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An experimental drug recently concluded a successful third-phase clinical trial and could potentially offer a new treatment for about 300,000 Canadians who have worsening chronic heart failure.

The VICTORIA (Vericiguat Global Study In Subjects With Heart Failure With Reduced Ejection Fraction) clinical trial examined the effects of a drug called vericiguat on patients at a high risk of death or hospitalization from heart failure.

The results showed that rates of cardiovascular death or hospitalization among the patients who received vericiguat were 10 per cent lower than the rates among the placebo group. This was clinically meaningful because it meant an absolute reduction in negative health events in 4.2 per cent of patients already receiving optimal heart failure care.

It was the first large study to focus exclusively on the condition, and to specifically evaluate those with a low proportion of blood being pumped out of their hearts, a measure called ejection fraction.

"Although we have good guideline-based therapy for patients with heart failure, there is still a need for new drugs to help treat those patients who deteriorate despite optimal current care," said U of A distinguished professor of medicine Paul Armstrong, who was the chair of the study.

"What we were looking for in VICTORIA was a novel approach to address that unmet need, and we've found vericiguat provided that when added to guideline-based treatments," said Armstrong.

Over nearly four years, the VICTORIA trial enrolled more than 5,000 patients at 600 centres across 42 countries, including 145 Canadian patients with chronic heart failure that included low ejection fractions. In the Phase III clinical trial, half of the participants were randomly selected to receive vericiguat in combination with standard heart failure therapy. The other half received standard treatment and a placebo drug.

Along with reducing cardiovascular death and hospitalization in patients, vericiguat was also found to have few side-effects, and positive effects as early as three months into the trial.

Vericiguat works by stimulating an enzyme in the body called soluble guanylate cyclase (sGC), which is important for enhancing heart function and helping blood vessels relax to provide better blood flow. In patients with heart failure, sGC is reduced and unable to adequately stimulate cyclic guanosine monophosphate (cGMP), necessary for transmitting chemical signals to blood vessels, which results in vascular and coronary dysfunction. Vericiguat is the first drug of its kind to be investigated as a once-daily oral treatment for patients with worsening chronic heart failure.

"Because this guanylate cyclase stimulator agent approaches and targets a new pathway in heart disease, we think it may open up a new horizon for other cardiac issues that deserves to be explored," said Armstrong, who is also the founding director of the Canadian VIGOUR Centre.

"Not only does this new drug have the potential to help patients, but we also expect it will reduce the burden of repeat hospitalizations for heart failure in our health-care system," said Armstrong.

Justin Ezekowitz, a professor of cardiology, co-director of the Canadian VIGOUR Centre and the Canadian national lead for the study, said patients with heart failure who have just been hospitalized are at the greatest risk of death or readmission to the hospital.

"So far, no one has been able to demonstrate any other therapies with this mechanism of action to have a major impact," he said. "Vericiguat may be an important new addition to consider during hospitalization, or after a patient is discharged, to help most patients with a broad range of heart failure and ejection fractions stay out of the hospital."

With the successful completion of the Phase III trial of vericiguat, the trial co-sponsors Merck & Co, Inc. and Bayer AG expect to share the study results with regulatory agencies around the world.

A separate study is also underway to investigate whether vericiguat offers benefits for those with heart failure with preserved ejection fraction, a different form of the disease for which there are even fewer treatment options available, Armstrong said.

The results of the VICTORIA trial were presented on March 28 at the virtual American College of Cardiology's Annual Scientific Session "Together With World Congress of Cardiology," and published in the New England Journal of Medicine and Circulation.

The VICTORIA trial was led by the Canadian VIGOUR Centre, in collaboration with a team at Duke Clinical Research Institute in Durham, N.C., led by Adrian Hernandez. The international team also included Christopher M. O'Connor from the Inova Heart & Vascular Institute in Falls Church, Va. and Burkert Pieske from the Charité University Medicine and German Heart Center in Berlin, Germany. The trial was co-sponsored by pharmaceutical companies Merck & Co, Inc and Bayer AG, the co-developers of the drug.

DUARTE, Calif. -- A City of Hope scientist is one step closer to discovering what weakens a pathogen that appears to cause babies to be born with abnormally small heads.

Interestingly, it takes studying "mini brains" to understand why certain unborn babies infected with cytomegalovirus (CMV) enter the world with shrunken brains, said Yanhong Shi, Ph.D., senior author of the new study, director of the Division of Stem Cell Biology Research and the Herbert Horvitz Professor in Neuroscience at City of Hope.

In the United States, the most common cause of infectious-related birth defects is CMV. About 1 in 5 babies with congenital CMV infection will have birth defects or other long-term health problems. Among those congenital conditions is microcephaly, or abnormally small heads, a concern many soon-to-be mothers had during the 2015 Zika outbreak. However, CMV is a far more common culprit for microcephaly, Shi said.

