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Saturday, July 20, 2019

How diabetes leads to vascular disease

A team of UC Davis Health scientists and physicians has identified a cellular connection between diabetes and one of its major complications — blood vessel narrowing that increases risks of several serious health conditions, including heart disease and stroke.
The authors hope their work leads to diabetes treatments — beyond blood sugar monitoring and insulin therapy — that target the molecular source of its damaging effects on the vascular system.
The same team previously found that high blood glucose, the hallmark symptom of diabetes, activates an enzyme known as protein kinase A (PKA), which increases calcium channel activity and constricts blood vessels.
“This was a surprise, since PKA is typically associated with blood vessel widening and wasn’t really on our radar,” said senior author Manuel Navedo, professor of pharmacology at UC Davis Health. “We wanted to understand the molecular processes that created this opposite reaction.”
For the new study, published in The Journal of Clinical Investigation, the Navedo lab team conducted a series of experiments on the effects of high glucose on cerebral blood vessels and arterial cells that control blood flow. The tests were conducted on a unique genetically modified mouse and two mouse models of diabetes that were developed at UC Davis for studies of cardiovascular health.
The researchers focused on the relationship between PKA and adenylyl cyclase (AC) — an enzyme involved in cyclic AMP (cAMP) production, a cellular messenger with a critical role in vascular cell function. Their results showed that one AC in particular — AC5 — mediated cAMP and PKA activation, triggering increased calcium channel activity and blood vessel narrowing. They also found that AC5 was essential for blood-vessel constriction during diabetes.
The team now hopes to test the effects of the AC5 chain reaction in high-glucose conditions in human cells. This step could confirm it as a treatment target for reducing the vascular complications of diabetes, which can include eye, kidney, cerebral, gastrointestinal and cardiovascular disease.
“We see every day in our clinics the devastating impact of diabetes on the health and lives of our patients,” said co-author Nipavan Chiamvimonvat, the Roger Tatarian Endowed Professor in Cardiovascular Medicine at UC Davis Health. “Our work brings into much clearer focus how high glucose can damage the vascular system and gives us a new target for blocking its effects.”
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The study, “Adenylyl Cyclase 5-generated cAMP Controls Cerebral Vascular Reactivity During Diabetic Hyperglycemia,” is available online.
In addition to Navedo and Chiamvimonat, study authors (all of UC Davis Health) were Arsalan Syed, Gopireddy Reddy, Debapriya Ghosh, Maria Paz Prada, Matthew Nystoriak, Stefano Morotti, Eleonora Grandi, Padmini Sirish, Johannes Hell, Luis Santana, Yang Xiang and Madeline Nieves-CintrĂ³n.
This work was funded by the National Institutes of Health (grants R01HL098200, R01HL121059, T32HL086350, T32GM099608, R01HL131517, R01HL142710, K99HL138160, R01NS078792, R01AG055357, R01HL127764 and R01HL112413), American Heart Association, UC Davis School of Medicine and UC Davis Academic Federation.

U.S. overdose deaths post annual drop for first time in two decades

U.S. overdose deaths dropped last year for the first time in nearly two decades, the Centers for Disease Control and Prevention said on Wednesday, in a sign that a nationwide epidemic of drug-related deaths is abating.
About 68,500 Americans died of a drug overdose in 2018, compared with about 72,000 the year prior, a 5% decrease, according to the CDC’s provisional data.
The drop marks the first time that the number of overdose-related deaths has fallen since 1999.
Some physicians describe the decrease as “encouraging,” but not worthy of celebrating.
“Overdose deaths are only one method to measure the epidemic,” said Anna Lembke, professor of psychiatry and behavioral sciences at Stanford University and author of “Drug Dealer, MD – How Doctors Were Duped, Patients Got Hooked, and Why It’s So Hard to Stop.”
Lembke said the number of people battling substance abuse was another crucial metric in evaluating progress in fighting the epidemic. That data is not included in the CDC’s figures.
But the number of people with a substance use disorder has also dropped. An estimated 19.7 million American adults battled a substance use disorder in 2017, compared with 20.1 million in 2016, according to the National Survey on Drug Use and Health.
While the number of overdose deaths fell as a whole, the CDC data shows that deaths involving cocaine and psychostimulants like methamphetamine and MDMA have actually risen from 2017 to 2018.

