Click to Translate to English Click to Translate to French  Click to Translate to Spanish  Click to Translate to German  Click to Translate to Italian  Click to Translate to Japanese  Click to Translate to Chinese Simplified  Click to Translate to Korean  Click to Translate to Arabic  Click to Translate to Russian  Click to Translate to Portuguese


Forum Home Forum Home > General Discussion > Latest News
  New Posts New Posts RSS Feed - Therapy could stop superbugs on farms
  FAQ FAQ  Forum Search   Events   Register Register  Login Login

Online Discussion: Tracking new emerging diseases and the next pandemic; Now tracking the Aussie Flu.

Therapy could stop superbugs on farms

 Post Reply Post Reply
Author
Message
carbon20 View Drop Down
Admin Group
Admin Group


Joined: April 08 2006
Location: West Australia
Status: Offline
Points: 17526
Post Options Post Options   Thanks (0) Thanks(0)   Quote carbon20 Quote  Post ReplyReply Direct Link To This Post Topic: Therapy could stop superbugs on farms
    Posted: June 09 2017 at 2:54pm

Therapy could stop superbugs on farms

By Pallab GhoshScience correspondent, BBC News
Pigs

Researchers at Leicester University have shown that it might be possible to develop an alternative to antibiotics for treating diseases in pigs.

They have identified a range of viruses, called bacteriophages, that can be used to kill common pig infections.

The aim is to reduce the risk of antibiotic resistant bacteria emerging on farms that could also infect humans.

If trials in pigs work, the new therapy could be extended to treat people.

Prof Martha Clokie presented her interim results to a pig industry meeting in Solihull. She told BBC News that the early results indicated that phage therapy could be "completely transformative for human health".

"There are many infections that we just can't treat with antibiotics because they have become resistant to them. So using the phage therapy for specific diseases could change the way we treat infection. It could give us a whole new armoury."

Scientists have been trying to develop phage treatments for more than a century but they have mostly proved to be unreliable. But Prof Clokie has found more precise ways of isolating phages and assessing their effectiveness.

The research has been funded by the Agriculture & Horticulture Development Board which is responding to concerns about the possibility of so called superbugs developing in farm animals and entering the food chain. Charlotte Evans is leading the project for AHDB.

"Pig producers are responding to a pig health and welfare point of view and also reacting to consumer expectations, to help make sure we are being responsible about our antibiotic usage and ensure we safeguard them for the future," she said.

PhageImage copyrightMICHAEL ROSSMAN/PURDUE UNIVERSITYImage captionArtwork: Phages latch on to infections and kill them by injecting their own DNA

In the UK, 40% of all antibiotics are used to treat animals. They are the same as those used to treat people.

A review published last year by Lord Jim O'Neil called for reductions in the unnecessary use of antibiotics in agriculture, especially those that were "highly critical" to human health.

Prof Clokie has shown that phage therapy can in principle offer a viable alternative to antibiotics.

Phages occur in nature and are the natural enemy of many infectious agents. There are many phages, each of which is specific to different infectious bugs. The phages home in on these agents like a guided missile. Once they find their target, they latch on to them and inject their DNA into the bug rendering it harmless.

Like all viruses, they reproduce inside the infectious bug and these new phages go on to hunt other infections

Prof Clokie and her team have identified a range of disease-killing phages, including one that disables a salmonella bug that infects pigs. Her team has shown that it works in the lab and the scientists have also developed a powdered form of the phage which remains active. This is an important step because it enables the researchers to add the phage to pig feed and see if it works in practice.

The team plans to begin trails later this year.

If the approach is found to be effective, other phage treatments could be developed for a range of animal diseases. It would also speed the development of phage treatments for people.

12 monkeys!!!!!
Back to Top
jacksdad View Drop Down
Chief Moderator
Chief Moderator
Avatar

Joined: September 08 2007
Location: San Diego
Status: Offline
Points: 39621
Post Options Post Options   Thanks (0) Thanks(0)   Quote jacksdad Quote  Post ReplyReply Direct Link To This Post Posted: June 10 2017 at 3:49am
We just need to accept that the way we raise food animals is dangerous to our health, and downright cruel. It's a system that's going to turn around and bite us if we don't wise up and fast.


