And that's how antibiotic resistance happens.
“But I would like to sound one note of warning. Penicillin is to all intents and purposes non-poisonous so there is no need to worry about giving an overdose and poisoning the patient. There may be a danger, though, in underdosage. It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body.
The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant. Here is a hypothetical illustration. Mr. X. has a sore throat. He buys some penicillin and gives himself, not enough to kill the streptococci but enough to educate them to resist penicillin. He then infects his wife. Mrs. X gets pneumonia and is treated with penicillin. As the streptococci are now resistant to penicillin the treatment fails. Mrs. X dies. Who is primarily responsible for Mrs. X’s death? Why Mr. X whose negligent use of penicillin changed the nature of the microbe. Moral: If you use penicillin, use enough.”
Edit: Fleming's full Nobel lecture:
Stern warnings with no information about possible consequences is heavily lambasted in movies, yet we repeat this behavior with medicine and expect different results.
If you tell someone not to do something and don't tell them why not, and the consequences aren't otherwise clear, expect them to do what you said not to do.
My mother was a nurse so she always reminded me of the critical missing reason why, and I've always dutifully finished all antibiotics prescriptions as a result.
But that was a simple thing the doctors writing the prescription should have been doing themselves, and an apparent systemic failure of the medical profession to account for messy human psychology in a critical procedure.
Gone are the days where a doctor should be taken at his judgment 100% as if medicine is a black box enigma. The average HNer would be wise to google about their conditions and drugs they consume. A doctor can only remember so much - they are primarily valuable for their experience in hueristic diagnosis -- not for knowing everything medical and everything pharmacutical. It is wise to relinquish some responsibility to a professional but not all.
Most of medicine aside from surgical methods can be understood by a mildly intelligent person who cares enough, because of wikipedia and google, everything except actual experience is very accessible.
I dont see how your astonishment is anything other than misinformed hyperbole.
For the most part, of course. Cultural evolution does occur, however it's unpredictable and not something that can be easily forced.
Stepping down off a high dosage in halves is the exact same strategy used to ease people out of addiction.
As a kid, I thought anti-biotics were this far-out medicine, so strong and hazardous that coming down off them was something you had to do carefully.
I got strep throat a few times as a kid. I don't have perfect recall about the details of what I had to take and when or why, though. But I do remember having to vary dosage.
Given an instruction when you don't understand the "why" is highly ineffective. As seen by your experience with your doctor.
There is also a further problem in that antibiotics treat not just you, but prevent infection in the wider population. People in general find it hard to think about the wider impact, which is something we see every day with regards to the world wide population's regards to the impact of their own pollution. It's why we recycle but then drive SUVs.
"Take all of the prescribed medication" : "They're just greedy and want to make me buy more"
"Take all or you'll breed antibiotic-resistant bacteria that cannot be treated and you will die and kill the human race" : "I better follow this prescription"
Both of them are wrong, btw. Pharma companies are greedy and they do everything they can to make you spend more. Doctors are influenced by them, often very subtly. That is a fact, not a conspiracy. But the fact also is, that doctors save lives and most have noble intentions (despite the meat grinder medical career is). One needs to learn what information belongs more to "greedy companies" category, and what belongs to "life saving science" category. It's no surprise people get confused about this - and that's why you absolutely need to explain to them why they need to finish antibiotics treatments.
It's from Friedrich Nietzsche's "Twilight of the Idols": "What does not kill me, makes me stronger."
Also, most people don't know that either. Today it's just a saying, that's been repeated by people for decades.
I'm ashamed to admit that the big part of my adult life I didn't know the reason behind that, and always assumed that to be of a kind "you must eat your whole meal" constantly told by grandma. I'm sure I'm not the only one..
I agree with the observation that telling people to do something without explaining why is stupid and will only lead to disappointment.
Understanding the process that leads to antibacterial resistance requires understanding evolution. So it's no surprise that much of the world fails to understand it.
Turned out this was a major point of the anti-evolution stance at his church. I've since encountered the same viewpoint from a number of other people, all going to primarily small, ostensibly non-denominational, churches.
I am happy to base my work on the currently best working scientific models.
My faith is also based on "best practices": what worked well for my parents, grandparents and me and which also happened to help create the western culture we enjoy today.