California settles decades-long lawsuit over lead paint, but outcome is mixed

When Californian counties and cities first sued paint makers in 2000, they wanted the companies to pay billions to remove dangerous old lead paint from hundreds of thousands of homes.
After a 19-year legal struggle, they have finally succeeded in getting the companies to fund a remediation program, albeit on a much smaller scale. Sherwin-Williams, ConAgra Grocery Products Co. and NL Industries have agreed to a $305 million settlement, according to a filing in Santa Clara County Superior Court in California on Wednesday.
The resolution marks a rare success for a public nuisance claim, under which counties and municipalities can sue corporations for past activities – including those conducted decades ago – they say have harmed communities.
High-profile public nuisance claims have proliferated in recent years in the United States as local governments try to use the courts to make corporations pay for societal ills like lead poisoning, the opioid addiction crisis and climate change.
Yet the glacial pace and complex twists in California’s lead paint case highlight just how difficult it can be to use the public nuisance strategy against corporations, even in a state whose courts are particularly consumer friendly.
A trial judgment in 2014 ordered the paint companies to pay $1.15 billion, but an appeals court decision led to the amount being slashed by more than half in 2017. Once the companies had exhausted the appeals process, they threatened to sue individual property owners who received help cleaning up their properties, by claiming they had failed to properly maintain their housing.
“This landmark settlement will allow thousands of homes to be remediated, and as a result current and future generations of California children will no longer face the threat of lead poisoning,” said James Williams, County Counsel for Santa Clara County, where the lawsuit was first filed.
“We’re pleased that we’ve been able to hold lead paint manufacturers accountable and responsible,” he said.
The defendant paint companies did not admit any wrongdoing under the settlement, and Sherwin-Williams and ConAgra welcomed the end of the legal battle.
“Sherwin-Williams is pleased to have reached an agreement to resolve this litigation, and it will continue to vigorously and aggressively defend against any similar current or future litigation,” the company said in a written statement.

BITTERSWEET VICTORY

The number of U.S. children poisoned by lead has fallen sharply since the United States banned the toxic metal from residential paint and gasoline, during the 1970s and 80s.
But for California districts like Oakland and Los Angeles, where childhood lead poisoning still exacts a heavy toll, the outcome of the legal struggle is bittersweet.
In the decades it took the local governments to prevail, tens of thousands more children in California have been exposed to dangerous levels of lead, state public health data shows.
In Alameda County, for example, some zip codes have lead poisoning rates higher than those found in Flint, Michigan, at the peak of that city’s water contamination crisis (reut.rs/2XUaLWq).
County inspectors found dangerous paint dust in the East Oakland home of 3-year-old Alexander Avila, who tested with lead levels more than five times the elevated standard of five micrograms per deciliter set by the Centers for Disease Control and Prevention (CDC).
When a reporter visited the nearly century-old home last month, Alexander was a ball of hyperactive energy. His mother Stephanie, 26, said he is able to speak few words and has trouble engaging with other kids at preschool. She fears his past lead exposure will affect him for life.
“People just don’t know what’s in their own houses, or the dangers their kids can face,” she said.
A county program helped fix lead paint hazards at the home, but public funds are scarce to repair housing before it can harm children.
In nearby Hayward, California, another predominantly working class city in the San Francisco Bay Area, five members of the Mariscal family, including two children, were poisoned by lead paint at their old home during 2017 and 2018, county health data and inspection reports show.