"We are among the first to model human CMV-induced microcephaly using brain organoids. This is a first step to one day studying more complex neurological complications such as Alzheimer's disease and Parkinson's disease," Shi said, adding that much more developed brain organoids, as the mini brains are more popularly known, are needed for scientists to study complex nervous system diseases that develop later in life.

The study, published in Cell Reports Medicine on March 25, solves a problem that has befuddled scientists for decades - how to create an experimental model that can mimic the complexities of the human brain in order to study neurological disorders. Until recently, scientists were restrained to studying the problem mostly in two dimensional models in a petri dish because they couldn't replicate many key features of neurological disorders in animal models. Notably, animals cannot be used to study human CMV (HCMV)-specific brain disorders because the disease is specific to humans.

Shi and her colleagues, however, found that a strain of HCMV called TB40/E appeared to replicate what HCMV does to an unborn baby's brain in the transition between the first and second trimester. The TB40/E-infected brain organoids were significantly smaller than the control models. Of the 10 genes that were reduced, three were related to calcium signaling, an indication that brain connections were not being made and that the brain's electrical network was not functioning properly. Further testing showed that TB40/E affected critical genes involved in brain development, including ones responsible for the development of the hippocampus, the center of learning and memory.

"A similar organoid strategy can be used to understand how infection by the SARS-CoV-2 virus leads to COVID-19 so that we can test potential therapies for the disease," said Guoqiang Sun, Ph.D., lead author of the study and a staff scientist in the Department of Developmental and Stem Cell Biology at Beckman Research Institute of City of Hope.

To take the study one step further, Shi and her colleagues collaborated across disciplines with Don Diamond, Ph.D., professor in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope. Diamond has been studying CMV for three decades and is developing vaccines to prevent congenital CMV infection.

The City of Hope scientists tested what could one day prevent or lessen the birth defects created by HCMV-induced microcephaly. They introduced a protective immune system antibody currently in development in the Diamond Lab. When tested in the brain organoid model, it appeared early intervention with these "neutralizing antibodies" may prevent or reduce the most severe consequences of HCMV infection.

"Now that we have a model that replicates how HCMV-induced microcephaly happens, we can use it to test antiviral agents," Shi said. "We can now start looking for real-world solutions."

The Journal of the American Geriatrics Society (JAGS) this week rushed to publication a special article describing critical points for combatting the coronavirus disease (COVID-19) pandemic for older adults and those in long-term care.

The article offers a summary of current information and evidence, noting the imperative for understanding and acting upon the "ABCDs" of the COVID-19 crisis:

How to foster awareness of key clinical differences for older adults.

How to initiate quick, appropriate behaviors to manage infections, particularly in long-term care.

How to begin COVID-19 containment and maximize preventive interventions (especially in long-term care)

How to empower healthcare leaders, policymakers, and government agencies to make decisions that address rapid access and results of testing and treatment, as well as the costs and societal impacts of the pandemic.

"All aspects of life have changed dramatically for now," note the authors: Heather D'Adamo, MD; Thomas Yoshikawa, MD; and Joseph G. Ouslander, MD. "The groups most susceptible to COVID-19 are older adults and those with chronic underlying chronic medical disorders...In this article, we provide information, insights, and recommended approaches to COVID-19 in the long-term facility setting."

The article is available to all for free at https://onlinelibrary.wiley.com/doi/epdf/10.1111/jgs.16445. Researchers, clinicians, and the public can also track COVID-19-related research published in JAGS by visiting https://onlinelibrary.wiley.com/action/doSearch?AllField=COVID-19&SeriesKey=15325415.

JAGS also is soliciting articles related to COVID-19 for rapid review and publication. These articles, which can be anything from reflections to original research, can be submitted by visiting https://onlinelibrary.wiley.com/journal/15325415.

Below please find link(s) to new coronavirus-related content published today in Annals of Internal Medicine. All coronavirus-related content published in Annals of Internal Medicine is free to the public. A complete collection is available at https://annals.org/aim/pages/coronavirus-content.

A War on Two Fronts: Cancer Care in the Time of COVID-19

Alexander Kutikov MD; David S. Weinberg MD, MSc; Martin J. Edelman MD; Eric M. Horwitz MD; Robert G. Uzzo, MD, MBA; Richard I. Fisher, MD

Ideas & Opinions

Free content: http://annals.org/aim/article/doi/10.7326/M20-1133

Media contact: To speak with lead author, Alexander Kutikov MD, please contact Amy Merves at Amy.Merves@fccc.edu.

What The Study Did: This study compared federal and foundation research funding for sickle cell disease and cystic fibrosis and investigated whether funding was associated with differences in drug development and research productivity.

