Virus co-opts immune protein to avoid antiviral defences

By discovering a trick the hepatitis C virus uses to evade the immune system, scientists have identified a new antiviral defence system that could be used to treat many virus infections, according to new research published today in eLife.

Viruses have many strategies to avoid immune system defenses. They often do this by hijacking the immune system’s own proteins. One immune protein that is frequently targeted by viruses, including HIV, hepatitis C, and the SARS coronavirus, is called cyclophilin A (CypA). Understanding how CypA is used by viruses could help scientists develop drugs that work against all of them, including the SARS-CoV-2 virus causing the COVID-19 pandemic.
“Previously, clinical trials have shown that blocking CypA reduces the ability of the hepatitis C virus to replicate and boosts the immune response,” explains lead author Che Colpitts, Assistant Professor of Biomedical and Molecular Sciences at Queen’s University, Kingston, Canada. “We set out to understand how CypA helps hepatitis C evade the immune system.”
In the experiments, the team used hepatitis C-infected human liver cancer cells with and without a functioning innate immune system. The innate immune system scans the body for potential threats such as viruses or bacteria and triggers a response. The scientists used a tool called a short hairpin RNA to selectively silence CypA and found that this stopped the virus from replicating only in the liver cells with a functioning innate immune system. They also showed that drugs called cyclophilin inhibitors help block the virus from co-opting CypA and prevent it from multiplying.
CypA is known to attach to an immune protein called protein kinase R (PKR), affecting its ability to detect viruses. So, the team used a gene-editing tool called CRISPR/Cas9 to cut out the gene for PKR in human liver cells with a working innate immune system. In cells without PKR, the cyclophilin inhibitors were less able to stop the virus from reproducing. This happened because PKR was not there to identify the virus and trigger antiviral defenses.
“These findings reveal a new antiviral defence mechanism that suppresses virus growth,” says senior author Greg Towers, Professor of Molecular Virology at University College London, UK. “This opens the door for the development of CypA-targeting antiviral drugs that can be used against many currently untreatable viruses.”

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Story Source:
Materials provided by eLife. Note: Content may be edited for style and length.

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Journal Reference:

1. Che C Colpitts, Sophie Ridewood, Bethany Schneiderman, Justin Warne, Keisuke Tabata, Caitlin F Ng, Ralf Bartenschlager, David L Selwood, Greg J Towers. Hepatitis C virus exploits cyclophilin A to evade PKR. eLife, 2020; 9 DOI: 10.7554/eLife.52237

https://www.sciencedaily.com/releases/2020/06/200616135808.htm

Novel antisense drug shows promise in slowing fatty liver disease

Using a first-of-its-class drug in a clinical trial, an international research effort headed by a scientist at University of California San Diego School of Medicine reports that inhibition of a key enzyme safely and effectively improved the health of persons with non-alcoholic fatty liver disease (NAFLD), a chronic metabolic disorder that affects hundreds of millions of people worldwide.

The gene silencing approach represents a novel way to reverse NAFLD. The findings are published in the June 15, 2020 online issue of The Lancet Gastroenterology and Hepatology.
NAFLD occurs when fat accumulates in liver cells due to causes other than excessive alcohol intake. The precise cause is not known, but diet and genetics are believed to play substantial roles. The condition is typically not noticed until the disease is well-advanced, and perhaps has transitioned to non-alcoholic steatohepatitis (NASH), a progressive form that can lead to cirrhosis, liver cancer and liver failure.
There is no cure. Treatment primarily consists of ameliorating contributory factors, such as losing weight, improving diet, exercising more and controlling for other conditions, such as diabetes and hypertension. No Food and Drug Administration-approved medications exist. In worst cases, a liver transplant may be required.
“NAFLD wasn’t even recognized as a disease three decades ago; now it is alarmingly prevalent, affecting roughly one-quarter of all Americans and emerging as one of the leading causes for liver transplant in the United States,” said the study’s lead author Rohit Loomba, MD, professor of medicine in the Division of Gastroenterology at UC San Diego School of Medicine and director of the UC San Diego NAFLD Research Center. “Given its relative ubiquity and its potentially calamitous consequences, safe and effective treatments are absolutely needed.”
In the double-blind, randomized, placebo-controlled Phase II trial, Loomba and colleagues enrolled 44 qualifying participants at 16 sites in Canada, Poland and Hungary. For 13 weeks, participants were injected with either an antisense inhibitor called IONIS-DGAT2 or a placebo. The inhibitor, produced by Carlsbad-based Ionis Pharmaceuticals, interferes with Diacylglycerol-O-acyltransferace or DGAT2, one of two enzyme forms required to catalyze or accelerate the production of triglycerides, a type of fat found in blood. High levels of triglycerides boost fat storage throughout the body, including the liver.
The researchers found that after 13 weeks of treatment, participants who received the enzyme inhibitor experienced measurable reductions in fatty liver levels compared to baseline, without elevated levels of fats, enzymes or sugars in the blood. There were six reported serious adverse events, including a cardiac arrest and deep vein thrombosis, but the researchers determined the events were unrelated to the study drug.
“These findings showed robust reduction in liver fat by MRI without corresponding increases in blood lipids,” said Loomba. “Given significant proportion of patients achieving roughly a 30 percent reduction in MRI-PDFF, the threshold that corresponds with higher odds of histologic response when treated for a longer duration, it looks like after just 13 weeks of treatment, the drug was actually slowing progression of NAFLD to NASH.
“All of this is very encouraging and argues for the next step: longer term trials to further investigate the potential of this drug in improvement of liver histologic features associated with NASH, the progressive sub-type of NAFLD.”