Three year-old Isaac, who tested at levels more than twice the CDC’s elevated threshold, suffered anemia – a common symptom of lead exposure – and, like Alexander, has also had speech problems.
The CDC says there is no safe level of lead in children’s blood. At least 4 million U.S. children remain at risk of exposure from chipping paint or lead dust in their housing, the agency says. Lead paint doesn’t pose an immediate danger unless it is deteriorating.
Many of the 10 counties and cities that brought the lawsuit have tens of thousands, or hundreds of thousands, of older housing units. Neutralizing lead paint hazards in a single home can cost thousands of dollars, so the settlement money may only cover the clean-up of a fraction of homes that need work.
“The litigation money can only go so far, but it’s a start,” Larry Brooks, director of Alameda County’s lead poisoning prevention program, said in an interview last month.
More than 6,300 children have been exposed to elevated lead levels in his county since 2000, when the litigation began, according to county health data.
Although the United States banned lead paint sales in 1978, most old housing still contains it, and thousands of U.S. neighborhoods still have alarming poisoning rates, Reuters found in a series of articles in 2017. (reut.rs/2MfnIGn)

NEW LEGAL PRECEDENT?

California jurisdictions are the first to have a public nuisance verdict upheld against former lead paint manufacturers. Several lawsuits in other states have failed since 2000, from Illinois to Missouri and Rhode Island.
The California case may set a new legal precedent for seeking remediation. Legal scholars say it could encourage new lawsuits against paint companies, and Californian local governments report receiving inquiries from counterparts in other areas of the country interested in bringing their own nuisance claims.
In product liability lawsuits, attorneys must prove harm to individual plaintiffs. In public nuisance cases, the plaintiffs don’t have to prove harm to specific people. Instead, they can claim that the defendants’ activities impeded broad community rights, such as the public right to enjoy property.
In California, the plaintiffs argued the companies were responsible for creating a public health threat and knew of the toxic dangers of lead paint when they marketed it, without properly warning consumers, for decades before the U.S. government banned its use in homes.
The paint companies argued that they stopped marketing lead paint products once risks became known. They contended that home owners were responsible for preventing any poisoning hazards in their living spaces.
Santa Clara County recently filed another public nuisance case against opioid pill manufacturers, and similar cases are popping up with increasing frequency nationwide.
Many of these suits share a common goal: making big business pay to fix high-cost societal burdens that their profit-making activities may have left behind.
Corporate defense attorneys worry that more wins for local governments under the public nuisance doctrine could saddle businesses with huge and unpredictable liabilities, in some cases for decades-old actions they thought were safe at the time.

WHY SETTLE NOW?

The California local governments and the companies settled after a marathon legal battle that saw both sides suffer setbacks.
Beyond seeing the earlier $1.15 billion judgment sharply cut back by an appeals decision, the plaintiffs were concerned with court-imposed restrictions on how the money could be used.
For instance, the terms had limited the remediation program to housing built before 1951, and only indoor paint hazards could be fixed. The local governments also faced a tight, four-year window to complete the program, after which any unspent funds would be returned to the paint companies.
As recently as January, court filings from the case show, lawyers for the paint companies vowed to sue California property owners who sought to use the remediation funds. Counties were concerned the mere specter of these suits would have a chilling effect on the remediation program, which will rely on housing owners’ voluntary participation.
It was an unusually bold move, legal scholars say.
“Talking about suing property owners is an aggressive tactic,” said Bob Rabin, a tort law specialist at Stanford University.

“I can’t think of another public nuisance judgment where defendants turned around and said recipients of the damages should be disqualified because they are to blame,” he said.
With the settlement in place, these threats and court-imposed limitations on how the money can be spent will now be lifted.
Paint companies have agreed not to target property owners with lawsuits, cities and counties can take as much time as they need fixing homes, and housing built through the 1970s – when lead paint was still being sold – are also eligible for help, including on exterior walls.

