Carprofen is a member of the class of drugs known as NSAIDS (non-steroidal anti-inflammatory drugs), the same class as such common over-the-counter remedies as Advil (Ibuprofen), Aleve (Naproxen), Orudis (ketoprofen), and Aspirin. The chief use for such drugs in the dog has been pain relief, usually joint pain or post-surgical pain relief.
stomach ulceration - even perforation and rupture of the stomach can occur. This is not only painful but life-threatening.
platelet deactivation - platelets are the cells controlling the ability to clot blood and, as a general rule, it is preferable not to promote bleeding. We would prefer platelets to remain active and able to function should we need them.
decreased blood supply to the kidney - this could tip a borderline patient in to kidney failure.
The veterinary profession has been in need of an NSAID that could effectively relieve pain without the above risks. In 1997, Pfizer Animal Health released this medication for dogs in the U.S. as the answer to this need. This medication had been available in the U.K. since 1994 and has earned a reputation for effectiveness and safety.
Carprofen is used in the treatment of pain and is usually given twice a day. It takes 1-3 hours after oral administration for a dose of carprofen to reach its maximum effect.
Carprofen is approved only for canine use officially and dogs may safely take this medication long term with no ill effects. Injectable carprofen, only available in the U.K., is commonly used for post-operative pain relief in the cat but only one or two doses are typically given.. Do not use this medication in a cat without specific veterinary guidance.
There is an approximately 4% or less chance of a dog on Carprofen showing any of the following side effects: nausea, appetite change, diarrhea, lethargy or constipation. If a dog develops nausea, vomiting, or appetite loss while on carprofen, it is important that the medication be discontinued and that blood testing be done to rule out a liver necrosis syndrome that occurs in one in 5000 dogs on carprofen. This syndrome is rare but can be fatal if early warning signs are ignored. This syndrome has been described primarily in Labrador retrievers taking carprofen for longer than 3 weeks.
Platelet deactivation was not found in the testing of this medication; however, Carprofen is not recommended for animals with known bleeding disorders.
Carprofen should not be used in patients with pre-existing liver disease, inflammatory bowel disease, or with known tendency towards GI ulceration.
Drugs of the NSAID class should not be used concurrently as the potential for the aforementioned side effects increases. For similar reasons, NSAIDS should not be used in conjunction with corticosteroid hormones such as prednisone, dexamethasone etc. The University of California at Davis recommends a two week "rest" period when changing from any NSAID to carprofen or from carprofen to another NSAID.
Carprofen has not been tested in pregnant or nursing females and thus is not recommended for use in such individuals.
Hepatic necrosis syndrome in large breed dogs (especially Labrador retrievers) is a rare condition (one in 5000 at most). It is important to put this in proper perspective and follow the guidelines as described here. Many exaggerated reports and rumors have surfaced on the internet and it is important to consider only confirmed and properly investigated information.
Page at the above address.
veterinary prescription only. The approved drug sponsor is Pfizer Animal Health of Exton, PA.
administration. Based on the studies submitted to CVM, the risk of Rimadyl® was thought to be negligible.
reports for dogs involved death of the dog, either on their own or by means of euthanasia.
In spite of the high standards for safety and effectiveness that exist for FDA approval, not everything is known about a drug when it is first marketed.
Due to the limited number of animals and controlled nature of pre-marketing clinical trials, only the most common adverse effects will be observed.
Uncommon effects or problems may not be discovered until after the drug has been widely used.
involving the drug. In May 1997, CVM asked Pfizer to change the adverse reaction section of the label.
containing safety information for veterinarians to give to owners at the time Rimadyl® is dispensed.
gastrointestinal system. Adverse effects on the kidney and liver have also been documented.
Rimadyl® continuously for more than 30 days.
disease condition more pronounced in older dogs. Older dogs in general may be more susceptible to carprofen-related adverse effects.
communication is not occurring in many instances.
using these products in dogs.