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Story Source:
Materials provided by University of California – San Diego. Original written by Scott LaFee. Note: Content may be edited for style and length.

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Journal Reference:

1. Rohit Loomba, Erin Morgan, Lynnetta Watts, Shuting Xia, Lisa A Hannan, Richard S Geary, Brenda F Baker, Sanjay Bhanot. Novel antisense inhibition of diacylglycerol O-acyltransferase 2 for treatment of non-alcoholic fatty liver disease: a multicentre, double-blind, randomised, placebo-controlled phase 2 trial. The Lancet Gastroenterology & Hepatology, 2020; DOI: 10.1016/S2468-1253(20)30186-2

https://www.sciencedaily.com/releases/2020/06/200616135737.htm

Medicaid Rolls Surge, Adding to Budget Woes

Many of the tens of millions of Americans who have lost their health insurance along with their jobs are enrolling in Medicaid — and with state budgets decimated by the pandemic, state officials worry they won’t have the money to pay for their health care.
Nearly 27 million Americans could lose their employer-sponsored health insurance over the course of the pandemic, the Kaiser Family Foundation projected last month. Medicaid, the joint federal-state health plan for low-income Americans, already consumes more than a fifth of state budgets.
“When the economy goes down, people need Medicaid and other supports more than ever,” said Matt Anderson, assistant commissioner of Minnesota’s Health Care Administration and the state’s Medicaid director. “But for Minnesota and all other states, that is happening at the exact moment our budgets are suffering.”
At the same time, officials worry that if people delay or decline treatment because they aren’t covered by Medicaid or other insurance, the coronavirus will spread.
States are pushing for more federal money so they can avoid an array of measures to cut Medicaid costs, from eliminating some of the optional benefits they now provide to reducing the already low reimbursement rates paid to Medicaid providers.

Enrollment Increase

Georgetown University’s Center for Children and Families late last month published an analysis of public data on Medicaid enrollment in 21 states from February through April. It found a 2.8% overall increase in enrollment.
The center was able to get May totals for three states, all of which showed a continued upward trend. Minnesota’s four-month increase was 8.4%, Kentucky’s 8.1% and North Carolina’s 3.4%. (The federal Centers for Disease Control and Prevention publishes monthly Medicaid enrollment data, but it lags a few months. The most recent numbers are from January, prior to the impact of the pandemic.)

Those increases are substantial, but likely to be dwarfed by what is coming, said Joan Alker, executive director of the Georgetown center. “We haven’t seen the real surge yet.”
That prediction is in line with modeling by researchers. An unemployment rate of 15% would increase the Medicaid rolls (excluding those over 65) from 50.3 million before the pandemic to 58.5 million, according to Urban Institute projections last month, a 16.3% increase.
Coincidentally the U.S. unemployment rate last month was 16.3%, once a misclassification error in federal data is taken into account.
If unemployment reaches 20%, the Urban Institute forecasts Medicaid enrollment could reach as high as 62 million.
Just last week, Colorado Medicaid officials said in a news briefing they expect to add more than half a million people to the rolls by the end of the year at an additional state cost of $47 million. In April, 1.2 million Coloradans were enrolled in Medicaid.
Economic downturns usually lead to upticks in Medicaid numbers. Enrollment increased by 7.6% in 2008 during the Great Recession.
With the pandemic, Medicaid is even more vital than usual as a gateway to health services, experts say. That is particularly the case for African Americans, who are at much higher risk of contracting and dying from the coronavirus. Black people account for 1 in 5 Medicaid enrollees.