"Render therefore to Caesar the things which are Caesar's; and to God the things that are God's."
Probably the opposite, if you look at any conflicts they were involved in, or what social advances were blocked.
I am, to a certain degree, that evidence. (Edit: this holds true to some degree even if you look at it from a purely techical POV which makes me smile : )
> Probably the opposite, if you look at any conflicts they were involved in, or what social advances were blocked.
This is meaningless unless you also take into account the advances brought forward because of it.
And, FWIW, you have to cast your net wide and far to find anything real horrific.
This is not to say we are better people than other, but trying to say our faith made us worse than the alternative (warrior tribes as they existed some hundred years ago) seems very wrong.
The point of Creationism (the non-laughable variety, at least) is that some transcendental being designed this Universe with all its fundamental laws and specific constants, including Evolution, with the express intent to have us here, now, in the exact shape we are.
It is not something that can be easily refuted, BTW, nor proven. Which is why it's a matter belonging to faith and not science, for now.
This is a strawman, as it's quite explicitly not what's being discussed in the parent comment, which specified "created....thousands of years ago" (I assume that kind of creationism is what you're referring to as "laughable").
Today's religion is different in many ways. The ones that say that bible is the 100% correct source of truth are the crazy ones.
There are a lot of atheist scientists that are perfect bayesian reasoners while doing research, but when they step out of the lab they suddenly get as irrational as the rest of the general population. People are way too good at compartmentalizing beliefs.
Furthermore in Hospitals you make people wash their hands (as in you post security gaurds at the hand washing stations and none shall pass a station without washing) and you have separate wards for those with MRSA and those without MRSA.
If you need an antibiotic that is not in rotation, you are hospitalized while everyone makes sure you take your full course.
Doing these things eliminates about 90% of the problem.
There are third world countries that don't care and will not follow any of those rules. Also foreign prison systems, particularly in Russia, which breed TB.
Then there are people that are prescribed low doses of antibiotics for things like acne. I imagine that's a huge risk more than all the other things, taking it every single day.
And, as others have mentioned, agriculture uses about 50% of the world's supply of antibiotics IIRC, and that's not really safe.
It's much easier to make antibiotics prescription only. Which we have. For humans at least.
I don't think the decision has been conscious.
More importantly the costs and benefits haven't been amortised over the life (and impact) of those decisions. Or, if you will, it hasn't been worth it yet. Unfortunately at the point where we can properly assess the enormous cost of these decisions, the opportunity will be long gone.
When I see something like this I start to question our governing system. Its way to slow and sluggish to react to these kind of events that requires immediate attention.
Each of these events would cost a few (hundreds of?) billions to address or mitigate. It requires a super human intelligence to separate the chaff from the wheat. And this is hard to know what is scaremongering, and what is really dangerous.
Indeed. Also there are increasing evidence that many scientific studies aren't reproducable.
We need a better System to identify 'useful signals' among noises. But in our current socio-economic structure, this topic never comes up as the most important issue. Abraham Lincoln founded National Science Foundation that laid out a solid ground work for this movement, but nobody(correct me if I am wrong) picked it up where he left of and pushed Scientific inquiry as one of our top agenda.
Farmers use antibiotics basically by default and in large doses to avoid bacterial problems with their cattle.
I remember reading a stat that said 93% of all anti-biotics use is in agriculture.
On the one had it is as you said, as a preventative measure to head off infection (which is obviously very bad), but it's worse than that - industrial farmers use antibiotics so they don't have to inspect and treat each animal. Just dump antibiotics into their food and if they are injured somewhere along the way it will hopefully heal on its own. Inspecting and treating each animal individually would be a lot more expensive.
The other reason antibiotics are given to livestock is to cause weight gain. If the antibiotics cost less than the value of the extra meat produced, then you make more money.
It's a fucked up practice that we'll be all pay for in a few decades.
Note the wiki page is an ok source, but is in need of some attention from someone outside the industry.
At some point, it will become obvious enough that victims' estates will start winning lawsuits :)
I see some great opportunities in technology for streamlining processes behind fair and high-quality agricultural products.
If we were serious about humanity's future, antibiotics would only be given in hospitals and all of your bodily waste would be incinerated until it no longer tests positive for antibiotics. You'd leave the hospital with a shaved head too, since hair may come to contain the antibiotics as it grows.
