down further as to why people avoided going to the ED and what happened to them as a result. They'll be looking at "pre-hospital" data, such as people who dialed 9-1-1, he said, and examining the numbers of deaths in the field. He noted that recent studies conducted elsewhere have confirmed that people with serious conditions indeed stayed home to avoid going to the emergency department during the pandemic.

"We want to understand what happened to people who didn't make it to the hospital and the barriers to seeking and receiving care," Melnick said.

As a follow-up, Melnick looked at additional ED visit trends and hospital admission rates from April to June 30. He reported that after April 8, ED visits in all five states began to increase, but never returned to baseline.

PHILADELPHIA--Inherited mutations in a gene that keeps nerve cells intact was shown, for the first time, to be a driver of a neuropathy known as Charcot-Marie-Tooth (CMT) disease. This finding is detailed in a study led by researchers in the Perelman School of Medicine at the University of Pennsylvania, which published in Neurology® Genetics, an official journal of the American Academy of Neurology.

The findings, thanks to siblings treated at Penn since the late 1980s, present a clearer picture of the disease's genetic underpinnings that could inform the development of gene therapies to correct it.

The mutations in the gene known as dystonin (DST) add to a growing list of malfunctions found to cause their type of CMT, known as CMT2, which is defined by the loss of the nerve fibers, or axons, in the peripheral nerve cells. The researchers also showed that these mutations affect two key protein isoforms, BPAG1-a2 and BPAG1-b2, that are involved in nerve fiber function. Mutations in other isoforms of the same protein were previously tied to a blistering skin disease.

Neuropathies are common, occurring in nearly half of all diabetic patients, while hereditary neuropathies affect nearly one of out of 2,000 people. CMT is a debilitating neurodegenerative disorder that usually strikes in the second or third decade of life, and leaves patients with numbness and weakness in the hands and feet, among other neurological-related conditions.

There are more than 100 mutations found to be associated with CMT, with likely many more out there. Past studies from Penn researchers have identified some of these mutations by studying patients treated at Penn Medicine.

"We are determined to fill in the blanks of this giant jigsaw puzzle," said senior author Steven S. Scherer, MD, PhD, a professor of Neurology. "This latest paper is but one of many examples of where breakthroughs have happened between patients and the doctors at Penn and the support of different organizations and institutions to bring it all together."

The researchers applied whole exome sequencing to analyze the more than 30 million base pairs of DNA that encode the 20,000 proteins in humans. By examining three siblings--two affected and one unaffected--the researchers were able to deduce the genetic basis of mutations that caused the two siblings to be affected.

Backed by a mouse model from past studies showing a role of dystonin in neuropathies, the researchers identified two recessive mutations on the DST gene, each received from a biological parent, as the culprit. Together, the two mutations in the affected siblings disrupt the BPAG1-a2 and BPAG1-b2 isoforms, the researchers found, which weakened their axonal health. The DST gene gives rise to proteins that regulate the organization and stability of the microtubule network of sensory neurons to allow for transport of different cellular material along the nerve fibers.

"We have collaborated with this family for 30 years, and now we finally have an answer," Scherer said, "and the answer was a new genetic cause of neuropathy."

The findings put the field steps closer to developing new targeted therapeutics as well as CMT gene therapies designed to replace missing genes or correct mutations driving the disease. Clinical trials to investigate these latest mutations and others are not far off in the future, the researchers believe, particularly at an institution like Penn, which is home to the second largest clinic for CMT patients in the country and well-known for its gene therapy program.

"We are in the era where treatments for genetic diseases are possible," Scherer said. "This brother and sister stand to benefit from that approach because we know the gene that is missing, and if we could replace it, that should at least prevent their progression."

Fewer people would die of colorectal cancer if health care providers adopted a new model of screening that combines better risk assessment, more options for noninvasive testing and more targeted referrals for colonoscopy.

That's the course laid out by the American Gastroenterological Association (AGA) in a white paper titled "Roadmap for the Future of Colorectal Cancer Screening in the United States" published in July.

"If we offered tests that were convenient, accurate and lower cost, and we could help people choose the best option based on their individual cancer risks, we would save more lives," said lead author, Joshua Melson, MD, MPH, associate professor, Rush Medical College, and a member of the AGA Center for GI Innovation & Technology.

The paper sets the target and the steps for scientists and industry partners to take in exploring new biomarkers and developing tests that will turn the tide.