"Buy it cheap. Stack it deep"
"Any community that fails to prepare, with the expectation that the federal government will come to the rescue, will be tragically wrong." Michael Leavitt, HHS Secretary.
Back to Top
carbon20 View Drop Down
Admin Group
Admin Group


Joined: April 08 2006
Location: West Australia
Status: Offline
Points: 17526
Post Options Post Options   Thanks (0) Thanks(0)   Quote carbon20 Quote  Post ReplyReply Direct Link To This Post Posted: June 10 2017 at 1:42pm
I first heard about Phages about 30 years ago,they havnt done much with them,

probably antibiotics were cheap and easy to produce ,

but now we in Trouble we need to fast track all options ,

the alternative is ..................

very horrifying...............


12 monkeys!!!!!
Back to Top
carbon20 View Drop Down
Admin Group
Admin Group


Joined: April 08 2006
Location: West Australia
Status: Offline
Points: 17526
Post Options Post Options   Thanks (0) Thanks(0)   Quote carbon20 Quote  Post ReplyReply Direct Link To This Post Posted: June 10 2017 at 1:44pm
The first person to receive penicillin — a powerful antibiotic discovered in 1928 — was a British policeman who had a life-threatening infection.

It caused sores on his scalp to ooze pus; doctors even had to remove one of his eyes. The cause of the infection? He’d scratched his face on a thorn while strolling through his garden.

In a recent TED Talk, Maryn McKenna — a journalist who spent a decade reporting on the CDC and who has authored an award-winning book on the drug-resistant superbug, MRSA — tells this tale to warn against the reality we will soon face now that, experts warn, we’re fast-approaching a “post-antibiotic era.”

Hailed as “miracle drugs” in the 1940s and 1950s, antibiotics turned raging infections — which were once seen as veritable death sentences — into manageable conditions. What killed us in the early 20th century was now easily remedied with a shot or a pill.

But now, bacteria are developing defences against these potent medicines, rendering them increasingly useless for some types of infections. Doctors try one antibiotic, then a stronger one, and eventually the strongest ones we have — when none of them work, a patient is often out of options.

That means infections that were easily treatable are becoming life-threatening once again.

When it comes down to the warfare between humans and bacterial invaders, we are fighting a losing battle if we aren’t armed with effective antibiotics, or at least developing new alternatives. If we don’t come up with some innovative strategies and new solutions quickly, everyone around the globe will be affected. Millions already are.

The “golden age” of antibiotics is coming to an end, and it’s not going to be pretty. “Antibiotics support almost all of modern life,” McKenna says in her talk. Here is what she warns we’ll lose when they stop working.

Minor infections will be something to fear.

As with the British policeman, everything from a scratch to catching a cold could kill before antibiotics were introduced. Strep throat led to heart failure. Simple cuts and scrapes induced raging infections requiring amputations.

The simple fact is that bacteria — from innocuous ones that we don’t even notice are there, to those that help us digest nutrients from food and even those that cause us harm — are everywhere. There’s no avoiding them, and if we’re left with nothing that can effectively fight them off, risks that are now considered minor ones will suddenly loom large.

“More than anything else, we’d lose the confident way we live our everyday lives,” McKenna says. “If you knew that any injury could kill you, would you ride a motorcycle? Bomb down a ski slope? Climb a ladder to hang your Christmas lights? Let your kid slide into home plate?”

Life will be especially dangerous for pregnant women and children.

Even in the cleanest hospitals, McKenna notes, giving birth used to kill about one in every 100 women. Pneumonia killed three children out of every 10. Antibiotics changed this, but if they stop working, these horrors could once more become a terrifying reality.

Receiving treatment for other diseases will be more dangerous.
Because some therapies impact our ability to fight off infections, a lack of working antibiotics will make certain cures and treatments more dangerous and sometimes unfeasible.

Cancer patients receiving chemotherapy are particularly at risk of developing an infection. Certain chemo drugs damage and tamp down infection-battling white blood cells.

Organ-transplant recipients, who take immune-weakening drugs to stop their bodies from attacking their new organs, are also in danger. If they can’t take antibiotics to help fight infections they get while on these drugs, they are more likely to get sick and even die.

Many other people with compromised immune systems — including AIDS patients and premature babies — will be much more likely to get ill and potentially die without antibiotics.

Anyone whose treatment involves a foreign object like an artificial joint or a catheter will also be at high risk for a potentially deadly infection.