Authors: John J. Strouse, M.D., Ph.D., of Duke University School of Medicine in Durham, North Carolina, is the corresponding author.

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

(10.1001/jamanetworkopen.2020.1737)

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

COVID-19 can have fatal consequences for people with underlying cardiovascular disease and cause cardiac injury even in patients without underlying heart conditions, according to a review published today in JAMA Cardiology by experts at The University of Texas Health Science Center at Houston (UTHealth).

Experts have known that viral illnesses such as COVID-19 can cause respiratory infections that may lead to lung damage and even death in severe cases. Less is known about the effects on the cardiovascular system.

"It is likely that even in the absence of previous heart disease, the heart muscle can be affected by coronavirus disease," said Mohammad Madjid, MD, MS, the study's lead author and an assistant professor of cardiology at McGovern Medical School at UTHealth. "Overall, injury to heart muscle can happen in any patient with or without heart disease, but the risk is higher in those who already have heart disease."

The study authors explained that research from previous coronavirus and influenza epidemics suggest that viral infections can cause acute coronary syndromes, arrhythmias, and the development of, or exacerbation of, heart failure.

In a clinical bulletin issued by the American College of Cardiology, it was revealed that the case fatality rate of COVID-19 for patients with cardiovascular disease was 10.5%. Data also points to a greater likelihood that individuals over the age of 65 with coronary heart disease or hypertension can contract the illness, as well experience more severe symptoms that will require critical care.

According to the study authors, critical cases are those that reported respiratory failure, septic shock, and/or multiple organ dysfunction or failure that resulted in death. "It is reasonable to expect that significant cardiovascular complications linked to COVID-19 will occur in severe symptomatic patients because of the high inflammatory response associated with this illness," said Madjid, who also sees patients at the UT Physicians Multispecialty - Bayshore clinic.

The novel virus that causes COVID-19 was first identified in January 2020. This novel virus originated in Wuhan, China, and by March 11, 2020, the World Health Organization had declared it a global pandemic. The three most common symptoms of COVID-19 include fever, cough, and shortness of breath. Other less common symptoms are muscle pain, sore throat, nasal congestion, and headache. Symptoms can appear as soon as two days after exposure to the virus to up to14 days after. There is a high viral load in both symptomatic and asymptomatic patients, meaning asymptomatic spread between person to person is likely.

Previously identified coronaviruses known to cause severe illness in humans include Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome (MERS-CoV). SARS-CoV was first identified in southern China in 2002, and by 2003 it had killed over 8,000 individuals in 29 countries. Data suggests that SARS-CoV may have resulted in cardiovascular complications, such as acute coronary syndrome and myocardial infarction. MERS-CoV was first discovered in 2012 in Saudi Arabia. As of 2019, 2,494 cases have been confirmed along with 858 deaths in 26 countries.

Current COVID-19 treatment options are being researched, and there is a large effort to develop vaccines for prevention and to test antivirals for the treatment of the disease. In the meantime, the study authors encourage all individuals to consult with their health care providers about being vaccinated against influenza and that at-risk patients seek advice on receiving a pneumonia vaccine from their primary care physician. While these vaccines will not provide specific protection against COVID-19, they can help prevent superimposed infections alongside COVID-19.

In the current situation when the fear of virus infections in the public is common, it is good to remember that some viruses can be extremely beneficial for mankind, even save lives. Such viruses, phages, infect bacteria. The research conducted at the University of Jyväskylä shed some light on the phage therapy history. It revealed that Brazil was a strong user and developer of phage therapy in 1920-40's. The research was published in Lancet Infectious Diseases -publication on March 2020.

After decades of antibiotic use and misuse, natural selection is giving bacteria the upper hand. The World Health Organization (WHO) warned that we are reaching the post-antibiotic era. As more pathogens become resistant, our chances to find new antibiotics diminish. Therefore, alternatives are urgently needed.

Use of phages, viruses that kill bacteria, as therapeutics was developed in Paris around 1920. Since these viruses could be safely used to treat patients, phage therapy quickly spread, but then slowly disappeared from the western world decades later, as antibiotics became common. Now, the revival of phage therapy is considered one viable solution to the antimicrobial resistance crisis.

Researchers of the University of Jyvaskyla investigated a forgotten hotspot of phage therapy of the past. Historical medical records in Portuguese (1915-1952) revealed that Brazil was a strong user and developer of phage therapy. From pioneer mass testing of phage products to routine, details have been uncovered about the safe use of phages against dysentery and staphylococcal infections. This information was made available to the modern research community by a historical review publication.

The practical and clinical data revealed can be important to shape modern phage therapy, against acute dysenteric infections and against dangerous resistant pathogens such as MRSA.