The sooner, the better.

At least one if four Americans who should be screened for colorectal cancer has never been tested. Yet colorectal cancer (CRC), the nation's second deadliest cancer, is highly preventable and treatable when found early. That's after years of effort to increase compliance with testing recommendations.

The AGA gathered 60 experts in gastroenterology and research to envision how screening could reach its full potential. Their conclusion: To significantly reduce the number of colorectal cancer cases and deaths would require a universal approach to screening that reaches more people and offers alternatives in addition to colonoscopy.

"Approximately 67% of eligible Americans are screened for colorectal cancer. We need to improve our strategies to curb the cancer that ranks second for deaths in the U.S.," said Sri Komanduri, MD, AGAF, chair of the AGA Center for GI Innovation and Technology. "AGA is proud to introduce this white paper -- the first step in our mission to develop a more structured screening program that can increase screening rates, catch more colorectal cancers early, and save countless lives."

Currently, CRC screening usually begins when a physician recommends a colonoscopy based on the patient's age or other risk factors. The colonoscopy allows the gastroenterologist to fully examine the colon and remove any precancerous polyps that are found. Polyps are found about a quarter of the time. But having a colonoscopy requires scheduling well ahead of time, taking time off work, arranging a ride home and going through a bowel-emptying routine.

A new approach would:

Offer noninvasive testing upfront, such as stool testing, and integrate these options with colonoscopy.

Share decision-making with the patient and consider personal risk factors: colonoscopy for those at high risk, or initial noninvasive testing for those at lower risk.

Assign colonoscopy when it would provide the greatest benefit, rather than as the default screening method. This would improve access to patients who most need a colonoscopy.

Systematically initiate screening, follow-up testing and surveillance, rather than rely only on a physician's recommendation.

Ensure appropriate screening is readily available to at-risk individuals, with no social, racial or economic disparities.

To make this vision a reality, the authors set a course for development of affordable, highly accurate, easy-to-use noninvasive tests, as well as research into how best to integrate the different types of tests and who would benefit most from each based on individual risk factors.

Two noninvasive tests in use today are the stool-based fecal immunochemical test (FIT) and the multi-target stool DNA test (MT-sDNA).

FIT, which looks for hidden blood in the stool, is the most readily available. The MT-sDNA has emerged as an alternative to FIT that is more sensitive in detecting colorectal cancer but less specific in its findings. Both tests can identify markers of large colon polyps and cancer. MT-sDNA tests carry a higher price - more than $500 compared to about $25 for FIT.

"The ideal test needs to be highly sensitive and highly specific, as well as convenient, with low risk and low cost," Melson said. "It would identify lesions that have a high potential to progress to colorectal cancer in the short term."

To achieve that goal, the AGA initiative defined targets for industry partners and scientists who are developing colorectal cancer screening tests and exploring novel molecular biomarkers, including biochemical, microbiome, genomic, proteomic or epigenomic markers. With input from the major endoscopic and noninvasive testing companies, the authors defined criteria for meaningful endpoints of what are the important lesions a noninvasive marker would be able to detect and at what level of accuracy, in an affordable way.

The authors set forth the aspirational goal of developing a minimally invasive, easy-to-use test that will "detect advanced adenomas and advanced serrated lesions with a one-time sensitivity and specificity of no less than 90%."

In addition, all types of CRC screening would benefit from a better understanding and more thorough identification of risk factors to help identify the most appropriate screening for the individual patient.

Thanks to advancements in electronic health records, health care providers can share information across institutions that will provide a full picture of the patient's medical history, including screening history and results. This would allow for more accurate risk assessment paradigms that include past colonoscopy polyp data, molecular markers if found, and family history.

With a clearer risk assessment, the provider and patient could share in deciding the most appropriate test - colonoscopy for those at high risk, or initial noninvasive testing for those at lower risk. Also, more thorough risk assessment would reduce the number of colonoscopies performed that provide little benefit and flag those patients who would benefit most from colonoscopy. Test rates would benefit from patient buy-in and from easier access.

Ultimately, these advances will support the development of organized screening programs that can identify and connect people who need to be screened with the testing best suited for them.

Metastasis - the development of tumor growth at a secondary site - is responsible for the majority of cancer-related deaths. It occurs when the primary tumor site sheds cancerous cells which are then circulated through the body via blood vessels or lymph nodes. These become seeds for eventual tumor growth at a secondary location in the body.