This is a case where government just needs to step in and ban the practice.
The reader and the software are going to be a few hundred dollars or maybe a couple thousand. But it's a one time investment, plus ongoing implants as the herd changes over time.
I suspect the main selling point is going to be the one-time capital investment aspects and the fact that antibiotics are being painted as an undesirable additive in meat and dairy. When the general public starts to dislike a substance, suppliers scramble to distinguish their products, e.g. "No added growth hormones" and the like.
Maybe the startup could manage to do it for a cost that's less than organic meat?
Example: almost all turkey meat that's so in fashion today comes from farmers that use antibiotics as preventative measure. I personally source meat from small family run farms that adhere to biological agriculture principles, (there only ill animals get antibiotics and those aren't butchered and sold later as meat).
Better example is doctors writing prescriptions for common cold infections that are viral anyway so they can appease patients by "doing something."
Your condition is the reason that I find myself prescribing courses of amox even when chances of chronic strep colonization are much more likely than true acute infection. It's a real diagnostic quandary.
They really don't seem to understand the concept of antibiotic resistance. They're all engineers too, they really should know better.
And he completely understood the concept of antibiotic resistance. He just gave a sheepish grin when I confronted him like "Aw, shucks, ain't I a scamp". He was a really nice guy, except for this case where he was a sociopathic asshole.
Some studies suggest though that 90% of cases can be resolved with less antibiotics.
It is a famous and time-honored rationalization that sidesteps doing the right thing because the wrong thing is certain to occur anyway. The logic is faulty and self-serving, of course. Sometimes someone else won't do it. The soldiers asked to fire on their own people when the Iron Curtain governments were crumbling all refused, one after another. Sometimes someone else does it, but the impact of the refusal leads to a good result anyway. When Elliot Richardson was ordered by Richard Nixon to fire Watergate Special Prosecutor Archibald Cox, he refused and resigned. Cox ended up being fired anyway, but Richardson's protest helped turn public opinion against the White House. Even if neither of these are the final result, the individual's determination to do right is always desirable in itself. The Futility Illusion is just a sad alternative to courage.
Do you have any scientific evidence to back up your theory? Or, said another way, where is this science you speak of documented and tested?
As far as evidence against your theory, evolution (e.g. bacteria becoming resistant to antibiotics) is the result of mutation and selective pressure. If antibiotics are never used, then there is no selective pressure. Significant percentages of a bacterial species do not just decide to become immune to some antibiotic that doesn't exist or is never used.
When the selective pressure of an antibiotic is present, however, those mutations that provide immunity to the antibiotic are selected (as the others die) and become a larger percentage of the total population of the species.
This is also why you take the full dosage of an antibiotic. Otherwise, you leave the most resistant alive (those more vulnerable to the antibiotic die first, in theory).
Also why farms are considered to be the leading cause of antibiotic resistance. By constantly administering antibiotics when they are not needed, you are providing a constant selective pressure, forcing adaptation to occur.
Bleach is vastly more effective at sterilization than any known antibiotic. Their only advantage is inside an organism by nocking things back immune systems can win. However, for example in imunocompromized people they have minimal effect.
It's well known that bacteria live and reproduce outside the human body. Many strains, like listeria or salmonella, can live in food, outside of any human or animal host. Cholera lives in sewage. Also, animals are reservoirs for a large number of bacterial species. Unless we're going to dose all humans, all animals, and the environment as well, then we're not going to succeed.
Further, 80% or so of most antibiotics get excreted right out of the body in urine within a matter of hours. This means that the environment is going to get dosed with a low level of antibiotics, just the perfect environment for breeding immunity.
Finally, bacteria can exchange plasmids inter-species, so if some innocuous bacterium in the environment develops immunity, it can transfer that to a virulent species at a later time.
I think however it's not enough to conclude that consciously avoiding using antibiotics provides a net gain.
It, in my mind, becomes a bit of an economics question if you consider the trade-offs. Not dosing cattle could to food poisoning which could lead to higher human consumption of antibiotics.
I also have a fear of this becoming a panic, much like the anti-vaccine panic which leads people away from getting proper medical treatment.