People who have stents in their arteries to prevent stroke by enhancing blood flow to their brain, for example, will be susceptible to resistant infections. Similarly, those who have insulin pumped through their skin for diabetes or those on dialysis will be affected. Joint replacements are also particularly vulnerable. Of those receiving new hips and knees, for example, about one in every six patients would die if antibiotics no longer worked, McKenna says.

Most surgeries will become nearly impossible.

Among the vulnerable would be people in need of now-common procedures such as heart surgeries, prostate biopsies, and cesarean sections. “We’d lose the ability to open the hidden spaces of the body,” McKenna says.

The main function of our skin is to keep bad things, like bacteria, out. So when we open up the body cavity it’s dangerous, even in a “sterile field.” While not all patients undergoing surgery get antibiotics pre-emptively, it’s important to have them on hand in case an infection occurs afterward.

More than 200 million surgeries are performed every year, many of which are necessary to keep patients alive. Researchers estimate that at least 20% of the global health burden is treatable with surgical interventions — losing the ability to treat all of these conditions would be devastating. A broken arm could mean a lifetime of disability; a ruptured appendix could end in death.

Watch McKenna’s TED Talk for more cautionary words about our antibiotic-free future.
< ="https://-ssl.ted.com/talks/maryn_mckenna_what_do_we_do_when_antibiotics_don_t_work_any_more." width="100%" height="315" border="0" scrolling="no" style="-sizing: border-;">

Follow Business Insider Australia on FacebookTwitterLinkedIn, and Instagram.



Read more at https://www.businessinsider.com.au/what-will-happen-when-antibiotics-stop-working-2015-6#kUWAXxFd7kZpW7AH.99
12 monkeys!!!!!
Back to Top
carbon20 View Drop Down
Admin Group
Admin Group


Joined: April 08 2006
Location: West Australia
Status: Offline
Points: 17526
Post Options Post Options   Thanks (0) Thanks(0)   Quote carbon20 Quote  Post ReplyReply Direct Link To This Post Posted: June 10 2017 at 1:49pm
< ="https://-ssl.ted.com/talks/maryn_mckenna_what_do_we_do_when_antibiotics_don_t_work_any_more."
12 monkeys!!!!!
Back to Top
carbon20 View Drop Down
Admin Group
Admin Group


Joined: April 08 2006
Location: West Australia
Status: Offline
Points: 17526
Post Options Post Options   Thanks (0) Thanks(0)   Quote carbon20 Quote  Post ReplyReply Direct Link To This Post Posted: June 10 2017 at 1:53pm
“The world is heading towards a post-antibiotic era in which common infections will once again kill. If current trends continue, sophisticated interventions, like organ transplantation, joint replacements, cancer chemotherapy, and care of pre-term infants, will become more difficult or even too dangerous to undertake. This may even bring the end of modern medicine as we know it."

Grand Challenges

In this special series, Future Now takes a close look at the biggest, most important issues we face in the 21st Century.

For two months, we'll bring you insight from leading scientists, technologists, entrepreneurs and influencers to help you make sense of the challenges we face in today's rapidly evolving world.

That’s what the Director-General of the World Health Organization said last April when she appeared before the United Nations. Dr Margaret Chan wanted to warn of what many deem to be one of the greatest threats to global health today: the increasingly common problem of infections that do not respond to antibiotic treatment.

It sounds alarmist, but it might actually not be alarmist enough.

The efficacy of the world’s antibiotics is quickly decaying – the drugs we’re using to treat infections are working less and less. If we continue at this rate without intervention, we may find that there is not a single antibiotic left to treat any type of bacterial infection.

“This would really change life as we know it,” says Dr David Weiss, director of the Antibiotic Resistance Center at Emory University. “Consider going to back to an era when a minor accident like a scrape could lead to death.” That’s what a world of total antibiotic resistance could lead to.

Antibiotic resistance

A combination of over-prescribing medications and a cultural dependence on antibiotics has led us to where we are today. (Credit: Getty Images)

But there’s good news: we are not likely to continue at this rate. The world is aware of the problem and there are many organisations, governments, and concerned citizens working hard to avoid a worst-case scenario.

The bad news is that the issue is extremely complex and widespread. And thanks to the very nature of bacteria and how they work – and the damage we have already done – the world will never be entirely free from resistance.