Detection of these very rare cells, known as circulating tumor cells or CTCs, is important for early prognosis of serious disease as well as to monitor the effectiveness of treatment. Currently, there is only one method for CTC detection approved by the U.S. Food & Drug Administration (FDA), CellSearch, which is used to diagnose breast, colorectal and prostate cancer.

Results from a recent study - a collaboration between Lehigh University, Lehigh Valley Cancer Institute, and Pennsylvania State University - demonstrate the potential for a new method of detecting circulating tumor cells. Unlike existing methods, which rely on an expensive and time-consuming process that involves labelling antibodies with fluorescence, this technique uses a powerful label-free detection method. Developed by Yaling Liu, a faculty member in Lehigh's Department of Bioengineering and in the Department of Mechanical Engineering and Mechanics, in collaboration with Xiaolei Huang, faculty member in Penn State's College of Information Sciences and Technology, the technique applies a machine learning algorithm to bright field microscopy images of cells detected in patient blood samples containing white blood cells and CTCs.

The blood samples were drawn from participating patients undergoing treatment for stage 4 renal, or kidney, cancer at Lehigh Valley Hospital-Cedar Crest under the care of Suresh G. Nair, M.D., Physician in Chief at Lehigh Valley Cancer Institute. The model yielded a high rate of accuracy: 88.6% overall accuracy on patient blood and 97% on cultured cells. The results have been published in Nature Scientific Reports in an article called "Label-free detection of rare circulating tumor cells by image analysis and machine learning." In addition to Liu, Huang, and Dr. Nair, authors include three Lehigh PhD students Shen Weng, Yuyuan Zhou and Xiachen Qin .

Dr. Nair says Liu's innovative technique to isolate rare circulating cancer cells in a tube of blood - which can number as few as 15 cells in one billion - represents "a simpler, elegant and cost effective approach to monitoring patients on therapies such as immunotherapy and targeted therapy for cancer at the circulating cell level rather than scans such as CAT scans, which look for 100 million or more cells organized into a one centimeter tumor."

"This study, though small, demonstrates that our method can achieve high accuracy on the identification of rare CTCs without the need for advanced devices or expert users, thus providing a faster and simpler way for counting and identifying CTCs," says Liu. "With more data becoming available in the future, the machine learning model can be further improved and serve as an accurate and easy-to-use tool for CTC analysis."

The method, he says, requires minimal data pre-processing and has an easy experimental setup. To arrive at the results, the team preprocessed the whole blood samples, capturing the bright field and fluorescent images of the cells. They trained a deep learning model with cropped single-cell in bright field images and used the corresponding fluorescent images as ground truth labels. They also trained and tested a model with cultured cell lines as a comparison. The group then did the testing and summarized the statistical results of the trained model.

"We tuned the details of the model to reach better results until the outcome reached the state-of-the-art," says Liu.

They essentially ran two experiments: one was a comparison group operated on the white blood cells and cultured cancer cell lines, and the other operated on the white blood cells and patient CTCs. They expected the first group of experiments using the comparison group to work fine because of the large number of training datasets for cultured cells. They used 1745 single-cell images and achieved an overall accuracy of 97.5%. The team did not expect the second group, from patient blood samples, to yield as high an accuracy rate as the first group because the training dataset was limited?based on 95 single-cell images as raw input.

"But when we applied the transfer learning technique with the pre-trained network, we were surprised by the improvement," says Liu. "We found that the machine learning model can identify CTCs with reasonable accuracy as good as 88%."

The blood samples were collected partially using a commercial enrichment kit and partially using a microfluidic device developed by Liu specifically to catch and release CTCs. He and his team continue to innovate in this area and are developing a device that combines optical image machine learning and acoustic sorting to automatically process the sample.

Dr. Nair and Liu, along with two Lehigh Valley Health Network Oncology Fellows Dr. Zach Wolfe and Dr. Saro Sarkisian, will continue to collaborate on the next steps. Among those is refining the technique to look at DNA mutation changes in the captured cells. According to Liu, this will provide even more information to physicians and enable them to make treatment adjustments that improve health outcomes, including prolonging patients' lives.