"The literature researched was an interesting trip to the past. This work is in principle a historical review, but it also provides relevant information to modern researchers. It might be an incentive to similar investigations on other countries, besides being a spark of hope to the recent Brazilian research community", says Postdoctoral Researcher Gabriel Almeida from the University of Jyväskylä.

Researchers at the VU University Medical Center in the Netherlands have tested a new drug in patient samples and mice with multiple myeloma and discovered that it was effective even in advanced disease - a point when many patients currently run out of options. These promising results could pave the way for the new drug to be tested in patients.

Multiple myeloma is a cancer that affects cells in the bone marrow that produce antibodies - small molecules that fight infections in the body. Multiple myeloma is not considered to be a curable cancer and almost all patients eventually relapse. In the UK, almost 6,000 people are diagnosed with multiple myeloma every year - that's 16 people per day.

The new drug, called FL118, has previously shown promise when tested on colon and head and neck cancer cells in the lab. This new study, led by Dr Tuna Mutis and funded by Worldwide Cancer Research and the Dutch Cancer Society, was recently published in the journal Haematologica.

Cancer cells can become resistant to treatment by recruiting surrounding healthy cells to support them. The researchers found that not only is FL118 effective at killing multiple myeloma cells when they are surrounded by these support cells, but it was also able to reverse treatment resistance. This suggests the drug could have potential to treat patients that are no longer responding to standard therapies.

Using patient samples of newly diagnosed and relapsed or treatment resistant patients, FL118 was found to be more effective against cancer cells from advanced disease patients, than the newly diagnosed cases. The researchers also found that FL118 enhanced the effect of melphalan and bortezomib - two drugs commonly used in the treatment of multiple myeloma. When tested in a mouse model of multiple myeloma, FL118 was able to reduce tumour volume to almost one sixth of its original size and delayed tumour growth for up to 5 weeks.

According to the researchers, FL118 could be used in combination with currently used drugs to overcome treatment resistance. They suggest that FL118 has the potential to be highly efficient in relapsed or treatment resistant patients - a group that urgently needs new therapeutic options.

Dr Tuna Mutis explained the next steps: "The first step towards using this compound in the clinic is to do a phase one trial, which judges the safety of the drug. Our collaborators, who also provided this compound, are now planning this trial. In addition to this, we are also testing whether this new drug could improve immune therapy. This would be another important effect, which could demonstrate its usefulness in a wide variety of cancers - not just multiple myeloma."

Dr Helen Rippon, Chief Executive of Worldwide Cancer Research, said: "This study is close to our heart as Worldwide Cancer Research's founder, Dr Colin Thomson, sadly passed away from multiple myeloma. The new findings take the first step towards a new drug that could one day be used to treat people with advanced multiple myeloma. As with any new treatment, there is a long journey ahead, but research such as this lays the groundwork for clinical trials in the future. Multiple myeloma is an incurable cancer that almost always comes back - even after seemingly successful treatment. Treatment resistance is a huge problem in cancer patients and exciting discovery research like this tackles this issue head on. We need to make sure that more bold new ideas like this are funded if we want to keep one step ahead of cancer."

Gardnerella bacteria in the cervicovaginal microbiome may serve as a biomarker to identify women infected with human papillomavirus (HPV) who are at risk for progression to precancer, according to a study published March 26 in the open-access journal PLOS Pathogens by Robert Burk and Mykhaylo Usyk of the Albert Einstein College of Medicine, and colleagues. According to the authors, the findings could lead to therapeutic strategies that manipulate the microbiome to prevent disease progression.

HPV infection is one of the most common sexually transmitted infections and the causal agent of cervical cancer. But it is still not clear why only a small proportion of high-risk HPV infections progress to cervical cancer. To investigate the potential role of the cervicovaginal microbiome, Burk, Usyk and their collaborators evaluated cervical samples from 273 women who had high-risk HPV infection and were participating in the Costa Rica HPV Vaccine Trial.

They found that the abundance of Lactobacillus iners was associated with clearance of high-risk HPV infections. By contrast, Gardnerella bacteria were the dominant biomarker for progression of a high-risk HPV. Additional analyses revealed that the effect of Gardnerella is mediated by increased cervicovaginal bacterial diversity directly preceding the progression of a persistent infection to precancer. The findings suggest that monitoring the presence of Gardnerella and the subsequent elevation in microbial diversity could be used to identify women with persistent high-risk HPV infection at risk for progression to precancer. If future studies support a causal role of the cervicovaginal microbiome and disease progression, then it might be possible to manipulate the cervicovaginal microbiome in a manner to activate a local immune response and prevent disease progression.

The authors add, "The investigators prospectively demonstrate that progression of a persistent high-risk HPV infection to cervical precancer is in part explained by unique features of the cervicovaginal microbiota."