- A diagnosis of hepatocellular toxicosis attributable to carprofen administration was made in 21 dogs on the basis of development of clinical signs and clinicopathologic abnormalities associated with hepatic disease and histopathologic documentation of hepatic necrosis. Clinical signs of toxicosis were anorexia, vomiting, and icterus. Hyperbilirubinemia and high serum activities of alanine transaminase, alkaline phosphatase, and aspartate transaminase were the most notable clinicopathologic abnormalities. In 7 of 9 dogs in which urinalyses were performed, abnormalities suggestive of renal tubular disease were detected. Clinical course of toxicosis was variable; however, most dogs had resolution of clinical signs and improvement or resolution of biochemical abnormalities with discontinuation of the drug and administration of supportive care. As with any medication, clients should be informed of possible adverse effects and reactions associated with administration of carprofen. In the event of those signs, clients should be instructed to immediately discontinue administration of carprofen to their dog and contact their veterinarian.
You might call it a made-for-TV drug. Approved for human use in the U.S. but not marketed that way, an arthritis medicine called Rimadyl languished for nearly 10 years in developmental limbo, then emerged in a surprising new form: Instead of a human drug, it was now a drug for arthritic dogs. And it became a hit.
With the aid of slick commercials featuring once-lame dogs bounding happily about, Rimadyl changed the way veterinarians treated dogs. "Clients would walk in and say, `What about this Rimadyl?'" says George Siemering, who practices in Springfield, Va.
Today, those TV spots are gone. The reason has to do with dogs like Montana.
A six-year-old Siberian husky with stiff back legs, Montana hobbled out of a vet's office in Brooklyn, N.Y., six months ago accompanied by his human, Angela Giglio, and a supply of Rimadyl pills. At first, the drug appeared to work. But then Montana lost his appetite. He went limp, wobbling instead of walking. Finally he didn't walk at all. He ate leaves, vomited, had seizures and, eventually, was put to sleep. An autopsy showed the sort of liver damage associated with a bad drug reaction.
Montana's owner, Ms. Giglio, is among them. After she informed Pfizer and the Food and Drug Administration of her relatively youthful dog's death, Pfizer offered her $440 "as a gesture of good will" and to cover part of the medical costs. Insulted by the offer and a stipulation that she agree to tell no one about the payment except her tax preparer, she refused to sign and didn't take the money. "There's just no way in my conscience or heart I can release them from blame," she says.
After reports of bad reactions and deaths started streaming in to the FDA, the agency suggested that Pfizer mention "death" as a possible side effect in a warning letter to vets, on labels and in TV ads. Pfizer eventually did use the word with vets and on labels, but when given an ultimatum about the commercials -- mention "death" in the audio or end the ads -- Pfizer chose to drop them.
Pfizer's director of animal-products technical services, Edward W. Kanara, says that when reports started coming in, "we acted extremely promptly based on the information we had." Pfizer points out that reported adverse events involve less than 1% of treated dogs.
While the numbers include cases "possibly" related to Rimadyl, it is hard to be sure. Many dogs given the arthritis drug are older, and few are autopsied after they die. Pfizer says it analyzed cases of Rimadyl-treated dogs that died in 1998 and found a link to Rimadyl to be "likely" in 12% of cases and "not likely" in 22%; it says there was too little information for a judgment about the others.
Rimadyl -- generically carprofen -- is an anti-inflammatory medicine. Developer Roche Laboratories expected to market it for people in 1988 and received FDA approval, but shelved the plan after concluding the market for such drugs was too crowded. In addition, some outside experts expressed concerns; a commentary in a pharmaceutical journal noted unusual liver-function readings in 14% to 20% of test subjects and opined that "until additional data on carprofen are available, older compounds should probably be tried initially."