"As Physician in Chief of Lehigh Valley Cancer Institute?a member of the Memorial Sloan Kettering Alliance?and as a physician leading clinical trials in academic community settings for thirty years, I have been incredibly proud of our collaboration," says Dr. Nair.

Tsukuba, Japan - Non-alcoholic fatty liver disease (NAFLD) had long been thought to be a liver disease afflicting obese patients, while recent evidence has shown that non-obese individuals can be equally affected by NAFLD. In a new study, researchers from the University of Tsukuba revealed how NAFLD presents itself differently based on the sex and body mass index (BMI) of affected patients.

NAFLD is the most common chronic liver disease and often associated with obesity, type 2 diabetes and dyslipidemia. People living in Asia are generally not as obese as those living in Europe or the USA, yet NAFLD is becoming increasingly common in this area. These findings have led to the discovery of non-obese NAFLD, which surprisingly has a higher mortality rate than obese NAFLD. Consequently, an important question that has remained is how to identify the risk factors for the development for non-obese NAFLD.

"We know that an abnormal body composition--as in reduced skeletal muscle mass and increased visceral fat--is a strong risk factor for the development of NAFLD," says corresponding author of the study Professor Junichi Shoda. "We do not have this type of insight for non-obese NAFLD, so we wanted to characterize patients with non-obese NAFLD based on their sex and body composition."

To achieve their goal, the researchers included 404 patients with NAFLD in their study and divided them according to their BMI in non-obese, obese, and severely obese patient groups. As a comparison, they included 253 non-obese patients without NAFLD in their study.

The researchers found that of the male and female patients, one quarter of the members of each group had non-obese NAFLD. Surprisingly, these patients had lower skeletal muscle mass and muscle strength (pre-sarcopenia) compared with obese NAFLD patients. Although afflicted by fatty liver disease, there was only a modest increase in liver fat accumulation and insulin resistance (a precursor to diabetes and often associated with NAFLD) in non-obese NAFLD patients compared with obese NAFLD patients. This was further corroborated by the fact the visceral, or belly, fat was overall low in non-obese NAFLD patients. Interestingly, fat accumulation in muscles was more common among women. An integrated analysis of the data showed that liver fat accumulation in non-obese NAFLD was mainly dependent on visceral fat content, leptin (a hormone produced in visceral fat tissue and that induces inflammation), myostatin (a protein produced by skeletal muscle to suppress muscle regeneration) and HbA1c (a blood marker for how well the body manages blood sugar levels in the long term).

"These are striking results that show how there are important differences in how NAFLD presents itself in non-obese men and women. Our results provide a novel insight into the pathophysiological factors governing NAFLD development," says Professor Shoda.

Autism spectrum disorder (ASD) is a heterogeneous disorder initiated early in development and characterized by abnormal social communication. Accumulating evidence supports the idea that specific mutations affect regulatory proteins that control arrays of cellular pathways.

A special case of autism is known as the Timothy Syndrome (TS) caused by a point mutation in the alternatively spliced exon 8A of the calcium channel Cav1.2. TS is a multisystem disorder characterized also by cardiac dysfunction, causing sudden death from cardiac arrhythmias.

There are two Timothy mutations, G406R and G402S that occur at the calcium channel Cav1.2. These two mutations modify the inactivation kinetics of the channel and by reducing voltage-dependent inactivation, causing an abnormal calcium overload leading to heart problems such as prolonged QT interval and cardiac arrhythmia. Surprisingly, only the G406R mutation is associated with ASD in 4 out of 5 patients carrying the mutation, while the G402S mutation fails to express the autistic phenotype.

The study sought to answer the question: How does the G406R single point mutation of the Cav1.2 channel affect cellular processes that could lead to a multifactorial disease such as autism? It is known that Cav1.2 and other calcium channels induce gene activation, which is responsible for long-term processes, such as neurodevelopmental disorders, cognitive setbacks, and psychiatric disorders including schizophrenia, bipolar disorder and autism.

The researchers, led by Professor Daphne Atlas at the Hebrew University of Jerusalem's Alexander Silberman Institute of Life Sciences, found that both the Cav1.2 Timothy channel mutants G406R and G402S, activate gene programs (transcriptional activity) via the Ras/ERK/CREB cellular pathway, similar to the native (non-mutated) calcium channel Cav1.2. "We were surprised and thrilled to discover that the autistic mutant G406R exhibits a constitutive (spontaneous) transcriptional activation and the G402S mutation does not." This difference might clarify a mechanism that could explain why G406R mutation confers autism whereas G402S does not "shared Atlas.