Seeking Federal Help

Medicaid costs rise or ebb depending on enrollment.
The state share of Medicaid depends largely on the per capita income in each state. State contributions range from about 22% for Mississippi to 50% for California, New York and 11 other states. The federal government pays the rest.
For the 36 states and Washington, D.C., that expanded Medicaid under the Affordable Care Act to make single adults eligible, the match rate is different for that population. The federal government pays 90% of the health care costs for those beneficiaries, and the states contribute 10%.
The pandemic has squeezed state budgets. The left-leaning Center on Budget and Policy Priorities estimated state revenue this year would be 10% lower than projected before the pandemic and 25% lower next year.
It estimates state revenue shortfalls of $615 billion through fiscal 2022. The Great Recession resulted in $690 billion in shortfalls over a four-year period, from 2009 to 2013.
Dave Richard, a deputy health secretary in North Carolina and head of its Medicaid agency, said that although the federal government helped states at the start of the Great Recession in 2007, officials had to go back to the legislature to cover Medicaid shortfalls that persisted until joblessness recovered.
To help states during the pandemic, the federal government has raised its share of the Medicaid match by 6.2 percentage points until the administration lifts the health emergency. But that bump does not apply to costs associated with the expansion populations.
The National Governors Association called that increase inadequate and asked that it be increased to 12 percentage points. The House approved a stimulus bill that would make it 14. The Senate has not taken up that bill, and Republican senators have downplayed the possibility of another stimulus bill before July.

Some advocates say that the increase should not be tied to the length of the health emergency. “I think it’s fair to say that the economic downturn will be longer,” said Lindsey Browning, program director for Medicaid operations for the National Association of Medicaid Directors.

Cut Doctors’ Pay?

States don’t have a lot of leeway to curb Medicaid expenses. In providing the enhanced Medicaid match during the pandemic, Congress barred states from dropping beneficiaries from the rolls or tightening eligibility requirements. They also have to maintain most services and can’t introduce or raise premiums.
States often review beneficiary eligibility, typically by checking for changes in income, which frequently results in people losing coverage. That cannot happen during the pandemic.
Minnesota estimates that retaining enrollees who might otherwise have been dropped will account for 1.2% of the 10.1% increase in Medicaid enrollment officials forecast in the coming year.
States could save money by eliminating some of the optional benefits they now provide under Medicaid, including adult dental care, some behavioral health services, prescription drugs, and physical, occupational and speech therapies.
States are reluctant to push their most potent cost-reduction lever: reducing the reimbursement rates paid to Medicaid providers. A Kaiser Family Foundation analysis in 2016 found that nationwide, reimbursements for primary care services in Medicaid were more than a third lower than in Medicare, the public health plan for seniors. Commercial insurers generally pay more than either public plan.
Organizations representing health care providers and advocating for low-income populations have long argued that low Medicaid reimbursement rates discourage doctors from seeing Medicaid beneficiaries, limiting the options available to enrollees.

Further cuts would be disastrous for Medicaid providers, said Shawn Martin, incoming CEO of the Academy of Family Physicians. “We’re really, really worried without being all-out panicked.”
Although Congress in March authorized $100 billion to keep health care providers afloat during the crisis, most of it has gone to hospitals, doctors and other medical providers with high volumes of Medicare patients.
That’s left out many Medicaid providers, even as many are seeing fewer patients, who fear becoming infected while seeking medical care. Last week, CMS announced it would direct $15 billion of that money to providers in Medicaid and its sister program, the Children’s Health Insurance Program.
Dr. William Cooke, a family practice doctor in rural southern Indiana, said lower Medicaid reimbursement rates would cause more doctors to limit the number of Medicaid patients they see or stop seeing them altogether. Already, too few providers accept Medicaid patients, he said.
But reductions in reimbursements are exactly what some doctors are expecting. “We know that as we add enrollees, there will be cuts,” said Dr. Beverly Jordan, a family practice doctor in Enterprise, Alabama, who cares for Medicaid patients. “There are some limits in what they can cut but we are not one of those limitations.”
Melanie Cleveland, spokesperson for the Alabama Medicaid agency, said last week, “At this time we are not planning to reduce reimbursement rates; however, the agency will continue to monitor the full impact of COVID-19 on the state’s Medicaid program.”
Reducing reimbursements is not something North Carolina is considering right now, said Richard of that state’s Medicaid agency. “To pile on with a rate reduction now would just be bad policy at a time when the health system is already fragile.”
Like other states, he said, North Carolina is banking on additional federal help.
https://www.pewtrusts.org/en/research-and-analysis/blogs/stateline/2020/06/16/medicaid-rolls-surge-adding-to-budget-woes

Video game approved as prescription-only ADHD treatment: FDA

EndeavorRx demonstrates the healing power of video games.