What is resistance?

Say you contract a staph infection. In the past that was easily treated with penicillin. But today, it is very possible that your staph infection is actually MRSA – a version resistant to antibiotics (only 10% of current staph infections aren’t MRSA). Penicillin is useless against it. In fact, studies show that two in 100 people are carrying around the MRSA bacteria.

Here’s how resistance develops: just like people, bacteria have DNA. And just like in humans, that DNA can mutate or change. Then, when inputs from the outside world interact with those mutations, survival of the fittest means only the strongest variations live on.

This would really change life as we know it. Consider going to back to an era when a minor accident like a scrape could lead to death – Dr David Weiss

So, when humans use antibiotics to kill off bacteria, in some cases, those bacteria spontaneously mutate their genes, which changes their makeup in such a way that the antibiotics cannot kill them. The bacteria that survive those encounters pass these genes on to other bacteria through simple mating (technically known as 'conjugation') – and those resistant bacteria can spread from one living thing to another.

The tricky part of this is that bacteria can share these genes with each other across bacterial species – so they don’t even have to be that genetically similar to pass along resistance. Humans and animals, who are teeming with trillions of different types of bacteria, then pass the resistant bugs along to each other. And, on top of it all, we introduce those resistant species to each other inside our own bodies. So, even if a human or an animal has been exposed to an antibiotic just once in their lives they can contain mutant bacteria that can be easily spread.

Bacteria, it turns out, don’t care about political borders or immigration policies – for example, researchers have even found drug-resistant bacteria on the rear-ends of seagulls in Lithuania and Argentina.

The most important part of this is that bacterial resistance is essentially a numbers game: the more humans try to kill bacteria with antibiotics, and the more different antibiotics they use, the more opportunities bacteria have to develop new genes to resist those antibiotics. The less we use, the less bacteria can develop and share resistance.

How big is the problem?

It’s hard to say for sure, but the US Centers for Disease Control and Prevention (CDC) estimates that in the US alone there are about 23,000 people who die every year from antibiotic-resistant infections. For example, they estimate that resistance to antibiotics that treat Clostridium difficile (C. difficile) causes almost 500,000 infections in the US every year, which lead to about 15,000 deaths. (But Amanda Jezek, a spokesperson specialising in policy and government relations at the Infectious Diseases Society of America, a group that represents many of the country’s infectious disease doctors and scientists, says the overall number of deaths is a conservative estimate and likely higher.

Meanwhile, a 2015 study published in Nature found that global antibiotic consumption went up 30% between 2000 and 2010.

Antibiotic resistance

A world of total antibiotic resistance could change life as we know it, experts warn, making even minor ailments life-threatening. (Credit: Getty Images)

The WHO estimates that with tuberculosis alone there are about 480,000 people worldwide with drug-resistant strains of the disease. In 2014 they estimated that 3.3% of all new cases of TB were resistant to multiple drugs, and in recurring cases, 20% were resistant. They have also tracked cases of resistance (some very common and some less so) in drugs used to treat E. coli, urinary tract infections, HIV, gonorrhea, malaria, pneumonia, and staph infection (the drug resistant version of which is MRSA).

And according to Public Health England, the “UK government considers the threat of antibiotic resistance as seriously as a flu pandemic and major flooding.” If left unchecked, antibiotic resistance could lead to 10 million deaths by 2050 worldwide, costing some £66 trillion.

How did we get here?

Plain and simple, humanity has drastically overused antibiotics.

Not only have doctors spent decades handing out antibiotics to any patient that asked (regardless of whether or not they were needed), some countries still consider antibiotics to be over-the-counter medicines – as easy to purchase as Anadin or Tylenol. According to Dr Marc Sprenger, director of the antimicrobial programme at the WHO, much of Europe is three times more likely to use antibiotics than their fellow European countries Sweden or the Netherlands, where they are used only occasionally. “This has nothing to do with more people getting sick. This is a cultural phenomenon,” he says.

On top of that, for many decades agricultural pursuits worldwide have fed huge amounts of antibiotics to livestock and food-producing animals – not only as a means to reduce infection, but also as a method to increase growth. And, while humans do not ingest those antibiotics, they do ingest and handle the bacteria that resides within those animals. So if those animals carried drug-resistant bacteria, you potentially could, as well.