It is known that in addition to modifying channel inactivation, the two variants of the Timothy channel differ in their activation kinetics. The G406R mutation causes specific gain-of-function changes in Cav1.2 channel gating, exhibiting a "leftward shift" of voltage-dependent activation and G402S does not. This leftward shift facilitates channel activity even at resting potentials, which means that the channel is spontaneously active, as opposed to the G402S mutant.

The research findings of facilitated spontaneous activity of the G406R channel correlates with a constitutive gene activation. This uncontrolled spontaneous gene activation, imposed by a leftward voltage-shift in the activation kinetics of the channel, implies a mechanism of conferring autism. The induction of uncontrolled long-term dysregulations such as autism by facilitated spontaneous activity of the channel and subsequently spontaneous gene activation can be compared to a dripping faucet.

These results were further supported through screening the literature for channel mutants that are associated with long-term abnormalities. All mutated channels that display a leftward-shift in channel activation are associated with long-term dysregulations. These findings imply that channel mutants that exhibit a facilitated channel activity at rest--with no stimulation--imposed by a negative shift in channel gating, are likely to exhibit a spontaneous and uncontrolled gene activation, similar to the Timothy mutant.

"Further studies are required to establish whether the uncontrolled activity of the channel at rest, which is associated with uncontrolled activation of gene programs in Timothy G406R mutant, is the underlying a mechanism by which other mutated channels confer a high risk for neurodevelopmental disorders in humans," explained Atlas.

Based on altering calcium channel kinetics and gene activation exhibited by the Timothy mutant, these results provide insight into the cellular mechanism that allows predicting disease risk, and genetic diagnosis of individuals with neurodevelopmental disorders.

Experts document progress made through rehabilitation interventions that improves quality of life for patients with cerebral palsy, in this special issue of the Journal of Pediatric Rehabilitation Medicine

Amsterdam, NL, August 3, 2020 - Cerebral palsy (CP) is one of the most common developmental movement disorders in children. It is associated with complex healthcare needs and for some a shortened life expectancy depending on the severity of the disorder and co-existing medical conditions. In this special issue of the Journal of Pediatric Rehabilitation Medicine, experts present advancements made by rehabilitation medicine in the care of patients with CP, improving quality of life and research.

This special issue is guest-edited by two of the leading experts in the field, Deborah Gaebler-Spira, MD, Feinberg Northwestern University School of Medicine and Shirley Ryan Ability Lab/Lurie Children's Hospital, Chicago, IL, USA; and Michael M. Green, DO, Clinical Pediatric Rehabilitation Medicine Attending at Primary Children's Hospital, University of Utah, Salt Lake City, UT, USA.

"One of our most significant challenges is understanding the effect of all of our interventions on children through the lifespan," commented Dr. Gaebler-Spira and Dr. Green. "This second CP-focused special Issue of the journal continues to explore the impact of rehabilitation medicine on the care and research for those with CP."

An important contribution to the issue showcases the use of bibliometrics, which has considerable potential for healthcare scientists and practitioners to discover new information about academic trends, pharmacotherapy, disease, and broader health sciences trends. Margret Turk, MD, the most recent Gabriella E. Molnar-Swafford Lifetime Achievement Award recipient, and co-authors demonstrate the expanding literature emphasizing function and quality of life for persons with CP including performance, aging, and health, compared to earlier studies when diagnostic feature and brain pathology dominated research. Their findings highlight the transition from diagnosis and identification to management of specific conditions and providing guidance for the continuum of needs that patients with CP experience over the course of a lifetime.

This issue introduces "Needle Tips," devoted to the art, science, and practice of injecting neurolytics such as botulinum toxin and phenol in in children with CP. "It was conceived as a unique forum in which the active community of injectors would express some of the daily problems, challenges, and nuances that are the bread and butter of our daily practice," Dr Gaebler-Spira explained.

Botulinum toxin injections now have a "green light" for managing spasticity in children with a variety of neuromuscular conditions. Current randomized clinical trials utilizing botulinum toxin are on children with CP, which has current FDA approval for lower and upper limb injections. However, questions remain. To address these issues injectors from the pediatric rehabilitation community present their views and rationale on current use of botulinum toxin, adverse events, dilution, and diagnoses.