A phone game a day keeps the doctor away.
That’s right, the US Food and Drug Administration gave the green light Monday to the first-ever video-game based therapy for attention deficit hyperactivity disorder (ADHD). The video game, dubbed “EndeavorRx,” can now be prescribed to kids aged 8 to 12 who suffer with certain kinds of ADHD, a mood disorder marked by trouble paying attention and controlling behavior that affects nearly 4 million children, according to the Centers for Disease Control and Prevention.
“The EndeavorRx device offers a non-drug option for improving symptoms associated with ADHD in children,” Jeffrey Shuren, director of the FDA’s Center for Devices and Radiological Health, said in a statement. The pixelated pharmaceutical, created by Akili, is even billed on the site as a “first-of-its-kind attention treatment for children with ADHD . . . delivered through a captivating video game experience.”
The “EndeavorRx” medical designation came after the FDA reviewed five clinical studies on more than 600 children that demonstrated that it was an effective form of ADHD treatment. Indeed, over 30% of test subjects “no longer had a measurable attention deficit on at least one measure of objective attention” after playing the virtual obstacle course simulator for just 25 minutes a day, five days a week for four weeks, per the study published in the Lancet.
Not only that, but the benefits of the prescription-only video game therapy reportedly lasted for a month afterward, while side effects were limited to “frustration, headache, dizziness, emotional reaction, and aggression” — which are apparently the norm for hardcore gamers.

However, the study doesn’t give Xbox addicts carte-blanche to glue themselves to their screens all day. The FDA statement specifies that the digital remedy “is intended for use as part of a therapeutic program that may include clinician-directed therapy, medication, and/or educational programs.”
Still, EndeavorRx, which can be downloaded as a mobile device application, “is an important example of the growing field of digital therapy and digital therapeutics,” Shuren says.
“We’re proud to make history today with FDA’s decision,” said Akili CEO Eddie Martucci in a press release from the gaming firm, reports CNN. 
This isn’t the first time a video game has been touted as an alternative form of medicine. One UK study found that the phone game Sea Hero Quest can detect Alzheimer’s symptoms while other research shows that Candy Crush could potentially boost brain function.
Conversely, other studies demonstrate that certain pixelated pursuits could heighten the risk of dementia and schizophrenia.
https://nypost.com/2020/06/16/video-game-approved-as-prescription-only-adhd-treatment-fda/

Miami pauses reopening as Florida’s new coronavirus cases rise

Miami has put the brakes on moving into the next phase of reopening because of concerns over rising coronavirus cases, the mayor said.
“We’re not going backwards as of yet, but we’re kind of sounding the alarm,” Miami Mayor Francis Suarez said Monday, NBC6 reported.
Suarez said there are “major concerns” about entering phase three because of rising local cases, partially among people ages 18 to 35.
“We’re going to be put in a situation where we’re going to have to make tough choices and that’s not where we want to be,” Suarez said. “Now is not a time to let your guard down.”
The city currently is under phase two of reopening, which allowed bars, movie theaters and tattoo parlors to resume business with restrictions.
Suarez said there were no current plans for the city to return to stay-at-home orders, despite the uptick in cases.
“We understand that these are some historically difficult times right now, where 42 million people are unemployed, and implementing a stay-at-home order is something that while effective, and we saw how effective it was mathematically, it’s a measure of last resort,” Suarez said.
The Sunshine State reported two consecutive days of more than 2,000 new daily cases over the weekend as additional beaches were reopened.
https://nypost.com/2020/06/16/miami-pauses-reopening-as-floridas-new-coronavirus-cases-rise/

Ready to see your doctor but scared to go? Here are some guidelines

What happens when a pandemic brings in-person visits with your doctor to a grinding halt? While the world grappled with managing COVID-19, millions found routine appointments—for vaccines, pap smears, mammograms, colonoscopies or other chronic disease management—deferred or canceled. Now, as U.S. coronavirus incidence appears to level offand states begin to reopen, many are wondering when they can safely return to their doctor’s office. This is especially important as it pertains to childhood vaccinations, as vaccination rates declined across the U.S. throughout this first surge of the pandemic.