And from that story, it talked about Colistin (the drug this patient's E. coli is resistant to):
"Some of the antibiotics farmers use are those that doctors hold in reserve for the most difficult cases. Colistin is not much used in people because it can damage their kidneys, but it is a vital last line of defence against Acinetobacter, Pseudomonas aeruginosa, Klebsiella and Enterobacter, two of which are specifically mentioned on the CDC watch list. Last year bacteria with plasmids bearing colistin-resistant genes were discovered, to general horror, in hospital patients in China. Agricultural use of colistin is thought to be the culprit."
Considering the same article says that "In America 70% of [antibiotics] sold end up in beasts and fowl" it seems that an easy thing to do would be to stop giving antibiotics to animals
Working antibiotics are among humanity's most precious and most limited natural resources. In a century they'll be gone, with devastating impact on routine medical care. We're living in the one glorious sliver of humanity's history that we have access to antibiotics, and we're squandering them to make meat a few cents/pound cheaper. It's criminally irresponsible toward future generations.
eg. If all animals are given penicillin that does not explain why we see resistance to cipro.
Modern medicine is over! Get to the zombie apocalypse shelter!
Not really though; everything scary in this article is either wrong, exaggerated or both. Ars Technica explains it expertly:
This actually means there is almost certainly a lot of unexplored potential, but getting drug makers interested is quite difficult (though in the last 5 years the field has been 10x more popular).
Most antibiotics on the market are just penicillin variants (well, β-lactam variants), mostly because that was one of the first things to blow onto a petri dish, was non-toxic, easy to manufacture, small molecular weight, and it happened to work quite broadly. Most bacteria share β-lactamase encoding plasmids with each other, so resistance is conferred within years (I think the original penicillin made it 4 years). Honestly we have done very little outside of this space.
β-lactamase inhibitors (basically blocking the method of resistance with a separate drug) have a lot of potential, as do many other combination therapy techniques. There are also many other non-β-lactam templates we could play around with.
With modern sequencing, you can actually identify the exact resistance mechanism of each strain you encounter. If we move to rapid diagnostic sequencing, we can tailor the treatment to avoid any existing resistance for the specific infection.
The worry here isn't that antibiotics will suddenly become useless and whenever anyone gets a bacterial infection they'll have no hope. The worry is that there will be a number of prevalent bacterial illnesses which can't be treated with antibiotics.
Currently antibiotics work for an overwhelming majority of bacterial illnesses, that's not going to change overnight. What will change is the idea that bacterial illnesses are trifles because they can be cured every time by antibiotics. A few diseases will emerge, more and more over time, that have much worse consequences than we are used to thinking about right now, but the rest will be the same.
I don't mean to underplay the threat, but if we keep pushing this rhetoric, people will discredit the threat when it turns out that 50 years later we're still using antibiotics for most illnesses that people actually get (because antibiotic-resistant strains are effectively quarantined). People will compare it with the "we're going to run out of oil" scare.
If you remove the exposure to the antibiotic, they will revert back to the wild strain pretty quickly.
If we just stopped using antibiotics in agriculture, especially to promote growth, this could actually be possible.
Is it a problem that needs to be addressed? Yes. Is it the end of the world? Unlikely.
Bacterial pneumonia, bacterial meningitis and bacterial septicemia all carry a substantial risk of death even in affluent countries with good healthcare systems.
It is really weird how we concentrate all sick people in one place, and then act surprised when they start growing weird diseases.
I don't think anyone finds it that surprising really. But healthcare is expensive and centralising in-patient care is the only practical and affordable system that we have come up with so far! Key things are to maximise hygiene and minimise length of stay :)
On a similar note, I have never once seen someone in my office wash their hands for more than 5 seconds. Also, on several occasions I've seen someone poop and simply run water over their hands for half a second. It boggles my mind.
1. Why were you watching?
2. The anus may need cleaning. The hands are not supposed to need cleaning.
2. Out of your own experience, how often you clean your anus without getting your hand dirty even in the slightest?
Ideally there are separate hospital buildings for patients with diseases, broken bones, new born babies, etc - often older hospitals that evolved over many decades are like that. Contrary to that are these centralized mega-structure hospital building from the 1960s to 1980s. Often the same small number of operating rooms (often centralized in one location, next to each other) are used for all kind of treatments.
>The strain found in the woman is treatable with some other antibiotics.