The section "Human-TIES come first" is a chance to introduce a piece of art, music, book, or in this case a film, to readers that will enhance understanding and create a human view of the experience of living with a disability. This issue includes a review of the documentary "Crip Camp," whose executive producers were Barack and Michelle Obama. It shows footage and interviews from Camp Jened, a summer camp for people with disabilities. The reviewer points out that terms such as "crip," "cripple," and "gimp" have been used by people with disabilities as terms of empowerment, taking formerly insulting terms and repurposing them into words of advocacy. "We consider this a must see for the field," said Dr. Green.

Other issue highlights include:

Use of robot-assisted gait training

Constraint-induced movement therapy

Autonomy - using "Skills for Growing Up"

Effects of solid ankle-foot orthoses

Balance, proprioception, and vestibular symptoms in children with hemiplegia

Association of hepatoblastoma, prematurity, and CP

Spasticity treatment for children with CP

"In the midst of the coronavirus pandemic Dr. Gaebler-Spira, and Dr. Green worked around the clock with specialists across the country and the world to culminate in a very special JPRM cerebral palsy issue. It was an absolute pleasure and an honor to work with our special guest editors," added Editor-in-Chief, Elaine Pico, MD, UCSF Benioff Children's Hospital, Oakland, CA, USA.

CP occurs in about 1.5 to more than 4 per 1,000 live births and individuals with CP benefit from ongoing rehabilitation throughout childhood and into adulthood. The symptoms of CP vary over the lifespan. Commonly the first symptoms are gross motor delay due to abnormal muscle tone and decreased motor control and coordination. As children age, the muscles become stiff and weak with subsequent orthopedic problems. Other systems affected may include vision, hearing, swallowing, speaking, bowel and bladder, and sensation. Although there is no cure, management and treatments such as medications and surgery can ameliorate complications and assist people with CP to live a full life.

Amsterdam, NL, August 3, 2020 - A review of currently registered clinical trials of agents targeting Parkinson's disease (PD) reveals that there is a broad pipeline of both symptomatic and potentially disease-modifying therapies currently being evaluated. Investigators report that the outlook for patients is encouraging, given the wide range of therapeutics being clinically tested. They emphasize the importance of engaging the Parkinson's community in the research. Their analysis and results are published in the Journal of Parkinson's Disease.

PD is a neurodegenerative condition for which there is currently no cure. The incidence of PD is increasing, with the number of cases expected to double worldwide by 2040. The majority of current pharmacological treatments for PD were approved for clinical use in the second half of the last century, and they only provide symptomatic relief. Derivatives of these therapies continue to be explored in clinical trials, together with potentially disease-modifying therapies that may slow, stop, or reverse the condition.

"With the discovery of the first genetic risk factors for PD at the turn of this century, researchers have begun to develop a better understanding of the possible biological pathways that may be governing/influencing the progressive neurodegeneration associated with PD," explained senior author Simon Stott, PhD, Deputy Director of Research, The Cure Parkinson's Trust, London, UK. "These discoveries have led to a growing number of clinical trials targeting an increasing number of potentially disease-relevant mechanisms of action. It is important for the research and Parkinson's communities to stay abreast of the extensive, ever-changing landscape in order to highlight trends and better manage expectations."

This analysis provides the first broad overview of currently registered clinical trials of agents targeting PD. It demonstrates that there is currently a tremendous amount of clinical research being conducted on therapeutic agents for PD that is exploring a wide range of agents that have different mechanisms of action and therapeutic targets.

"The outlook is encouraging for the clinical trial field, given the broad range of therapeutics being clinically evaluated," commented Richard Wyse, MD, Director of Research and Development, The Cure Parkinson's Trust, London, UK. "Development of Parkinson's biomarkers and new approaches to trial design, along with increasing levels of open data/open science and publishing of results for all trials will help hasten progress in bringing new Parkinson's treatments forward."

The investigators conducted a review of clinical trials of drug therapies for PD using trial data obtained from the ClinicalTrials.gov international database and performed a breakdown analysis of studies that were active as of January 21, 2020. They identified 145 registered and ongoing clinical trials for therapeutics targeting PD, of which 51 (35%) are Phase 1, 66 (46%) are Phase 2, and 28 (19%) are Phase 3. There are 57 trials (39%) focusing on long-term disease modifying therapies, with the remaining 88 trials (61%) investigating therapies for short-term, daily symptomatic relief. A total of 50 (34%) trials are testing repurposed therapies.

