Posts Tagged ‘alcohol’

Researchers at the University of Southern California looked at more than 17,000 brain scans to see if daily smoking and drinking advanced brain age. The study found that every gram of alcohol consumed a day aged the brain by 11 days. Smoking a pack of cigarettes a day for a year aged the brain by 11 days. It is one of the largest studies ever done on brain aging and alcohol, making the findings quite robust.

by Shira Feder

Over time, drinking a little bit more alcohol than recommended could accelerate the brain’s aging process, according to a new study.

Though previous studies have found the same, most were tentative findings based on small groups of people or large groups of mice.

The new study, from researchers at the University of Southern California, offers a more robust estimate, reached by examining 17,308 human brain scans from the UK Biobank — one of the biggest sample sizes ever seen.

The team found that for every gram of alcohol consumed a day, the brain aged 0.02 years — or, seven-and-a-half days. (The average can of beer or small glass of wine contains 14 grams of alcohol). People who reported drinking every day had brains which were, on average, 0.4 years older than people who didn’t drink daily.

Smoking had even stronger effect: the team found that those who smoke a pack of cigarettes a day for a year age their brains by 0.03 years (11 days).

The researchers took 30% of the brain scans in their study, all from people aged 45 to 81, and used them to train a computer, which scanned each brain to see how old or young they looked.

They then compared the computer’s estimates of each brain’s age with the person’s real age, and their self-reports of how much alcohol and tobacco they consume daily, in order to see if consuming alcohol or tobacco regularly aged the brain.

Comparing those results with the other 70% of their brain scans, they found that the more you drank and smoke, the more likely you were to have a brain aged beyond your actual age.

Lucina Uddin, director of the Cognitive and Behavioral Neuroscience Division at the University of Miami, who was not involved in the study, told Insider that the use of an algorithm is what makes this study’s findings so compelling.

“Back in the day we’d scan 20 or 40 subjects, if we were lucky, for neuroimaging studies,” Uddin said. “Now we’re getting bigger numbers like 200 or 300 individuals. But this is the biggest sample we’ve ever seen.”

Because the sample size is so big, scientists can ask questions that apply to the entire population, rather than just a few people.

Brain age is essentially a measure of brain health, says Uddin, who was not surprised by the study’s findings.

“Looking at brain age is a way of checking how well you’ve been taking care of your brain,” she told Insider. “My age is 40, but does my brain look more like a 50-year-old brain or a 60-year-old brain? Do you look younger than your age or older than your age?”

The lead author of the study, Arthur Toga, told Inverse: “The 0.4 years of difference was statistically significant. We suggest that daily or almost daily alcohol consumption can be detrimental to the brain.”

However, many super-agers — people who live well beyond 100 years old, and often appear resistant to the dementia gene — report drinking alcohol now and then.

What’s more, a recent Harvard study found drinking in moderation can have some benefits, particularly for the heart.

Dr. Qi Sun, a co-author of the Harvard study, previously told Insider: “If you drink alcohol, it’s very important that you drink responsibly, not in excess, and that you also focus on eating a healthy diet, maintaining a healthy body weight, not smoking, and exercising. If you don’t drink you don’t need to start drinking.”

https://www.insider.com/alcohol-every-day-ages-your-brain-quicker-17000-brain-scans-2020-1


Preliminary findings from a clinical trial of heavy drinkers suggest that the drug can weaken certain memories tied to the reward of imbibing, although the mechanisms aren’t fully clear.

by CATHERINE OFFORD

he anesthetic drug ketamine could be used to rewire heavy drinkers’ memories and help them cut down on alcohol consumption, according to a study published yesterday (November 26) in Nature Communications. In a clinical trial of people who reported consuming around 590 grams of alcohol—equivalent to nearly two cases of beer—per week on average, researchers found that a procedure that involved administering the drug while people were thinking about drinking durably reduced consumption.

While it’s not clear how the method works at a neurological level, the study represents “a really exciting development,” Amy Milton, a behavioral neuroscientist at the University of Cambridge who was not involved in the work, tells STAT. She adds that the findings mark “the first time it’s been shown in a clinical population that this can be effective.”

The study was designed to manipulate the brain’s retrieval and stabilization of memories—in this case, those linking the sight and thoughts of alcohol to the reward of drinking it, study coauthor Ravi Das, a psychopharmacologist at University College London, tells Science News. “We’re trying to break down those memories to stop that process from happening.”