Washington, DC (March 26, 2020) -- High blood pressure has a range of effects on the body that can influence both physical and mental health. Two studies in an upcoming issue of CJASN offer insights gained from "ambulatory" blood pressure monitoring, which is conducted while people go about their daily activities, including during sleep. This type of monitoring can provide more information than blood pressure measurements taken only in clinics.

In an analysis of 561 African Americans with and without chronic kidney disease who underwent ambulatory blood pressure monitoring, Paul Muntner, MD, Stanford Mwasongwe, MPH (University of Alabama at Birmingham), and their colleagues found that having kidney disease was associated with uncontrolled blood pressure measured in the clinic and outside of the clinic. Also, among participants with kidney disease, uncontrolled ambulatory blood pressure was associated with a higher prevalence of left ventricular hypertrophy, a marker of cardiovascular disease.

"Getting an accurate estimate of blood pressure is important for people with kidney disease given the association of blood pressure with cardiovascular disease and kidney disease progression in this population," said Dr. Muntner. "The current study showed that a high proportion of people with kidney disease have high blood pressure when measured outside of the doctor's office."

In another study that followed 1,502 adults with chronic kidney disease for 4 years, Lama Ghazi, MD (University of Minnesota) and her colleagues found that ambulatory blood pressure patterns were not linked with cognitive impairment or frailty. "However, among participants older than 60 years, those who demonstrated at least a 20% drop in average systolic blood pressure from day to night--called extreme dippers--had a higher risk of developing cognitive impairment," said Dr. Ghazi. Also, participants with masked hypertension (normal clinic-measured blood pressure but elevated ambulatory blood pressure) had worse physical functioning than participants with hypertension controlled with medication.

Dr. Ghazi noted that future research should assess links between ambulatory blood pressure and physical and cognitive function over a longer follow-up period.

An editorial accompanies the CJASN studies.

WINSTON-SALEM, N.C. - March 26, 2020 - More than 90% of the legal marijuana products offered in medical dispensaries are much stronger than what clinical studies have shown that doctors recommend for chronic pain relief, according to a study published in the March 26 online edition of the journal PLOS ONE.

To many that may seem like a good thing, but just the opposite is true.

"We know that high-potency products should not have a place in the medical realm because of the high risk of developing cannabis-use disorders, which are related to exposure to high THC-content products," said the study's lead author, Alfonso Edgar Romero-Sandoval, M.D., Ph.D., associate professor of anesthesiology at Wake Forest School of Medicine, part of Wake Forest Baptist Health.

"Several earlier studies showed that levels of up to 5% tetrahydrocannabinol (THC) - the main psychoactive compound in marijuana that provides pain relief as well as intoxication - were sufficient to reduce chronic pain with minimal side effects."

The goal of this study was to evaluate the advertised THC and CBD content of legal cannabis products to determine their suitability for medicinal use, and to compare the potency of the products offered in medical and recreational programs.

The researchers recorded the concentrations of THC and cannabidiol (CBD) - the non-euphoric compound in marijuana - in all plant cannabis products provided by legal dispensary websites and compared them between or within the states in the study: California, Colorado, Maine, Massachusetts, New Hampshire, New Mexico, Rhode Island, Vermont and Washington. A total of 8,505 cannabis products across 653 dispensaries were sampled.

Romero-Sandoval's team found that most of the products offered in the medical dispensaries in the study had more than 10% THC and that many had 15% or more, the same as what is available in products at recreational dispensaries.

This is problematic because between 60% and 80% of people who use medical marijuana use it for pain relief, Romero-Sandoval said. The higher the concentration of THC the greater risk, not only for developing dependency, but also for developing tolerance more quickly, which means higher and higher concentrations might be needed to get the same level of pain relief.

"It can become a vicious cycle," Romero-Sandoval said.

"Better regulation of the potency of medical marijuana products is critical. The FDA regulates the level of over-the-counter pain medications such as ibuprofen that have dose-specific side effects, so why don't we have policies and regulations for cannabis, something that is far more dangerous?"

This study provides the scientific evidence to help policy makers correct mistakes and to create a better framework to protect patients, he said.

Sepsis--the body's own immune response gone against it--is a major health problem worldwide. It is basically a "hyper"-immune response by the body to infection or injury, and is characterized by hyperinflammation, immune system paralysis, cell death, liver and kidney failure, blood clots, and even hemorrhage. An estimated 30 million people suffer from sepsis every year, of which 20% die. This incredibly high mortality rate, combined with a poor understanding of how sepsis occurs and lack of effective remedies, means that we need to considerably improve our understanding of sepsis onset and devise novel strategies to treat it. Now, in an important new study, scientists at the Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre in India, have made significant strides towards devising a novel therapeutic modality for sepsis.