The idea of switching the product to the animal-drug track soon arose. A couple of corporate transactions later, it ended up in the hands of Pfizer's animal-drug unit. There, it was treated to the kind of sophisticated marketing Pfizer does well. A survey of 885 dog owners was done. Besides shedding light on favorite dog names (Jake, Ginger, Lady), the poll revealed that one-fifth of dog owners would be willing to spend "whatever it took" to buy an aging dog an extra year or two of life. No fewer than 53% agreed that "my dog is a better companion than other members of my family."
The FDA requires safety and efficacy testing for animal drugs just as for human ones, but animal-drug tests are smaller. Pfizer says about 500 dogs got Rimadyl in various trials, which is no more than a fifth of the number of subjects in comparable human-drug trials. Some dogs showed unusual liver-function readings and one young beagle on a high dose died, but for the most part, the FDA and Pfizer didn't find side effects alarming. The drug was approved for an early-1997 launch. That same year, the FDA made it easier to market drugs directly to consumers on TV.
Soon, Pfizer was running commercials in which a once-stiff yellow Labrador retriever named Lady bounded over a fallen tree as she fetched tennis balls beside a lake. In another ad, a dog leapt through a window and slid down a banister. There were also full-page magazine ads and a public-relations campaign, whose results, the PR firm later said, included 1,785 print stories, 856 radio reports and 245 TV news reports "generating 25.5 million positive impressions on the product." Early on, vets were floored by the drug's effects.
"The results in some cases have been pretty darn close to miraculous," says David Whitten of the Hilldale Veterinary Hospital in Southfield, Mich. "I'm using this drug on my own dog. It has been effective. But as with all medications, side effects are certainly a problem." Indeed, within months of the launch, vets at Colorado State University in Fort Collins noticed troubling reactions. Labrador retrievers seemed particularly affected. Since the safety studies for Rimadyl had emphasized testing on young beagles, Pfizer went back to conduct another, small test just on Labs; it says that test showed no particular problem.
Bill Keller, an FDA veterinary-medicine official, notes that "any time you take a product from the investigation and put it into actual practice, you're going to see things you didn't expect." But reports about Rimadyl came in by the hundreds. The FDA had received just over 3,000 animal-drug bad-reaction reports in 1996, the year before Rimadyl's launch; in 1998, the drug's first full year, Rimadyl alone produced more than that many. They swamped the FDA's tiny Center for Veterinary Medicine in Rockville, Md. Pfizer was scrambling as well. "Basically, their response," says Dr. Keller, " was `Tell us what you want us to do. We love the fact that it's selling so well, but we don't know what to do with all these adverse reactions.'"
The FDA and Pfizer discussed a "Dear Doctor" letter to be sent to vets. FDA records show the agency found parts of an early Pfizer draft "unacceptable as they are promotional in tone. . . ." It was revised. The records also show Pfizer disagreed with the FDA's suggestion that the letter cite "death" as a possible side effect. To get the letter out, the FDA told Pfizer it was "agreeing to your exclusion of the 'death' syndrome from the letter at this time. However, we will revisit the 'death' syndrome issue and other potential side effects for possible inclusion in labeling at a later date." So the term didn't appear in the first warning Pfizer sent, in mid-1997.
Meanwhile, dog owners were asking for Rimadyl. "It was their advertising that sold me on the drug," says Michelle Walsh, a Phoenix woman who says her miniature schnauzer was given it and later died. Not that vets needed much convincing. They saw clear benefits from the drug. On top of that, they could get points from Pfizer for each Rimadyl purchase they made; points were redeemable for PalmPilots, Zip drives for PCs and other equipment.
Although Pfizer's letter told vets to explain to owners the signs of a bad reaction to Rimadyl, such as vomiting, lethargy or diarrhea, it is evident that a great many didn't. The FDA's Dr. Keller says, "There are a lot of veterinarians who don't think they need to take the time, or who forget, or for whatever reason are not providing animal owners with this information."