To do that, the team asked 30 of the participants to look at a glass of beer, followed by a sequence of images of alcoholic and non-alcoholic drinks. On the first day of tests, the session ended with participants being invited to drink the beer. On the second day, after viewing the beer and images, the screen cut off, and instead of drinking the beer, participants were given a shot of ketamine.

Among various functions, ketamine blocks NMDA receptors—key proteins in the brain’s reward pathways—so the researchers hypothesized that administering the drug during memory retrieval would help weaken participants’ associations between the sight or contemplation of alcohol and the reward of drinking it. Their results somewhat support that hypothesis. Nine months following the several-day trial, the volunteers reported cutting their drinking back by half.

“To actually get changes in [participants’] behavior when they go home and they’re not in the lab is a big deal,” Mary Torregrossa, a neuroscientist at the University of Pittsburgh who was not involved in the work, tells Science. But she notes that it’s not clear whether it was the ketamine or some other part of the procedure that led to the effect.

Another 60 participants, split into two control groups, received slightly different procedures that involved either beer or ketamine and still showed, on average, a 35 percent decrease in alcohol consumption after nine months. The participants themselves were recruited to the study through online ads—meaning that the researchers may have selected for people already interested in reducing consumption.

Whatever the mechanisms behind the effect, the results so far suggest the method is worth investigating, David Epstein, an addiction researcher at the National Institute on Drug Abuse, tells Science News. “If a seemingly small one-time experience in a lab produces any effects that are detectable later in real life, the data are probably pointing toward something important.”

Catherine Offord is an associate editor at The Scientist. Email her at cofford@the-scientist.com.

https://www.the-scientist.com/news-opinion/ketamine-could-help-cut-alcohol-consumption-by-rewiring-memory-66792?utm_campaign=TS_DAILY%20NEWSLETTER_2019&utm_source=hs_email&utm_medium=email&utm_content=80070748&_hsenc=p2ANqtz-_mk5jB1Vyqx3xPsKPzk1WcGdxEqSmuirpfpluu4Opm4tMO6n7rXROJrCvQp0yKBw2eCo4R4TZ422Hk6FcfJ7tDWkMpyg&_hsmi=80070748


Microbes can produce so much alcohol that people become drunk—and sustain liver damage—without touching any booze.

by Ed Yong

The man’s troubles began in 2004, when, having moved from China to attend college in Australia, he got really drunk. That would hardly have been a noteworthy event, except that the man hadn’t consumed any alcohol—only fruit juice.

The bizarre incident soon turned into a pattern. About once a month, and out of the blue, he’d become severely inebriated without drinking any alcohol. Over time, the episodes became more severe and more frequent. He lost jobs because people suspected him of being a closet drinker. He was frequently hospitalized. In 2011, he returned to China and his mother cared for him while monitoring him with a Breathalyzer. His blood-alcohol levels, she found, would erratically and inexplicably soar to 10 times the legal limit for driving.

In June 2014, at the age of 27, he was admitted to the intensive-care unit of Chinese PLA General Hospital, in Beijing. At one point, so much alcohol was on his breath that he couldn’t sleep through the night. Another time, he threw up and blacked out after chugging some soda water. A CT scan showed that his liver was damaged, inflamed, and riddled with fatty deposits.

The man was diagnosed with a rare condition aptly known as auto-brewery syndrome, in which microbes in a person’s gut ferment carbohydrates into excessive amounts of alcohol. The earliest cases were documented in Japan in the 1950s, and a few dozen more have been reported since, in people all over the world, and even in children as young as 3. The microbial culprits are usually yeasts—the same fungi used to brew beer and wine—and the condition can often be treated with antifungal drugs.

But those drugs didn’t work on the Chinese patient. Baffled, a team of doctors, led by Jing Yuan from the Capital Institute of Pediatrics, analyzed the man’s stool samples and found that the alcohol in his body was being produced not by yeast, but by bacteria. During his first episode in the hospital, Klebsiella bacteria had bloomed so vigorously that it made up 19 percent of the microbes in his gut, and became 900 times more common than in healthy people.