DNA in our cells is stored as tightly packed units called "chromatin," which includes complexes of histone proteins and DNA. Prof Mittra says, "We previously showed that chromatin particles released from dying cells, into the bloodstream--called cell-free chromatin (cfCh)--can integrate into the DNA of healthy cells and disrupt it, causing cell death and inflammation." In the latest study, the scientists made a "hypothesis" that sepsis could possibly be caused by cfCh integrating into and disrupting the DNA of healthy cells; which, according to Prof Mittra, "then causes them to die and release more cfCh, thereby sparking off a terrifying 'cascade' of sorts that leads to more host cell death, thus leading to sepsis-related pathologies." To test this "hypothesis," the scientists first prepared compounds that would "inactivate" cfCh, including (a) anti-histone antibodies complexed with nanoparticles (CNPs) that target the histones in cfCh; (b) DNase I, which attacks DNA component of cfCh; and inactivates it and (c) a novel pro-oxidant combination of resveratrol (a plant antioxidant) and copper, called R-Cu2+, which also degrades DNA in cfCh via the medium of free radicals. Simultaneously, they induced sepsis in mice by injecting varying doses of a bacterial endotoxin called LPS. While they injected only LPS in one group of mice, they injected each of CNPs, DNase I and R-Cu2+ in the other groups. The scientists wanted to check if the cfCh-inactivating agents could reduce sepsis/death caused by LPS in the mice. And for this, they specifically looked at the following parameters: levels of cfCh in extracellular spaces in organs and circulation, levels of "pro-inflammatory cytokines" (signaling molecules that trigger cellular events related to inflammation), DNA damage, cell death, and inflammation in the thymus and spleen (indicative of immune system failure, a classic sepsis sign), and other vital organs (lungs, brain, heart, small intestine), liver and kidney damage, coagulopathy and fibrinolysis, and death.

And what the scientists found was unprecedented: all the three cfCh-inactivating agents were effective in ameliorating all the parameters related to sepsis, which were initially increased by LPS. The effects on survival were the most notable. When the mice were given potentially fatal doses of LPS, only 10% mice in the LPS-only group survived; however, among the treatment groups, R-Cu2+ and DNase I increased the survival rate drastically, to 50%, while CNPs increased it to 30%.

All these findings validated their hypothesis: one of the ways in which sepsis is caused is indeed the integration of cfCh into healthy host cell DNA and subsequent DNA damage, apoptosis, and inflammation, which triggers a vicious cycle and a chain reaction of further apoptosis and inflammation.

To verify that the cfCh-inactivating agents themselves did not harm DNA of healthy cells the scientists injected CNPs, DNase I, and R-Cu2+ into mice without any LPS. Prof Mittra says, "We didn't observe any DNA damage in these mice, which confirms our findings that these cfCh-inactivating agents are non-toxic."

Prof Mittra is encouraged by these findings, as he says, "Prior studies have shown increased levels of cfCh in the serum of sepsis patients. Our previous studies have shown that inflammation is caused by cfCh integration and its associated DNA damage. Our new findings suggest that previous clinical trials for drugs to treat sepsis might have failed because the drugs attempted to treat the symptoms of inflammation rather than attacking the root cause, which is integration of cfCh into DNA of healthy cells and disruption of DNA."

The promise of this study is not limited to research and treatment of sepsis. Prof Mittra adds, "Our group has also previously shown that the toxic side effects of chemotherapy stem from cfCh generated by healthy cells that are killed by the drugs; this creates a similar vicious cycle of more cell death that underlies the toxicity of chemotherapy."

Prof Mittra concludes, "This study has now highlighted that the inexpensive "resveratrol + copper" combination is a highly effective cfcH-inactivator. Although the current study is a pre-clinical study, we at Tata Memorial Centre have started Phase 1 and Phase 2 clinical trials in cancer patients on chemotherapy based on these findings. A proposed trial on sepsis patients has received approval from our Institutional Ethics Committee."

Could the targeting of cfCh be the start to yet another new era of modern molecular medicine? Only time will tell, but this study is surely a step in the right direction on several fronts.

Shortages of respiratory protective devices for healthcare personnel are major concerns during the COVID-19 pandemic. A team of researchers at Baylor College of Medicine, Emory University, the University of Texas Health Science Center at Houston and the National Institute for Occupational Safety and Health Centers at the Centers for Disease Control and Prevention have found that reusable respirators may be a suitable alternative to disposable N95 respirators currently in high demand. The study appears in the journal JAMA.

"Training and fit testing healthcare providers on respirators can be time consuming, and in an epidemic we want to train and fit test a large number of workers quickly," said first and corresponding author Dr. Lisa A. Pompeii, professor of pediatrics - epidemiology at Baylor.