Puerto Rico faces tougher scrutiny over federal Medicaid funding

U.S. lawmakers on Wednesday called for heightened scrutiny of Puerto Rico’s Medicaid program as the bankrupt territory seeks increased federal healthcare funding while it deals with repercussions from a government corruption scandal.
The House Committee on Energy and Commerce agreed to several accountability measures linked to a $12 billion funding boost over four years for the low-income healthcare program in Puerto Rico. A group of Republican U.S. senators, meanwhile, sought information on whether any safeguards are in place to deter misuse of the island’s federal Medicaid dollars.
Last week, Angela Avila-Marrero, former executive director of Puerto Rico’s Health Insurance Administration, pleaded not guilty to conspiracy and other charges related to her role in an alleged scheme to steal federal Medicaid dollars through a corrupt bidding process with private contractors. The charges were part of a 32-count indictment brought by U.S. law enforcement officials against six people in a government corruption probe.
The House committee adopted an amendment proposed by U.S. Representative Greg Walden, an Oregon Republican, that added provisions for federal audits and probes of contracts related to Puerto Rico’s Medicaid program, as well as a quarterly reporting requirement on how much of the money was spent.

“The legislation we are moving forward with today ensures that Puerto Rico Medicaid beneficiaries get the care they need while improving transparency, accountability, and integrity of the program that will help prevent this type of fraudulent activity from happening again,” Walden said in a statement.
U.S. Senate Finance Committee Chairman Chuck Grassley and other Republican senators requested detailed information on Puerto Rico’s Medicaid funding levels and measures related to transparency and accountability from the U.S. Department of Health and Human Services (HHS).
“The recent and unfortunate allegations concerning misuse of public funds in Puerto Rico’s health system, along with an ongoing lack of transparency in the government of Puerto Rico, raises important questions as Congress once again faces decisions on federal Medicaid funding for Puerto Rico,” the senators said in a letter to HHS Secretary Alex Azar.
Puerto Rico Governor Ricardo Rossello, who has resisted calls for his resignation over government corruption and controversial leaked group text messages, said on Tuesday that

he welcomes greater federal oversight as long as it does not slow the flow of federal money to the island.
Protests against the governor have erupted daily in Puerto Rico, which filed a form of bankruptcy in 2017.

Recent cannabis use tied to memory deficits, slowed mental processing

People who have recently used cannabis may be more likely to experience memory deficits or difficulties with cognitive function than those who don’t use the drug, a recent study suggests.
Researchers interviewed 1,121 adults 22 to 36 years old about any history of drug use and also tested participants’ urine for evidence of cannabis and other drugs. Then, participants completed neuropsychological evaluations, which assess things like memory, attention, processing speed, executive function and motor skills.
A total of 135 people, or 12%, had positive urine screens for tetrahydrocannabinol (THC), the chemical associated with marijuana’s psychoactive effects, suggesting they had used cannabis within the past week. People who tested positive for THC scored worse on tests of so-called episodic memory and of mental processing speed, the study found. None of the other brain functions showed a difference.
“This has implications for all cannabis users, but especially medical cannabis users who may be consuming daily or multiple times daily for symptom management,” said James MacKillop, senior author of the study and a researcher at McMaster University in Hamilton, Ontario.
“These individuals would likely have THC chronically circulating in their system and, in turn, cognitive consequences,” MacKillop said by email. “This applies to heavy recreational users who are consuming daily too of course.”
The findings also suggest that people in high-stakes professions that require split-second decisions like police and air traffic controllers might be impaired on the job even when they limit cannabis use to their time off, MacKillop said.
“Some cognitive consequences are present as long as THC is still detectable in urine,” MacKillop said. “Although the effects were very small, any (reduction) in performance may have significant consequences in a critical situation.”
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Cannabis is one of the most commonly used psychoactive drugs in the world; an estimated 2.5% of the world’s population has reported cannabis use in the past year, the study team notes in the Journal of Psychiatry and Neuroscience.
In the study, 482 participants, or 43%, had never used cannabis. Another 317 people, or 28%, had only tried cannabis up to 10 times, while 139 people, or 12%, used cannabis between 11 and 100 times.
A total of 109 people, or 9.7%, had current or previous cannabis use disorder, which includes chronic use of the drug. This condition was associated with lower fluid intelligence and cognitive functioning.
One limitation of the study is that the differences in neuropsychological performance associated with cannabis use were small, even though they were statistically meaningful.
Still, cannabis users might have short-term impairments that aren’t easy to spot but could be dangerous in certain situations, said Mary-Ann Fitzcharles, a researcher at McGill University, in Montreal, who wasn’t involved in the study. That’s because the deficits aren’t verbal; they relate more to visual and spatial skills.
“Episodic memory and processing speed were assessed by visual tests, rather than written/verbal assessment,” Fitzcharles said by email.