Klebsiella pneumoniae is extremely common in both soils and human bodies. Though usually harmless, it’s also an opportunistic pathogen that can cause severe infections if given the chance. And while Klebsiella is not known for intoxicating its hosts, Yuan’s team found that the patient had two particular strains that can churn out alcohol. Many gut microbes do this, but at such low levels that their boozy by-products are easily removed by the liver. The Klebsiella strains in Yuan’s patient were exceptions: At one point, they produced so much of the stuff that it was as if the man had knocked back 15 shots of whiskey. “We were surprised that bacteria can produce so much alcohol,” Yuan says.

Auto-brewery syndrome is extreme, but it has similarities to other, milder and more prevalent conditions. For example, people with nonalcoholic fatty liver disease (NAFLD) build up fatty deposits in their liver in the style of heavy drinkers, despite touching little or no alcohol. This condition is very common, affecting 30 to 40 percent of American adults; the causes are still unclear and likely varied. Yuan wondered if Klebsiella might be involved, and when she analyzed 43 Chinese people with NAFLD, she found that 61 percent had the same high-alcohol strains as the man with auto-brewery syndrome. By contrast, just 6 percent of people with a healthy liver carry those strains.

To see if those strains were actually causing fatty livers, the team fed them to mice that had been raised in sterile conditions and lacked microbes of their own. Within two months, the rodents had signs of liver disease, inflammation, and scarring, comparable to mice that had been drinking alcohol itself. The same thing happened if the team transplanted the stool from an NAFLD patient into germ-free mice, but not if they first removed the alcohol-making Klebsiella using a virus—a phage—that specifically kills those strains. Although studies in mice should be treated with caution, Yuan nonetheless suggests that these strains could be an important cause of NAFLD, through the alcohol they produce.

Other researchers have suggested this before. In 2000, Anna Mae Diehl from Johns Hopkins University noticed that obese mice often have alcohol on their breath, which goes away after antibiotic treatment. “Intestinal production of ethanol may contribute to the genesis of obesity-related fatty liver,” she speculated. Two groups later showed that alcohol-producing microbes are more common in the guts of people with NAFLD than in those of their healthy peers.

While Yuan’s team pointed their fingers at Klebsiella, “it was found in only 60 percent of the human subjects they studied with NAFLD,” says Susan Baker at the State University of New York at Buffalo. “Others have identified other likely bacteria as possible culprits.” She cautions against focusing on any specific microbe, and instead considering the entire ecosystem of the body—bacteria, yeasts, viruses, gut cells, immune cells, liver, and all.

Yuan agrees. She notes that NAFLD is a complex and varied condition, and that even if Klebsiella does turn out to be a cause, it would be one of many. It also raises several questions: Why do some strains produce so much alcohol? Where do they come from? What makes them bloom so vigorously in people such as the unfortunate Chinese man who launched this study—genetics, diet, or something else? And perhaps most important, what can be done about them?

Phages might eventually help, as they did in Yuan’s mice. But for her patient with auto-brewery syndrome, simpler measures did the trick. He was treated with an antibiotic and put on a no-sugar, no-carbohydrate diet for three weeks. His intoxication symptoms eventually subsided, and two months later he was released from the hospital.

https://amp.theatlantic.com/amp/article/598414/

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For what is thought to be the largest study of its kind, the researchers analyzed brain scans of 31,227 people aged 9 months–105 years.

In a paper that now features in the Journal of Alzheimer’s Disease, they describe how they identified “patterns of aging” from the brain scans.

These were done using single photon emission computed tomography (SPECT) and came from people with psychiatric conditions such as attention deficit hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder. They were all attending a psychiatric clinic that was based at several locations.

Each participant underwent two SPECT brain scans — one during a resting state, and another during completion of “a concentration task” — giving a total of 62,454 scans.

The scientists found that they could predict a person’s age from the pattern of blood flow in their brain.

Brain circulation varied over lifespan
They observed that blood flow varied from childhood into older age throughout the lifespan. They also saw that brain aging was more visible in scans of men and those with schizophrenia, anxiety, bipolar disorder, and ADHD.

Brain aging was also more strongly associated with use of cannabis and alcohol.

“Based on one of the largest brain imaging studies ever done,” says lead study author Dr. Daniel G. Amen, a psychiatrist and founder of Amen Clinics in Costa Mesa, CA, “we can now track common disorders and behaviors that prematurely age the brain.”