1. It's hard. You need to find a molecule that has a mechanism of action against bacteria, but only bacteria. Any cellular function you share with human cells is right out (this is why anti-fungals are double-plus hard mode). We got away with this by glueing new functional groups onto things to evade resistance, but inventing a new target never before seen in nature is...tricky. Most of the easy stuff got developed by the bacteria first - they've been working on this problem longer than we have.
2. It's very expensive. Fidaxomicin (aka Difficid) cost $175 million to develop, and it's on the cheaper side. While it might still be profitable, that's a steep up-front cost. One does not casually embark on developing a new antibiotic.
At first you can do it, then, all the easy ones get solved. The ones that remain all have a number of troubles: they are hard to reproduce, or the last person to touch that module quit last September, or that's a known issues with the architecture that has been put off for the last 2 releases, etc, etc.
Add to that the usual problems with drug discovery+development, e.g. stuff that works in a dish doesn't always work when critters eat it.
Add the problem that new antibiotics should be used only when necessary, e.g. you won't sell a lot of product until it's really old and off patent
Also, only in the US does profitability seem to affect making basic medicines. Bacterial resistance is a global issue, not just one like vaccines that is largely a US issue.
We're going to be flooded with new antibiotics in the years ahead.
Luckily, someone thought to grow them in dirt, and now there are many promising new antibiotics.
Thanks for completely ignoring that advice with a headline and three paragraphs of misleading information designed specifically to cause panic.
1. Stricter regulation of antibiotics, particularly in farming.
2. Better government funding of antibiotic discovery.
3. Stricter regulation of antibiotic use. No solo-drugs, all antibiotics used in stacks of 3 or more. Better monitoring of complete antibiotic use cycles.
Biologic resistance can be managed, HIV is more than enough evidence of it working. We have to get serious about it, the age of reckless antibiotic use needs to end, now.
This is purely from anecdotes, but I've heard from several friends who were exchange students from Pakistan/China/India that we have such a ridiculous system here, that back home they can just buy random antibiotics from the pharmacy whenever they catch a cold.
150 billion land animals raised yearly are a big evolutionary pool of bacteria. To become resistant to antibiotics takes much less time when you run the experiment in parallel 150 billion times per year, than a couple hundred million in humans.
One strain, isolated in one of the 150 billion animals can become resistant and spread around the farm. If it goes unnoticed it can quickly spread over the country.
Yeah, and they resell them on Amazon so Americans can have the same access.
Maybe you'll find doctors that will prescribe antibiotics for anything, but the amount of required paperwork seems to be eliminating the practice successfully.
The next generations will be a lot more expensive due to the cost of developing it. Sadly, this means that many will die not affording the medicine.
but I see that this story with the alarmist headline got more traction on the main page of HN. That's unfortunate for understanding the underlying issues.
Phage therapy is using viruses which will infect and attack the bacteria. Viruses can mutate and adapt just as well as bacteria (while say antibiotics are static in a way). So they can keep up with the mutations.
It is a pretty crazy but also ingenious approach.
Immune clearance: The immune system really enjoys soaking up phage. Blood titers drop stupidly fast. Maybe we could flood the colon with a phage-bearing solution to handle GI infections, but in general I'm really skeptical. There was a paper ~8 years ago describing serial passages in rabbits to enrich for immunocompatible phage. Don't know if further work has been done here.
Specificity: Phage really, really like their hosts. I had a strain of Phi X174 in lab that would simply never infect wild type E coli. To deploy phage effectively, you need to culture whatever it is that you're after. Next you'd want to infect the pathogen in culture and pass your phage for O(many) generations. A lot of human pathogens are just miserable to grow.
Efficacy: Antibiotics are just better at killing bacteria (resistance aside.)
Regulatory: You'd need to convince the FDA to approve a viral cocktail that is potentially going to kill the patient through anaphylaxis.
Needless to say, I could never get them to grow.
Edit: I found the protocol!
Phew. Did I mention: it was an anaerobe? Flushing an exotic growth media with nitrogen is a dull way to spend a Friday afternoon.