Donna Allen, whose chow-mix, Maggie, started on Rimadyl last summer, says, " All my vet did was give me this little bag of pills, with no information." She says Maggie "didn't want to take it, but I made her." After four weeks, Maggie began to vomit violently, Ms. Allen says. The dog vanished from their home outside Birmingham, Ala., and later was found lying in a ditch. Ms. Allen loaded her into a truck and sped 35 miles to a veterinary clinic, but the five-year-old dog died. Her vet wouldn't implicate Rimadyl in the death until Ms. Allen urged him to send the dog's internal organs to the University of Illinois vet school, where an examination showed liver toxicity. Maggie was buried under a marker adorned with the figure of an angel. And Ms. Allen took to the streets, delivering a letter to all the vets in the area urging them to "understand that Rimadyl helps certain dogs, but it is poison to other dogs."
As the complaints poured in, the FDA told Pfizer it would have to revisit the label issue. Pfizer had referred to "fatal outcomes" on the label as a possible effect of the drug class to which Rimadyl belonged, but not specifically of this drug. Now the agency asked that Pfizer cite "death" prominently as a possible side effect of the drug. Describing the back and forth with Pfizer, the FDA's Dr. Keller says, "They did it. They weren't enthusiastic about it, but they have always been cooperative. And that's part of the nature of the game we play with industry."
But the FDA also wanted the word "death" in the audio of commercials. Pfizer indicated this "would be devastating to the product," FDA minutes of a February 1999 meeting show. A company spokesman says that "putting 'death' on a 30-second commercial and in proper context was something we didn't think was possible." Rather than do so, it eventually pulled the commercials. Pfizer says it now will do traditional marketing to vets, making sure they know the proper way to use the drug.
Another "Dear Doctor" letter will soon go out, and the company will start attaching a safety sheet to pill packages. Pfizer acknowledges it has a perception problem with some dog owners; a consumer group, for instance, has mounted a campaign dubbed BARKS, for Be Aware of Rimadyl's Known Side-effects. The company is contacting dog owners who have told their stories on the Internet, and it is offering to pay medical and diagnostic expenses for some dogs who may have been harmed by Rimadyl.
But Pfizer stands firmly behind the value of the drug, of which it says sales have continued to grow. Most vets also remain strongly behind Rimadyl. Owners, too, generally say they think the drug is important -- they just want to know the risks. Atlantan Roger Williams gave his mixed-breed terrier, William, Rimadyl for more than a year and believes it contributed to the dog's death. "But if I had to do it all over, I would give my dog Rimadyl again," he says. "The difference is I would have known what to expect. Without Rimadyl, William was miserable. And what's the point of living another three years if you're miserable?"
the settlement remain confidential. Ms. Townsend refused.
hundreds of other dog owners whose pets had become ill or died.
what to do if side-effects occur.
and did not include a confidentiality provision.
Vioxx, the FDA benignly approved Previcox (firocoxib) for dogs.
more selective for cox2 than cox1, it is not a NSAID of the coxib class.
information except the FDA Freedom of Information Summary for Previcox.
Dockets website; however, the part that you want is illegible.
could the 37% not be a placebo effect?
human studies of these type drugs for osteoarthritis Conclude NSAIDs can reduce short term pain in osteoarthritis slightly better than placebo, but the current analysis does not support long term use of NSAIDs.
inhibitors (coxibs), in patients with osteoarthritis of the knee.
Main outcome measure Change in overall intensity of pain.
significant effect of NSAIDs compared with placebo at one to four years.
reduction of 0.23 (0.15 to 0.31).
CVM has reviewed safety and effectiveness data.
adverse events varies with the individual patient.
should be avoided or closely monitored.
clinical experience. The disclaimer that "clinical relevance has not been shown,"
insufficient to correct the overall misleading impression created by the materials.
higher than 0.0001 3 percent.
and refer the reader to the package insert for more information.
corticosteroids or potentially nephrotoxic drugs. They are, therefore, misleading.
superiority, and safety claims, and because they omit important risk information.
those described above, and explaining your plan for discontinuing use of such materials.
that only written communications are considered official.
with each applicable requirement of the Act and FDA implementing regulations.