He suggests that improving the treatment of these disorders could “slow or even halt the process of brain aging.”

https://www.medicalnewstoday.com/articles/322852.php

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Even the occasional drink is harmful to health, according to the largest and most detailed research carried out on the effects of alcohol, which suggests governments should think of advising people to abstain completely.

The uncompromising message comes from the authors of the Global Burden of Diseases study, a rolling project based at the University of Washington, in Seattle, which produces the most comprehensive data on the causes of illness and death in the world.

Alcohol, says their report published in the Lancet medical journal, led to 2.8 million deaths in 2016. It was the leading risk factor for premature mortality and disability in the 15 to 49 age group, accounting for 20% of deaths.

Current alcohol drinking habits pose “dire ramifications for future population health in the absence of policy action today”, says the paper. “Alcohol use contributes to health loss from many causes and exacts its toll across the lifespan, particularly among men.”

Most national guidelines suggest there are health benefits to one or two glasses of wine or beer a day, they say. “Our results show that the safest level of drinking is none.”

The study was carried out by researchers at the Institute of Health Metrics and Evaluation (IHME), who investigated levels of alcohol consumption and health effects in 195 countries between 1990 to 2016. They used data from 694 studies to work out how common drinking was and from 592 studies including 28 million people worldwide to work out the health risks.

Moderate drinking has been condoned for years on the assumption that there are some health benefits. A glass of red wine a day has long been said to be good for the heart. But although the researchers did find low levels of drinking offered some protection from heart disease, and possibly from diabetes and stroke, the benefits were far outweighed by alcohol’s harmful effects, they said.

Drinking alcohol was a big cause of cancer in the over-50s, particularly in women. Previous research has shown that one in 13 breast cancers in the UK were alcohol-related. The study found that globally, 27.1% of cancer deaths in women and 18.9% in men over 50 were linked to their drinking habits.

In younger people globally the biggest causes of death linked to alcohol were tuberculosis (1.4% of deaths), road injuries (1.2%), and self-harm (1.1%).

In the UK, the chief medical officer Sally Davies has said there is no safe level of drinking, but the guidance suggests that drinkers consume no more than 14 units a week to keep the risks low. Half a pint of average-strength lager contains one unit and a 125ml glass of wine contains around 1.5 units.

While the study shows that the increased risk of alcohol-related harm in younger people who have one drink a day is small (0.5%), it goes up incrementally with heavier drinking: to 7% among those who have two drinks a day (in line with UK guidance) and 37% for those who have five.

One in three, or 2.4 billion people around the world, drink alcohol, the study shows. A quarter of women and 39% of men drink. Denmark has the most drinkers (95.3% of women, and 97.1% of men). Pakistan has the fewest male drinkers (0.8%) and Bangladesh the fewest women (0.3%). Men in Romania and women in Ukraine drink the most (8.2 and 4.2 drinks a day respectively), while women in the UK take the eighth highest place in the female drinking league, with an average of three drinks a day.

“Alcohol poses dire ramifications for future population health in the absence of policy action today. Our results indicate that alcohol use and its harmful effects on health could become a growing challenge as countries become more developed, and enacting or maintaining strong alcohol control policies will be vital,” said the report’s senior author, Prof Emmanuela Gakidou.

“Worldwide we need to revisit alcohol control policies and health programmes, and to consider recommendations for abstaining from alcohol. These include excise taxes on alcohol, controlling the physical availability of alcohol and the hours of sale, and controlling alcohol advertising. Any of these policy actions would contribute to reductions in population-level consumption, a vital step toward decreasing the health loss associated with alcohol use.”

Dr Robyn Burton, of King’s College London, said in a commentary in the Lancet that the conclusions of the study were clear and unambiguous. “Alcohol is a colossal global health issue and small reductions in health-related harms at low levels of alcohol intake are outweighed by the increased risk of other health-related harms, including cancer,” she wrote.

“There is strong support here for the guideline published by the Chief Medical Officer of the UK who found that there is ‘no safe level of alcohol consumption’.”

Public health policy should be to prioritise measures to reduce the numbers who drink through price increases, taxation, or setting the price according to the strength of the drink (minimum unit pricing), followed by curbs on marketing and restricting the places where people can buy alcohol.