This has nothing to do with more people getting sick. This is a cultural phenomenon – Dr Marc Sprenger on antibiotic overprescription

Until recently antibiotics in the US actually listed animal growth as an indication for use on antibiotic labels and a prescription was not required for farmers to obtain them. To illustrate what a problem this is: just last November a strain of E. coli was discovered in Chinese pigs to be resistant to colistin – a last-resort antibiotic that has only been used in the US in the most dire cases of human infection, untreatable by all other antibiotics. In less than six months the CDC detected that strain of E. coli in a patient in Pennsylvania. 

So why not just develop new antibiotics that the bacteria can’t resist? It has been several decades since a drug company developed and sold a new antibiotic. “You would like to have new antibiotics to treat infections with resistant bacteria, but if you look at the timeline [of new releases] it is empty for almost 30 years,” Sprenger says.

That’s because the process of developing any new drug is extremely expensive and the potential profit in an antibiotic after that massive investment is relatively low. According to Sprenger, “there are no legal instruments to prohibit the use of a new antibiotic.” What that means is if a new antibiotic is released there’s no way to stop the world from overusing it. At current usage levels a new antibiotic, he says, would only have about two years on the market before bacterial resistance to it develops.

How do we get ourselves out of this?

First, the entire world needs to get on board. Two years ago this essentially happened when member states of the WHO agreed to accept a Global Action Plan – by then, antibiotic resistance was a problem that had already been on the radar for many decades. The plan lays out extensive solutions and best practices that all countries can take to reduce resistance. “That’s historic,” says Sprenger. Before then, he says, the only people actively discussing how to reduce resistance were people within medical circles, for the most part. "95% of the worldwide population is now living in a country where they have developed a national action plan. All these countries have increased activities in education, training, and prevention control.”

In the last couple of decades we’ve seen decreases in prescription to children in the US – Dr Katherine Fleming-Dutra

Then, last year, the UN addressed the issue before the General Assembly – only the fourth time in history that a health issue was discussed there. And just this May the G20 leaders signed a declaration on global health that included tackling antibiotic resistance. So it’s definitely a grand challenge that world leaders are taking seriously.

Antibiotic resistance

Worldwide consumption of antibiotics has skyrocketed in recent years: One study found that global consumption went up 30% between 2000 and 2010. (Credit: Getty Images)

Much of the WHO action plan focuses on hospital stewardship and supervision. The CDC is currently working closely with American hospitals to provide guidelines and education for the safe and reasonable prescription of antibiotics. “We have made some progress,” says Dr Katherine Fleming-Dutra, an epidemiologist at the CDC. “In the last couple of decades we’ve seen decreases in prescription to children in the US. We have seen less progress in adults. The rate in adults has been relatively stable.”

Once hospitals and physicians get on board with reducing prescriptions the next step is to change regulations around agriculture.

Ten years ago the European Union banned antibiotics as growth promoters. And just this January, the US Food and Drug Administration removed growth from the indicated use of antibiotics on drug labelling. According to Dr William Flynn, deputy director for science policy at FDA’s Center for Veterinary Medicine, “There was a real recognition that this was something [farmers] needed to take seriously and respond to. We’re encouraged by the fact that they were engaging and working with us to find ways to make it work.”

But other countries need to follow suit – as evidenced by the recent revelations about antibiotic resistance coming out of China.

One of the most important steps in tackling resistance is tracking it. The CDC have set up a system called the National Antimicrobial Monitoring System (NARMS). “Surveillance for antibiotic resistant bacteria is a big part of our mission,” says Dr Jean Patel, deputy director of the office of Antimicrobial Resistance at the CDC. “We do this to measure the burden of infection and also characterise the types of resistance we see. This helps us strategise how best to prevent resistance.”

We can only really slow the development of resistance. We’re not going to stop it completely. Even appropriate use of antibiotics does contribute to resistance – Amanda Jezek, Vice President for Public Policy and Government Relations, Infectious Diseases Society of America

The CDC funds state health departments around the US (and coordinates with laboratories worldwide) to maintain a network of antibiotic resistant bacteria data and samples. Says Patel: “We can use this to give us national estimates of infection rates to see how bacteria are changing, test new drugs against bacteria, and we also have used the bacteria we collect through this to help with vaccine development.” Though, it should be noted, the continued success of the programme could be in jeopardy as US President Donald Trump’s proposed budget suggests cutting funds to the CDC by 17% (or $1.2 billion).