It does seem to be undergoing a growth in interest in the research and development communities. I suspect that this might get squashed by the newfound ability to discover new classes of antibiotics pretty much as needed, however:
There's no way for them to jump domains prokaryotes to eukaryotes. It's just biologically implausible. Phage are very narrow spectrum and coevolve with their hosts. They're all over our environment and have been since just about the dawn of life.
Hypothetically, I guess you could accidentally sterilize your gut flora, but again: they aren't broad spectrum.
> Colistin is the antibiotic of last resort for particularly dangerous types of superbugs
and further down:
> Colistin is widely used in Chinese livestock ...
This is absurd. Preventive use of antibiotics on livestock works just like a giant training camp for hostile bacteria, and horizontal gene transfer will spread the necessarily created resistances to human microbes rendering them useless sooner or later.
>Health officials said the case in Pennsylvania, by itself, is not cause for panic. The strain found in the woman is treatable with some other antibiotics.
So the last resort doesn't work, but other stuff works. It's totally reasonable to assume that if bacteria becomes resistant to more common antibiotics, that some other kind of antibiotic could do the trick.
Though I guess it would be nicer to have some sort of "proof" that the bacteria _does_ get weaker to stuff it's less exposed to.
Actually, side note but wouldn't mass feeding of antibiotics for certain kinds of bacteria let us completely wipe it out, a la smallpox?
-- Viruses can't reproduce outside their host. They have a limited lifetime in the environment before they degrade.
-- Immunity lasts a long time, even a lifetime.
-- So, if you successfully immunize everyone in the population against a virus (like smallpox), and keep doing it for a few years, then eventually that virus will die out
This is not true for bacteria. Many bacteria can live in the wild, and in fact only opportunistically infect humans. Also, antibiotics are only effective while you are taking them, and many of them have negative consequences if taken for long times in therapeutic doses (stomach upset, light sensitivity, yeast infections, just to name a few). Next, 60% to 90% of a dose of penicillin is excreted into the urine fully intact, so our sewers, which are teeming with bacteria, would also be flooded with sub-therapeutic doses of antibiotics. Finally, bacteria can exchange DNA with each other, even inter-species, so if we train the sewer germs to survive an antibiotic dose, then they can transfer that capability to other more virulent bacteria that can infect humans. This is, in fact, probably the mechanism for formation of some of these multi-drug resistant strains.
This will just create the same selection pressure chemotheraputics did, except now you have the additional burden of fucking with your DNA (and probably risking cancer).
Staph Retreat - Nov 2015
Or load it up in your favorite mobile podcast app.
Sorry for the redundant comments, but it's important for people to hear this. More people die from MRSA than AIDS in the US, and the FDA is structurally against adaptive therapies.
And characterizing it as "free" is...flawed, at best.
This is the field I work in. Phage therapy is awesome, and actively being explored, but there is a reason antibiotics won out. Phages are anything but easy and general-purpose.
which sounds like a regulatory issue. And a bit of an unnecessary one it seems as the treatments seem harmless to humans.
Also, phage therapy killed people in the past. Mostly due to poor purification, but it's not inherently harmless.
Can you please explain how a full treatment course worth of Staphylococcus Aureus bacteriophage will only set you back about $100 in Moscow, Russia?
Additionally, Russia has done the investment in laboratory capacity in order to do phage therapy. Introducing it into the United States would require new equipment, space and staffing in order to facilitate more widespread culturing (as there are no "broad spectrum" phages), as well as the actual preparation of phage-based therapeutics.
You can't get sick if you're not near anyone else.
I know that bleach is used, but hospitals used to smell of the stuff.
Amputations are going to make a comeback big time.
Its going to be interesting if you can't go into surgury for fear of getting post op infection.
This will be interesting to watch.
A preventative measure was a gown with ventilation ports. I was told circulating warm air over the body surface has been shown to reduce post-surgical infections. As well, in the hospital IV antibiotics were administered as a further precaution. Fortunately for me I escaped infections, but a number of people I know did not have as favorable an outcome.
As you point out, using disinfectants is not a new idea. Readily available materials other than bleach are effective and not as malodorous or irritating as bleach. Hospitals are usually pretty careful about that, there are always mishaps, chance of carelessness, infections are hardly rare.
By all means avoid surgery if that's feasible. If not avoidable, may we find an excellent hospital with great, dedicated staff and be blessed with generous insurance benefits. And of course, one can never have too much good luck.