It’s clear that the coronavirus is here to stay, at least for a while. Epidemiologists predict another surge this fall, with more over the next two years. But during that time, people will still need to see their doctors for preventive care. As physicians specializing in family medicine, we can offer some suggestions to make that safer.
Optimize use of technology
During the pandemic, technology has already begun to play an increasingly critical role in health care. Telehealth – meeting up with your doctor via telephone or online—obviously eliminates the risk for COVID exposure and transmission.
But telehealth won’t work unless patients have the tools to optimize these visits. First, everyone must have affordable access to internet with video capabilities. Next, we must guarantee first dollar insurance coverage for scales, glucometers, and home blood pressure monitors; this means insurance companies pay for these devices without patients first meeting a deductible. Not only will these steps keep patients healthy and avoid the coronavirus, but ultimately, they will reduce overall health care costs.
Population health management
Within the U.S. health care system, population health management – the process of improving health outcomes through better care coordination and health care finance models—has historically been quite poor. But it doesn’t have to be that way.
There are ways to make it better. Providers can use electronic medical records to generate lists of patients due for vaccines, cancer screenings and chronic disease management—which covers conditions like asthma, diabetes, hypertension, congestive heart failure and chronic obstructive pulmonary disease. Reviewing clinic-wide data can also help providers identify where to dedicate more time and resources. For example, should the data show lagging vaccine rates, the clinic could make vaccinations its focus for the next month.
Create a safe in-clinic experience
As useful as the new technology is, it won’t completely eliminate the need for in-person visits. Because of limited COVID-19 testing in the U.S., as well as the limited accuracy of those tests, it is not possible to truly know who has COVID-19 and who does not. Fortunately, patients and staff can still be protected from exposure while delivering high-quality care in a warm and welcoming environment. Primary care physicians may want to consider the following:

• Continue rigorous infection control. Physicians have focused on hand-washing and proper cleaning of exam rooms and equipment for decades. All that preparation is paying off.
• Screen and triage. Providers may consider combining in-person and telehealth visits. In-person visits may include well-child exams, pap smears, colposcopies (for abnormal pap smears), mammograms, colonoscopies or other cancer screenings; the remainder of the visit would be conducted via telehealth. Or should a patient be sick with a cold or virus, providers may manage symptoms via telehealth to limit exposure to staff and other in-person patients.
• Manage patient volume and flow carefully. As clinics reopen, maintaining physical distancing remains crucial. This means limiting the number of patients in the waiting room, reducing the number of visitors who accompany patients and streamlining how visits are conducted to reduce touch points.
• Protect the vulnerable. The oldest and sickest patients, along with those whose immune systems are suppressed, should generally be scheduled early in the morning. That’s when waiting and exam rooms are the cleanest and with the least risk for COVID-19 exposure.

Patients will want to remember:

• Be flexible. New technology, like telehealth, can be unsettling. Try a videoconferencing visit to see if this helps with feeling “seen.” Register for the clinical practice portal so you can communicate with your doctor via email.
• Be proactive. If you are due for vaccines, cancer screenings or chronic disease management, call your doctor to inquire if an in-person or telehealth visit is indicated.
• Help keep the clinical space safe. If you have a fever or feel ill, notify your doctor beforehand. Be cooperative with the temperature check and screenings at clinic entrances, and wear a mask or face covering at all times. Dispose of used tissues in proper receptacles, and clean your hands.

It could be a challenging fall and winter. As the U.S. enters this initial lull, we must maximize vaccinations, screenings and chronic disease management ahead of time. We can harness the lessons learned from the pandemic’s first wave, including a robust demonstration of the critical value of primary care physicians in maintaining a community’s health. The foreseeable future holds great uncertainty, but this is abundantly clear: The adaptability of health care providers and patients alike will be key to navigating the complex intersections of preventive care, chronic disease management and COVID-19 transmission.
https://medicalxpress.com/news/2020-06-ready-doctor-guidelines.html

FDA OKs Merck’s Keytruda for second application based on biomarker

The FDA approves Merck’s (NYSE:MRK) Keytruda (pembrolizumab) to treat adult and pediatric patients with unresectable or metastatic solid tumors with tissue tumor mutational burden-high (TMB-H) ≥10 mutations/megabase, as determined by an FDA-approved test, who have progressed following prior treatment and who have no satisfactory alternative treatment options.

In May 2017, the agency approved the PD-1 inhibitor for adult and pediatric patients with solid tumors identified with a biomarker called microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

https://seekingalpha.com/news/3583617-fda-oks-mercks-keytruda-for-second-application-based-on-biomarker