Pfizer used the theme "Celebrate" in its promotional campaign for Celebrex to appeal to baby boomers beginning to suffer from arthritis.
his article was reported by Barry Meier, Gina Kolata and Andrew Pollack and written by Mr. Meier.
In the mid-1990's, the medical community reached an inescapable conclusion. Researchers at the Stanford University Medical School and elsewhere who had long been monitoring arthritis and rheumatism patient records had found that thousands of patients, perhaps as many as 16,500, were dying annually from bleeding ulcers and other problems caused by widely used painkillers like ibuprofen.
Within a few years, a new class of pain relievers, the so-called COX-2 inhibitors, burst onto the market with the promise they might reduce that toll. Sales of the best known products, Celebrex and Vioxx, quickly skyrocketed - thanks in part to changes in federal rules in 1997 that made it much easier for drug makers to advertise medications directly to consumers on television, in newspapers and in magazines.
Now, though, the flight path of these blockbuster drugs has been aborted. On Friday, Pfizer the maker of Celebrex, which is expected to end up with sales of $3.3 billion this year, disclosed that a patient trial by the National Cancer Institute had found significant risks of heart attacks. Vioxx, which was made by Merck and had sales of $2.5 billion last year, was pulled from the market in late September after similar findings.
In some ways, the story of the COX-2 drugs, a class that includes another troubled Pfizer medication, Bextra, is part of an age-old search for safer pain treatments. And some doctors say that they have helped. But it is also perhaps the clearest instance yet of how the confluence of medicine and marketing can turn hope into hype - and how difficult it is for the Food and Drug Administration to monitor the safety of drugs after they have been approved for the market. Celebrex and Vioxx, after fast-track approval from the F.D.A., hit the nation's pharmacies as revolutionary drugs that could not only treat arthritis patients' pain, but potentially save their lives.
But having spent hundreds of millions of dollars to develop their drugs, the makers of Celebrex and Vioxx, cheered on by Wall Street, had every motivation to expand their markets beyond the older people most at risk of ulcers to encourage the drugs' use by millions more people of all ages. That was so even as, at least in the case of Vioxx, there was evidence as early as 2000 that a COX-2 drug could cause heart problems.
"You have to realize that these medications, they are not candies, they are not placebos," said Dr. Gurkirpal Singh, a Stanford professor who has worked on the arthritis database project. A big problem with the COX-2 drugs, he said, has been the tendency of doctors to use them indiscriminately. "Like all medications, you have to identify which people will benefit the most, and which won't."
Since the drugs' release, the companies have spent hundreds of millions of dollars on television, newspaper and magazine advertising for them and, by some estimates, at least as much on marketing and promoting the drugs to doctors. As a result, many medical experts now say that Celebrex and Vioxx, selling for $2 or $3 a pill, have been too widely prescribed to patients who could safely obtain the same pain benefits from over-the-counter drugs costing pennies apiece.
Potentially wasted money, though, is not the main point about the sales push, now that there is clinical evidence that all the COX-2 drugs on the market can, in some circumstances, increase a user's likelihood of strokes or heart attacks.
On Friday, Pfizer characterized the cancer trial findings as an anomaly requiring further study and said it was not ready to withdraw the drug. But the news of the trial results was enough to send drug stocks plummeting and to cast grave doubts on the future of the entire COX-2 drug category. Only a few weeks ago, the F.D.A. ordered Pfizer to put a label warning on Bextra, noting that it could pose cardiac risks to patients recovering from heart surgery.
Pfizer and Merck have repeatedly said that their marketing has been accurate and responsible. "We market all of our medicines consistent with regulation," said a spokeswoman for Pfizer. "Doctors and patients are in the best position to say which drugs are most appropriate for them."