In this study, the researchers compared the time it takes to fit test and train healthcare personnel in the use of disposable respirators versus reusable elastomeric half-mask respirators that provide the same level of respiratory protection as N95 respirators. They found that healthcare personnel learned to use the reusable respirator quickly and that it took no more time to fit test them than it would take a disposable respirator.

"Our study shows that training and fit testing workers on these reusable respirators does not represent a barrier for possible use by hospitals," Pompeii said. "An advantage of reusable respirators is that there is no need to stockpile them."

(New York, NY - March 26, 2020) - In a series of four studies published today in Gastroenterology, a journal of the American Gastroenterological Association, Mount Sinai inflammatory bowel disease (IBD) researchers, describe the identification of predictive tools and a new understanding of environmental factors that trigger IBD.

"Early identification of individuals at high risk for disease development could allow for close monitoring and interventions to delay, attenuate, or even halt disease initiation. This is highly relevant as we seek to predict and prevent IBD, which continues to sharply increase in numbers across the globe," says Jean-Frederic Colombel, MD, Professor of Medicine (Gastroenterology) at the Icahn School of Medicine at Mount Sinai and Co-Director of Mount Sinai's Susan and Leonard Feinstein Inflammatory Bowel Disease Clinical Center. "In the absence of a cure, our clinical strategy will center on aggressive and innovative mechanisms to predict and prevent the disease," says Dr. Colombel.

The series of papers published in Gastroenterology provide four unique windows into IBD through the single lens of prevention. "As we approach nearly one hundred years since the discovery of Crohn's by Burrill Crohn at Mount Sinai Hospital in 1932, we see ourselves in a new era where our core scientific innovation will focus on prevention, as a cure continues to elude us. Therefore, our research focus and our team of researchers are aligned as the "Road to Prevention Group," says Dr. Colombel.

Prevention of Progression of Early Crohn's Disease

In a study demonstrating the critical impact of deep remission in recently diagnosed Crohn's disease patients, researchers collected and analyzed long-term follow-up data of 122 Crohn's disease patients in the CALM (The Effect of Tight Control Management on CD) study, a large, 31-site study that evaluated the effect of tight control of early Crohn's. The researchers observed that achieving deep remission early on was significantly associated with an 81 percent decrease in the risk of adverse outcomes over a median of three years. "The data suggests strongly that achieving deep remission early in the course of Crohn's disease can lead to disease modification with a significant decrease in long-term complications. The implication is that we can play a big role in slowing the disease progression if we catch and treat Crohn's early, highlighting the relevance of prediction and prevention in treating Crohn's," says lead author Ryan Ungaro, MD, MS, Assistant Professor of Medicine (Gastroenterology) at the Icahn School of Medicine at Mount Sinai and a member of Mount Sinai's Feinstein IBD Clinical Center.

Predicting Crohn's Disease Five Years Before First Symptoms

In a study of serum biomarkers of military personnel collected and stored by the U.S. Department of Defense, researchers derived a predictive model for Crohn's disease. In the PREDICTS study (Proteomic Evaluation and Discovery in an IBD Cohort of Tri-service subjects), researchers identified 51 protein biomarkers that were predictive of developing Crohn's disease within five years before diagnosis with a 76 percent accuracy. In total, the researchers evaluated 200 patients with Crohn's disease, 199 with ulcerative colitis, and 200 controls. "The study suggests that biological processes are activated many years before Crohn's, opening the possibility of developing targeted strategies that could work to prevent or delay disease onset. Although we recognize that a preventive strategy may still be many years down the road, studies analyzing samples taken years before diagnosis will likely contribute to a greater knowledge of disease pathogenesis and have the potential to help us improve treatments. When we combine this finding with the knowledge that early intervention can lead to better outcomes for our Crohn's patients, we have a truly relevant headline for a disease that has no cure," says lead author, Joana Torres, PhD, MD, Adjunct Assistant Professor of Medicine (Gastroenterology) at the Icahn School of Medicine at Mount Sinai. In contrast to Crohn's disease, no single marker, alone or in combination, provided good predictive performance for ulcerative colitis.

First Study to Evaluate Association of Metal Exposure and IBD

In a study of metal exposure in the baby teeth of patients who eventually developed IBD later in life, Mount Sinai researchers and colleagues in Portugal collected data from 28 adult Portuguese patients, taking advantage of the country's long tradition of parents storing their children's baby teeth. Baby teeth, like the growth rings in trees, retain information incrementally, storing evidence of environmental exposure from their initial development in the womb until they are shed. Investigators were able to retrieve the baby teeth of 12 IBD patients and 16 unaffected controls, allowing them to study for the first time the association between early-life metal exposures and future risk of IBD. "The data suggests that metal exposure during a critical window in early life may be a risk factor for IBD," says Manish Arora, PhD, Professor of Environmental Medicine and Public Health at the Icahn School of Medicine at Mount Sinai. Researchers investigated four metals--lead, copper, zinc, and chromium--and the developmental time periods during which exposure took place going back to the 25th week of pregnancy.