Parkinson's research advocates were the driving force behind this study.

As co-author Susan Buff, a Parkinson's care partner, research advocate, and publisher of http://www.PDTrialTracker.info, noted, "The patient community brings a combination of the lived experience of the disease, a sense of urgency, and an array of career backgrounds and skill sets that can all contribute immensely to the research process. Hopefully, having a clearer view of the trial pipeline will enable greater awareness around opportunities for researcher/patient collaboration."

Co-author Kevin McFarthing, PhD, a patient advocate and expert in innovation management who maintains The Hope List (https://bit.ly/ParkinsonsHopeList) and contributes to the Journal of Parkinson's Disease Clinical Trials Highlights section, added, "As patients and carers, we have a vested interest in the success of clinical trials, and we hope that a greater awareness of the pipeline will increase the chances of more therapies reaching patients in the near future. The number of clinical trials under way is encouraging for the Parkinson's community, especially the high proportion of repurposed initiatives that increase the chances of a new therapy becoming available more quickly. The breadth of targets for both symptomatic and disease-modifying therapies shows the value of primary research over many years.

Gary Rafaloff, PhD, a patient advocate and co-author of this study, has been involved in Parkinson's research since his diagnosis eight years ago, initially as a trial volunteer and more recently as a member of a research study team. "My hope is that this research review will make it easier for those who conduct research, those who fund research, and most importantly, those who volunteer to participate in research, to collaborate more efficiently with the ultimate goal of discovering more effective therapies, and possibly a cure, for the disease," he said.

"It is important not only for the research community to be aware of this clinical trial landscape, but also for the Parkinson's patient community from whom the pool of brave volunteers to participate in the trials is gathered. It is extremely important for the patient and carer community to become more engaged with the research, providing valuable insights into how different aspects of the clinical trial process could potentially be improved," concluded Dr. Stott.

Up to now, adult men with non-metastatic castration-resistant prostate cancer (nmCRPC) at high risk of developing metastatic disease usually continued their conventional androgen deprivation therapy (ADT) while the cancer was observed for the occurrence of metastases (so-called watchful waiting). The German Institute for Quality and Efficiency in Health Care (IQWiG) now examined in an early benefit assessment whether adding the drug darolutamide offers an added benefit for patients in comparison with the appropriate comparator therapy.

Since the advantages in overall survival, symptoms and late complications, as well as in health-related quality of life are not accompanied by disadvantages, there is an indication of considerable added benefit.

Study is ongoing

The early benefit assessment was based on data from the ongoing randomized trial ARAMIS, which compares darolutamide in combination with ADT with placebo treatment in combination with ADT. The study included adult men with high-risk nmCRPC who either had had both testes removed or who continued their drug ADT in addition to the study medication (darolutamide or placebo).

The study was double-blind until metastases or unacceptable toxicity occurred. After unblinding, the patients could choose to continue their darolutamide plus ADT treatment or receive darolutamide instead of placebo. There were no restrictions regarding other subsequent therapies.

In the benefit assessment, the first of two data cut-offs was used for all outcomes except overall survival, as analyses were not available for all included outcomes at the second data cut-off. Besides, the follow-up observation in the study is systematically shortened for all outcomes except overall survival. In addition, a number of patients (which was unequal in the two study arms) had discontinued treatment already at the first data cut-off; and many patients switched from the placebo plus ADT arm to the darolutamide plus ADT arm after the first data cut-off.

Patients live longer and have fewer symptoms

The certainty of results was rated as high for overall survival and as low for all other outcomes. Consequently, there is an indication of considerable added benefit in the outcome category of mortality, but no more than hints in the other outcome categories: The added benefit is considerable to major for morbidity (symptoms and late complications), and minor for health-related quality of life. In the category of side effects, there is no hint of lesser or greater harm from the new drug.

In the overall consideration, there is therefore an indication of considerable added benefit of darolutamide plus ADT versus watchful waiting while maintaining ongoing conventional ADT.

G-BA decides on the extent of added benefit

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

More English-language information will be available soon (Sections 2.1 to 2.5 of the dossier assessment as well as easily understandable information on informedhealth.org). If you would like to be informed when these documents are available, please send an e-mail to info@iqwig.de.