But the rapid rise and now shaky future of this class of drugs, some researchers say, is emblematic of the way drug companies' efforts to spur the use of costly new medicines can distort the medical realities of safety and effectiveness.
Too often, marketing can drown out medical science, said Dr. James F. Fries, the director for the Stanford arthritis database project, which receives funding from the National Institutes of Health. "Here, it was not a fair battle."
The roots of Celebrex and Vioxx reach back to the early 1990's. At the time, Harvey R. Herschman and colleagues at the University of California, Los Angeles were screening large numbers of genes trying to find ones that might be involved in cancer. The screen turned up a gene that was in many ways similar to a known gene for an enzyme called cyclooxygenase or COX.
It had long been understood that COX spurred the production in the body of chemicals called prostaglandins that contributed to pain, inflammation and fever. But it had always been thought that there was only one COX enzyme. Now in Dr. Herschman's laboratory emerged evidence of a new one, which came to be called COX-2. Similar discoveries were made about the same time in the laboratories of Donald A. Young at the University of Rochester and Daniel L. Simmons at Brigham Young University.
"It was totally unexpected, completely serendipitous," Dr. Herschman said of his own discovery, adding that he believed that to be true of the other labs as well.
But the implications were immediately clear to Philip Needleman, who had already hypothesized the existence of a second COX enzyme and had begun to characterize its role in the body. The original COX, now called COX-1, seemed to be present everywhere in the body and contributed to vital functions like protecting the stomach lining. COX-2 seemed to be present mostly during times of inflammation. So if a drug could be made to block COX-2 but not COX-1, the thinking went, it could relieve pain without causing ulcers.
Convinced of the importance of the discovery, Dr. Needleman had moved from Washington University in St. Louis to Monsanto in 1989 to lead an all-out effort to develop a COX-2 inhibitor. The result of Dr. Needleman's effort was celecoxib, or Celebrex. Monsanto's drug division, Searle, eventually was acquired by Pharmacia, which in turn was gobbled up by Pfizer, in a rush of mergers that swept the drug industry over the past decade to satisfy Wall Street's desire for rapid growth.
Thinking that Celebrex and Vioxx would help cut the rate of gastrointestinal bleeding, the F.D.A. took only six months to review the applications for both drugs, an accelerated process used only for drugs deemed medically important. But in both cases, the F.D.A. decided that the drugs had not sufficiently demonstrated that they reduced the rate of serious gastrointestinal problems compared with existing painkillers like aspirin and ibuprofen. So the drugs' labels contained the same warnings as the older drugs about such side effects.
Merck later conducted studies that persuaded the F.D.A. to change the label, but Pfizer's results were never convincing enough for the agency to remove the warning from Celebrex's labeling. In other words, the world's best-selling COX-2 has never been proven to the F.D.A.'s satisfaction to have the stomach-protecting benefits that originally were supposed to be the point of that category of drugs.
By the time they reached the market, the COX-2 drugs were marketed by makers as not simply improved versions of older treatments but as entirely new drugs.
"They wanted to use this as a discontinuity with the past," said Dr. Fries, the Stanford professor.
The audience also went beyond those at the highest risk of stomach bleeding - principally people over 65 years who have suffered from gastrointestinal problems or might be at risk for them.
Dorothy Hamill, the 1976 Olympic figure skating gold medalist, was the middle-aged celebrity face of Vioxx. Television commercials for Celebrex presented actors engaged in activities like riding bicycles and performing tai chi to the strains of the song "Celebrate" by the 1970's band Three Dog Night. The song's choice echoed more than the drug's name; it was also selected to appeal to a critical audience, baby boomers beginning to suffer from arthritis.
Celebrex has been one of the most heavily promoted prescription drugs in advertising aimed at consumers. For the first nine months of this year, Pfizer spent almost $71.2 million on Celebrex, up about 55 percent from almost $46.1 million spent in the same period a year ago, according to data from the research firm TNS Media Intelligence/CMR. The effect of such advertising, many doctors say, was to drive to consumer demand for COX-2 drugs far beyond the bulk of those patients who really benefit from them.