Study of Ashkenazi Jewish Families Suggests Environmental Link

IBD has a long-established familial incidence, and the Ashkenazi Jewish population has an approximately four-fold increased prevalence of IBD. In a study of IBD within Ashkenazi Jewish multiplex families, researchers studied 38 large families with three or more first-degree family members with IBD. The researchers hypothesized that, in a purely genetically inherited disease, affected siblings would be randomly distributed within the family. The researchers found that affected siblings were significantly more likely to be sequentially affected, with siblings with IBD clustering together within families. "The clustering of affected siblings suggests there are factors beyond genetics that lead to the development of IBD in these multiplex families, likely attributable to a shared environment," says lead author Elizabeth Spencer, MD, Pediatric Advanced IBD Fellow at the Icahn School of Medicine at Mount Sinai. "We are continuing to follow these families in an effort to pinpoint the precise factors. If we can identify these factors, we could alter them as a preventative measure for those at high risk of developing IBD."

Much remains unknown about how SARS-CoV-2, the virus that causes COVID-19, spreads through the environment. A major reason for this is that the behaviors and traits of viruses are highly variable - some spread more easily through water, others through air; some are wrapped in layers of fatty molecules that help them avoid their host's immune system, while others are "naked."

This makes it urgent for environmental engineers and scientists to collaborate on pinpointing viral and environmental characteristics that affect transmission via surfaces, the air and fecal matter, according to Alexandria Boehm, a Stanford professor of civil and environmental engineering, and Krista Wigginton, the Shimizu Visiting Professor in Stanford's department of civil and environmental engineering and an associate professor at the University of Michigan.

Boehm and Wigginton co-authored a recently published viewpoint in Environmental Science & Technology calling for a broader, long-term and more quantitative approach to understanding viruses, such as SARS-CoV-2, that are spread through the environment. They are also principal investigators on a recently announced National Science Foundation-funded project to study the transfer of coronaviruses between skin and other materials, the effect of UV and sunlight on the coronaviruses, and the connection between disease outbreaks and virus concentrations in wastewater.

Scientists and medical experts don't have a good understanding of what virus characteristics and environmental factors control virus persistence in the environment - for example, in aerosols and droplets, on surfaces including skin and in water including seawater, according to Boehm and Wigginton. "When a new virus emerges and poses a risk to human health, we don't have a good way of predicting how it will behave in the environment," Boehm said.

Part of the problem is historically there has been limited funding for this sort of work. The National Institutes of Health historically hasn't funded work on pathogens in the environment, and funding at the National Science Foundation for this work is limited. Also, coronaviruses and most of the emerging viruses that have caught the world's attention over the last decade are enveloped viruses that are wrapped in an outer layer of fatty lipid molecules that they've stolen from their hosts. Proteins on the surface of the envelopes can help these viruses evade the immune systems of the organisms they are infecting. "There has been much more work on the fate of non-enveloped or naked viruses because most intestinal pathogens in excrement are nonenveloped viruses - like norovirus and rotavirus," said Wigginton.

In their paper, Boem and Wigginton address potential threats that viruses such as SARS-CoV-2 pose to water sources. We usually only worry about viruses in water if they are excreted by humans in their feces and urine. Most enveloped viruses aren't excreted in feces or urine, so they aren't usually on our minds when it comes to our water sources. There is increasing evidence that the SARS-CoV-2 viruses, or at least their genomes, are excreted in feces. If infective viruses are excreted, then fecal exposure could be a route of transmission, according to Boehm, who added, "It's unlikely this could be a major transmission route, but a person could potentially be exposed by interacting with water contaminated with untreated fecal matter."

Drinking water treatment systems have numerous treatment barriers to remove the most prevalent viruses and the most difficult-to-remove viruses, according to the engineers. Research on viruses similar to the SARS-CoV-2 virus suggests they are susceptible to these treatments. "In terms of virus concentration and persistence, this isn't a worst-case scenario," Wigginton said.

Broadly, Wigginton and Boehm write, we tend to study viruses very intensely when there is an outbreak, but the results from one virus aren't easy to extrapolate to other viruses that emerge years later. "If we took a broader approach to studying many kinds of viruses, we could better understand the characteristics driving their environmental fate," Wigginton said.

The two researchers call for experts across various fields - including medicine and engineering and - to work together to move methods forward faster, make discoveries and formulate strategies that wouldn't be possible independently.