“The impairment is therefore assessed as being in the visuospatial domain which is not easily perceived to be an impairment by an individual,” Fitzcharles added. “For example, persons may believe that they are perfectly competent to drive a car, operate a crane, or respond quickly in an unexpected situation after cannabis use, but in fact are impaired and at risk.”
SOURCE: bit.ly/2JPd6gq Journal of Psychiatry and Neuroscience, online June 27, 2019.

Friday, July 19, 2019

Replace The Cadillac Plan Tax, Don’t Repeal It

If there is one thing that tends to unite economists across the political spectrum it’s the view that the government should not give unlimited tax subsidies to employer-provided health insurance. Yet that is what we have been doing
Partially as a remedy for that problem, Obamacare imposed a (yet to take effect) tax on expensive health insurance plans. But this week the House voted to repeal the tax and the Senate will likely follow suit. Here is why that matters.
When employers pay wages, that income is subject to income and payroll taxes. But if they buy health insurance for their employees instead, those amounts go completely untaxed. For the average employee, that means the employer can spend 25% more on health insurance benefits than would be available in the form of take-home pay. High-income employees in high tax states can have 50% more in health insurance than the take-home pay they could otherwise have.
There are several things wrong with this policy. First, it is highly regressive. Families in the top fifth of the income distribution get six times the tax relief for health care and health insurance expenses as families in the bottom fifth. Second, it encourages wasteful consumption. An employee in the 50% tax bracket, for example, has an incentive to buy health insurance until it is worth only 50 cents on the dollar. In fact, this is the principal reason the United Sates tends to overspend on health care.
Finally, the policy keeps families from achieving the level of well-being they otherwise could enjoy. They end up allocating too much of their consumption to health care and too little to other goods and services. Their overall consumption is skewed because they don’t get to choose among consumption alternatives on a level playing field.
So, what should be done? The Obama administration opted for a “Cadillac plan” tax. The idea was to allow employer-provided health insurance to be tax-free only up to a certain point. Beyond that, spending on the most expensive plans would be subject to a tax roughly equal to the marginal tax rate of high-income taxpayers. Nominally, employers pay the tax, but economists uniformly believe the real burden falls on the employees.
This tax was enacted as part of Obamacare. But its implementation has already been delayed twice. Currently it is scheduled to go into effect in 2022 and the tax will kick in once the cost of health insurance reaches $11,200 for an individual and $30,100 for a family. The Kaiser Foundation estimates that one out of every five employers offering health benefits will be affected. And because the threshold limits are not indexed to inflation, the number of those affected will rise over time – reaching more than one-third of employers by 2030. By that time, the tax could hit almost half of employers if contributions to Flexible Spending Accounts are included in the calculation.
Of course, once they hit the threshold, employers and their employees will have the option to buy less health insurance and receive taxable wages instead. But either way, the federal government will get more money. The Congressional Budget Office estimates that removing the Obamacare tax will cost the government almost $200 billion over the next ten years.
There are three problems with the Cadillac plan tax. First, it is a very crude way of solving the distortions that economists complain about – one that is very limited in its effectiveness. For families whose insurance costs less than $30,100 there is no effect at all. For families whose insurance costs a bit more than $30,100 the tax only affects the last few dollars of spending – completely missing the vast bulk of the expenditure.
Second, once the tax kicks in, it imposes a much higher rate on health insurance than average-income workers pay on their wages. So, instead of creating a level playing field, the tax will tilt the choice toward take-home pay and away from health insurance for most workers.
The final problem is political. The real purpose of the tax appears to be to get revenue to pay for Obamacare’s expansion of Medicaid and subsidies to low-income buyers of individual health insurance. But why should middle-income workers with health insurance bear a special burden to solve a social problem that affects all of us? No wonder organized labor has opposed the tax cap from the git-go.
Congress should consider a much better alternative. Instead of a Cadillac plan tax, we should offer employers and their employees the option of a dollar-for-dollar tax credit up to the amount of the tax subsidy they have been getting through the tax exclusion. As I have explained elsewhere, this would solve the problem economists complain about, put health insurance and take-home pay on a level playing field at the margin, and greatly reduce the incentives we all have to over-spend on health care.