Dr. Elizabeth Tindall, the president of the American College of Rheumatology, a professional group, said her group believed that COX-2's are an appropriate treatment for patients at high risk of stomach problems. But "we weren't saying to anyone if you have a 23-year-old with ankle pain put them on this drug," said Dr. Tindall, who practices in Portland, Ore. "That was the impression that the TV advertising was giving."
Within little more than a year, the drugs had grabbed about 40 percent of the market from traditional anti-inflammatory drugs like ibuprofen. Some efforts were made to determine who would most benefit from the drugs. Researchers at Stanford developed a scoring tool that physicians could use to determine, based on a patient's age and medical history, whether they were at high risk for stomach bleeding and, as a result, candidates for drugs like Celebrex and Vioxx.
Dr. Singh, the Stanford professor, said that most patients did not fall in the high-risk category.
Few groups or individuals, however, used the scoring tool. One organization that did was Kaiser Permanente, one of the nation's largest health care systems. Dr. David Campen, a medical director at Kaiser, said that because of the scoring system only about 5 percent of Kaiser's patients received a COX-2.
Beyond their heavily promoted use as prescription-strength painkillers, COX-2's have been extensively studied for other potential uses, like fighting or even preventing cancer. And, perhaps ironically for the drug companies, it was cancer prevention studies that ultimately provided clinical evidence that Vioxx and Celebrex posed cardiac risks.
For years scientists have pursued evidence that aspirin-like drugs may help control the occurrence of polyps in people at risk of colon cancer. But there was a problem with testing such drugs as cancer preventatives in healthy people: the drugs could cause ulcers and bleeding.
So when Vioxx and Celebrex were developed as drugs that might act like aspirin, without the risks of bleeding, cancer researchers saw their chance. In fact, based on tests Searle had conducted with the National Cancer Institute, the F.D.A. approved Celebrex for patients at high-risk of getting colon cancer.
By last year, more than a dozen studies of Vioxx and Celebrex were under way with people at high risk for cancers of the lung, breast, skin, prostate, colon, mouth, bladder or esophagus. They were being studied along with standard treatments in patients who already had cancer.
The trials that disclosed the dangers involved healthy people who had already had polyps removed from their colons and who were randomly assigned to take a placebo or a COX-2 inhibitor. Each study sought to learn if taking a COX-2 inhibitor prevented the subsequent formation of polyps.
That answer is not yet known and the researchers have not released those data. But in both studies, the participants taking the COX-2 inhibitor had more heart attacks and strokes than those taking a placebo. The problem was seen in the Vioxx trial after 18 months and after a longer period in the Celebrex trial among patients taking high doses.
For all their early promise, the future of COX-2's is uncertain.
Dr. Lester Crawford, the F.D.A.'s acting commissioner, said Friday that doctors should consider switching their Celebrex patients to other drugs. He said the F.D.A. had "great concerns" about Celebrex and Pfizer's Bextra and was considering regulatory measures that could include forcing Celebrex's withdrawal or placing severe warnings on its label.
Merck has a successor to Vioxx, called Arcoxia, pending approval at the F.D.A. But the agency, which has a panel planning to hold hearings on the entire class of drugs early next year, has tabled that application for now.
Some physicians, like Dr. Tindall, the rheumatologist in Portland, said they were concerned that if Celebrex or Bextra, or perhaps both, were withdrawn from the market that some patients who need such drugs will not get them. Indeed, many former Vioxx patients have complained about the withdrawal of that drug, saying it was the only pain medication that worked for them.
As it turns out, deaths and hospitalizations from stomach problems related to the use of ibuprofen and aspirin peaked in 1992 and had already dropped significantly before the appearance of Celebrex and Vioxx, according to data collected by Stanford University. In 1999, the year of the two drugs introductions, those problems also had another sharp decline.