But there are also some non-traditional methods being attempted. Emory University in Atlanta, Georgia, has established a unique Antibiotic Resistance Center. One of its main goals is to build diagnostic tests using mutated bacteria collected by the national surveillance system and physicians in their own clinic that can spot resistant bacteria.

“The goal is to have scientists, clinicians, and epidemiologists all working together to address this issue. That’s something that hasn’t traditionally happened. There has been division between what the scientists and clinicians are doing,” says the centre’s director David Weiss. “I’m not a doctor. I need to know from the clinicians a lot of what they’re seeing on the front lines to help guide our research to be as relevant as possible.”

Antibiotic resistance

Animals also develop antibiotic resistance, which means they could pass their drug-resistant bacteria onto you, too. (Credit: Getty Images)

A comprehensive, collaborative approach could work: last year, the National Health Service of England announced that in 2015, antibiotic prescribing reduced by 5.3% compared to 2014. Public Health England says that more responsible prescribing is key: it says that it advised the NHS in 2015 on the development of better practices that aim to slash prescriptions by 10% from 2013 to 2014 levels.

Lastly, there need to be incentives that encourage the development of new antibiotics.

The US National Institute of Health and the Biomedical Advanced Research and Development Authority have set up a biopharmaceutical accelerator called CARB-X. The fund is allotting $48 million to support antibiotic drug discovery projects. “They work with companies in the very early discovery stages to give them funding and technical support to get to the point that they have a product they can do clinical trials with,” says IDSA’s Jezek. Along those same lines, the IDSA is also currently working to develop legislation that would provide funding for clinical trials so that companies can avoid those hefty costs and stand a chance of making a profit from new antibiotics.

With all of these programmes working together, and similar efforts taking place around the world, there is a lot of hope that humanity will manage to get a handle on the problem. Still, “we can only really slow the development of resistance. We’re not going to stop it completely,” says Jezek. “Even appropriate use of antibiotics does contribute to resistance.”

And that means the challenge will always be immense. As long as there are humans and those humans carry and transmit disease – which they will – the entire world will have to continue fighting for resistance.

--

Join 800,000+ Future fans by liking us on Facebook, or follow us on Twitter.

12 monkeys!!!!!
Back to Top
jacksdad View Drop Down
Chief Moderator
Chief Moderator
Avatar

Joined: September 08 2007
Location: San Diego
Status: Offline
Points: 39621
Post Options Post Options   Thanks (0) Thanks(0)   Quote jacksdad Quote  Post ReplyReply Direct Link To This Post Posted: June 10 2017 at 3:23pm
We're heading toward a future where learning to treat wounds and minor infections before they become systemic will be what saves lives. The blood poisoning of old (a term that fell out of favor when sepsis became far less common) will be back to haunt us all too soon if we don't find alternatives and learn to use them properly (prescribe them responsibly, and don't feed them to food animals to promote growth).

It shouldn't be that hard. Seriously.


"Buy it cheap. Stack it deep"
"Any community that fails to prepare, with the expectation that the federal government will come to the rescue, will be tragically wrong." Michael Leavitt, HHS Secretary.
Back to Top
EdwinSm, View Drop Down
Adviser Group
Adviser Group


Joined: April 03 2013
Status: Offline
Points: 4995
Post Options Post Options   Thanks (0) Thanks(0)   Quote EdwinSm, Quote  Post ReplyReply Direct Link To This Post Posted: June 10 2017 at 9:21pm
Recently I saw an old episode of "Trust Me I am a Doctor" where they talked of bacteriophages.  The programme brought up one problem of phage therapy in that it has to be specifically targeted whereas antibiotics are wide ranging.  Ie one antibiotic will cover a range of problems, but it seems like there will have to be many, many different phages to tackle the same range. 



ps. this whole thread is hitting home as my wife recently needed major surgery to treat a broken shoulder (the ball of the socket was broken in a fall).  Without antibiotics, would they have had to leave her in a lot of pain until she died, or to put her directly on hospice care under heavy medication?  The pain after the operation was bad, but not nearly as bad as before. 
Back to Top
 Post Reply Post Reply
  Share Topic   

Forum Jump Forum Permissions View Drop Down