Human Vaccine Created Solely by Artificial Intelligence

For the first time ever, a human drug has been created entirely by artificial intelligence (AI). This news comes from a team at Flinders University in Australia, who claims to have created an enhanced influenza vaccine using an AI program known Search Algorithm for Ligands (SAM). Though computers have been used to make drugs before, this was the first time it was done independently by an AI system.
The researchers described this drug as a flu vaccine with an added compound that better stimulates the human immune system. This addition causes more antibodies to be formed against the flu virus than with the traditional vaccination, increasing the vaccine’s efficacy.
Nikolai Petrovsky, Professor at Flinders University and leader of the work noted that the AI essentially searched for all possible compounds to find a working drug. To the best of his knowledge, this was the first flu vaccine to be created with AI that had advanced to human trials.
“We had to teach the AI program on a set of compounds that are known to activate the human immune system, and a set of compounds that don’t work,” he explained. “The job of the AI was then to work out for itself what distinguished a drug that worked from one that doesn’t. We then developed another program, called the synthetic chemist which generated trillions of different chemical compounds that we then fed to SAM so that it could sift through all of these to find candidates that it thought might be good human immune drugs.” Petrovsky also serves as the Research Director at Vaxine, an Australian biotechnology company.
Once SAM had identified some potential treatments, the researchers recreated them in a lab and tested their effects on human blood cells. Petrovsky noted that these tests showed that SAM not only chose good treatment candidates but that it actually found compounds that outperformed existing therapies. These treatments that SAM had created were then developed and tested in animals to “confirm their ability to boost influenza vaccine effectiveness.”
This use of AI has the potential to expedite the treatment discovery process by decades according to Petrovsky and can save hundreds of millions in spending as well. The team’s research is underway with 12-month clinical trials being conducted in the US. These trials are funded by the US National Institute of Allergy and Infectious Diseases, which is a part of the National Institutes of Health. The study will aim to analyze roughly 240 volunteers to see how they respond to the vaccine.
“We already know from animal testing that the vaccine is highly protective against flu, outperforming the existing vaccines,” Petrovsky said. “Now we just need to confirm this in humans.”
This use of AI not only facilitates the drug discovery process but can find more optimal treatments than humans can as well. Using neural networks that mimic the human brain, this technology can process much more information than the human brain.
Petrovsky feels that AI could become strongly integrated into the drug developmentprocess within the next 20 years. Within the next three years, he believes that his team’s vaccine could be available to the general public.
“Given the need and the pull to provide a better flu vaccine this is not something that’s going to sit on the shelf for the next 10 years,” he concluded.
Exponential Medicine@ExponentialMed
Australian researchers have developed a new  believed to be the first in the world to be designed by  (via @BIAUShttps://www.businessinsider.com.au/australian-researchers-just-released-the-worlds-first-ai-developed-vaccine-and-it-could-prevent-another-horror-flu-season-2019-7 

Australian researchers just released the world’s first AI-developed vaccine and it could prevent…

A team at Flinders University in South Australia has developed a new vaccine believed to be the first human drug in the world to be completely designed by artificial intelligence (AI).
businessinsider.com.au