“These approaches should come as no surprise because these are also the most effective measures for curbing tobacco-related harms, another commercially mediated disease, with an increasing body of evidence showing that controlling obesity will require the same measures,” she wrote.

Ben Butler, a Drinkaware spokesperson, said: “This new study supports existing evidence about the harms associated with alcohol. Our research shows that over a quarter of UK adults typically exceed the low risk drinking guidelines and are running the risk of serious long term illnesses.”

But David Spiegelhalter, Winton professor for the public understanding of risk at the University of Cambridge, said the data showed only a very low level of harm in moderate drinkers and suggested UK guidelines were very low risk.

“Given the pleasure presumably associated with moderate drinking, claiming there is no ‘safe’ level does not seem an argument for abstention,” he said. “There is no safe level of driving, but government do not recommend that people avoid driving. Come to think of it, there is no safe level of living, but nobody would recommend abstention.”

https://www.theguardian.com/society/2018/aug/23/no-healthy-level-of-alcohol-consumption-says-major-study

Scientists have revealed a new link between alcohol, heart health and our genes.

The researchers investigated faulty versions of a gene called titin which are carried by one in 100 people or 600,000 people in the UK.

Titin is crucial for maintaining the elasticity of the heart muscle, and faulty versions are linked to a type of heart failure called dilated cardiomyopathy.

Now new research suggests the faulty gene may interact with alcohol to accelerate heart failure in some patients with the gene, even if they only drink moderate amounts of alcohol.

The research was carried out by scientists from Imperial College London, Royal Brompton Hospital, and MRC London Institute of Medical Sciences, and published this week in the latest edition of the Journal of the American College of Cardiology.

The study was supported by the Department of Health and Social Care and the Wellcome Trust through the Health Innovation Challenge Fund.

In the first part of the study, the team analysed 141 patients with a type of heart failure called alcoholic cardiomyopathy (ACM). This condition is triggered by drinking more than 70 units a week (roughly seven bottles of wine) for five years or more. In severe cases the condition can be fatal, or leave patients requiring a heart transplant.

The team found that the faulty titin gene may also play a role in the condition. In the study 13.5 per cent of patients were found to carry the mutation – much higher than the proportion of people who carry them in the general population.

These results suggest this condition is not simply the result of alcohol poisoning, but arises from a genetic predisposition – and that other family members may be at risk too, explained Dr James Ware, study author from the National Heart and Lung Institute at Imperial.

“Our research strongly suggests alcohol and genetics are interacting – and genetic predisposition and alcohol consumption can act together to lead to heart failure. At the moment this condition is assumed to be simply due to too much alcohol. But this research suggests these patients should also be checked for a genetic cause – by asking about a family history and considering testing for a faulty titin gene, as well as other genes linked to heart failure,” he said.

He added that relatives of patients with ACM should receive assessment and heart scans – and in some cases have genetic tests – to see if they unknowingly carry the faulty gene.

In a second part of the study, the researchers investigated whether alcohol may play a role in another type of heart failure called dilated cardiomyopathy (DCM). This condition causes the heart muscle to become stretched and thin, and has a number of causes including viral infections and certain medications. The condition can also be genetic, and around 12 per cent of cases of DCM are thought to be linked to a faulty titin gene.

In the study the team asked 716 patients with dilated cardiomyopathy how much alcohol they consumed.

None of the patients consumed the high-levels of alcohol needed to cause ACM. But the team found that in patients whose DCM was caused by the faulty titin gene, even moderately increased alcohol intake (defined as drinking above the weekly recommended limit of 14 units), affected the heart’s pumping power.

Compared to DCM patients who didn’t consume excess alcohol (and whose condition wasn’t caused by the faulty titin gene), excess alcohol was linked to reduction in heart output of 30 per cent.

More research is now needed to investigate how alcohol may affect people who carry the faulty titin gene, but do not have heart problems, added Dr Paul Barton, study co-author from the National Heart and Lung Institute at Imperial:

“Alcohol and the heart have a complicated relationship. While moderate levels may have benefits for heart health, too much can cause serious cardiac problems. This research suggests that in people with titin-related heart failure, alcohol may worsen the condition.

“An important wider question is also raised by the study: do mutations in titin predispose people to heart failure when exposed to other things that stress the heart, such as cancer drugs or certain viral infections? This is something we are actively seeking to address.”

The research was supported by the Department of Health and Social Care and Wellcome Trust through the Health Innovation Challenge Fund, the Medical Research Council, the NIHR Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield NHS Foundation Trust and the British Heart Foundation.

Reference: Ware, J. S., Amor-Salamanca, A., Tayal, U., Govind, R., Serrano, I., Salazar-Mendiguchía, J., … Garcia-Pavia, P. (2018). Genetic Etiology for Alcohol-Induced Cardiac Toxicity. Journal of the American College of Cardiology, 71(20), 2293–2302. https://doi.org/10.1016/j.jacc.2018.03.462

https://www.technologynetworks.com/genomics/news/faulty-gene-leads-to-alcohol-induced-heart-failure-304365?utm_campaign=Newsletter_TN_BreakingScienceNews&utm_source=hs_email&utm_medium=email&utm_content=63228690&_hsenc=p2ANqtz-9oqDIw3te1NPoj51s94kxnA1ClK8Oiecfela6I4WiITEbm_-SWdmw6pjMTwm2YP24gqSzRaBvUK1kkb2kZEJKPcL5JtQ&_hsmi=63228690

“Civilization begins with distillation,” said William Faulkner, a writer and drinker. Although our thirst for alcohol dates back to the Stone Age, nobody has figured out a good way to deal with the ensuing hangover after getting drunk.

As a chemical engineering professor and wine enthusiast, I felt I needed to find a solution. As frivolous as this project may sound, it has serious implications. Between 8 and 10 percent of emergency room visits in America are due to acute alcohol poisoning. Alcohol is the leading risk factor for premature deaths and disability among people aged 15-49 and its abuse leads to serious health problems, including cardiovascular and liver cancer. Despite these sobering facts, current treatments for alcohol overdose largely rely on the body’s own enzymes to break down this drug.

I decided to design an antidote that could help people enjoy wine or cocktails or beer without a hangover, and at the same time create a lifesaving therapy to treat intoxication and overdose victims in the ER. I chose to create capsules filled with natural enzymes usually found in liver cells to help the body process the alcohol faster.

Together with professor Cheng Ji, an expert in liver diseases from Keck School of Medicine at the University of Southern California, and my graduate student Duo Xu, we developed an antidote and tested it in mice.

Inspired by the body’s approach for breaking down alcohol, we chose three natural enzymes that convert alcohol into harmless molecules that are then excreted. That might sound simple, because these enzymes were not new, but the tricky part was to figure out a safe, effective way to deliver them to the liver.

To protect the enzymes, we wrapped each of them in a shell, using a material the U.S. Food and Drug Administration had already approved for pills. We then injected these nanocapsules into the veins of drunk mice where they hurtled through the circulatory system, eventually arriving in the liver where they entered the cells and served as mini–reactors to digest alcohol.

We showed that in inebriated mice (which fall asleep much faster than drunk humans), the treatment decreased the blood alcohol level by 45 percent in just four hours compared to mice that didn’t receive any. Meanwhile, the blood concentration of acetaldehyde – a highly toxic compound that is carcinogenic, causes headaches and vomiting, makes people blush after drinking, and is produced during the normal alcohol metabolism – remained extremely low. The animals given the drug woke from their alcohol-induced slumber faster than their untreated counterparts – something all college students would appreciate.

The ability to efficiently break down alcohol quickly should help patients wake up earlier and prevent alcohol poisoning. It should also protect their liver from alcohol–associated stress and damage.

We are currently completing tests to ensure that our nanocapsules are safe and don’t trigger unexpected or dangerous side effects. If our treatments prove effective in animals, we could begin human clinical trials in as early as one year.

This sort of antidote won’t stop people from going too far when consuming alcohol, but it could help them recover quicker.

https://www.technologynetworks.com/neuroscience/articles/a-hangover-pill-tests-on-drunk-mice-show-promise-302970?utm_campaign=NEWSLETTER_TN_Neuroscience_2017&utm_source=hs_email&utm_medium=email&utm_content=63148685&_hsenc=p2ANqtz-_9-CBGC564lH1Jr5Fxrauf8vQZ42sDx9gSSQj_dPJTj3gm3QDvY74R4WiynR1vM5L7tdtTLBIV40iEWBKcEB7JzwFUnQ&_hsmi=63148685