Dr. Fries of Stanford said the drop-off over the past decade reflected, among other things, the use of lower doses of various painkillers. There has also been growing use of less toxic ones, not only COX-2's but other medications, like Mobic, that other drug makers began to sell in response to concerns about stomach bleeding. Many doctors also have patients taking medications like Prilosec to offset the stomach irritation of some painkillers.
In terms of stomach bleeding, the relative risks of some other less irritating painkillers like Mobic appear indistinguishable from COX-2's, Dr. Fries said. But because of the expense and difficulty of conducting broad-based clinical trials, there have been no studies comparing those drugs with one another and with the COX-2's.
Dr. Fries said the story of the COX-2's was emblematic of the consumer marketing forces that now propel the drug industry.
It is a market, he said, in which the lure of the new can run ahead of science.
"You have to have a new generation of drugs," said Dr. Fries. And under that model, "the old ones are dangerous, and the new ones are safe." Or until proven otherwise.
What are approved NSAIDS in the United States?
WASHINGTON (Reuters) - Novartis AG failed to give the government prompt, accurate reports about deaths of dogs treated with a painkiller in the same class of medicines now linked to heart problems in humans, U.S. regulators have charged in a letter.
The drug, Deramaxx, is a COX-2 inhibitor approved for relieving arthritis and post-surgical pain in dogs.
Similar drugs for people are under heavy scrutiny after studies associated them with heart attacks and strokes. One of the drugs, Merck & Co Inc.'s Vioxx, was pulled from the market because of safety risks.
Death has been reported "in rare situations" when dogs were treated with Deramaxx, according to the drug's label instructions.
The Food and Drug Administration, in a warning letter dated Nov. 29, said Novartis Animal Health Services should have forwarded complaints about deaths and health problems in dogs given Deramaxx within 15 working days, but in some cases delayed as long as 10 months. Some reports, including ones involving deaths, appeared to have incorrect dates, the FDA said.
"Novartis failed to submit timely and accurate information to the FDA regarding serious (adverse drug experiences) associated with the administration of its FDA-approved animal drug product Deramaxx ... during its first year of marketing," the FDA said.
The company also failed to submit proper information about post-approval studies of Deramaxx, the FDA charged. The drug is known generically as deracoxib.
Novartis officials could not immediately be reached for comment.
The FDA sends dozens of warning letters per year. Most of the issues raised are resolved without further regulatory action, although the letters sometimes lead to tougher steps such as product seizures.
Arthritis Medicines and Cardiovascular Events—"House of Coxibs"
The principal cardiovascular event data for APC are summarized in the Figure. This was a trial of 2026 patients, with randomization to 1 of 3 groups: placebo; celecoxib, 200 mg twice daily; or celecoxib, 400 mg twice daily. The patients, each of whom had an adenomatous polyp removed before enrollment, were followed up for a mean of 33 months (of a planned 60 months) while taking the study drug, with the primary objective of limiting the development of colorectal cancer.
The difference for events between the 400-mg and 800-mg dose was not significant (OR, 0.7 [95% CI, 0.4-1.4]; P=.30). OR indicates odds ratio; CI, confidence interval. The dose response trend across all groups, P=.007.
A significant excess of major cardiovascular events was demonstrated, with a dose-response effect (odds ratio, 2.5 for celecoxib 400-mg dose, and 3.4 at the 800-mg dose, vs placebo) (Figure). The absolute excess of major cardiovascular events of 13/1000 patients at the 400-mg dose and 21/1000 patients at the 800-mg dose is similar in magnitude to the results of trials with rofecoxib and valdecoxib.1, 3 However, it is not possible to meaningfully interpret interdrug differences because the patient populations in the various trials were different; the drug doses, strength, and duration of therapy were different; and each of the drugs in the coxib class are distinct molecules with specific biological properties. While celecoxib is the least COX-2 selective in the class of 5 agents that have gone through pivotal trials,4 lumiracoxib is the most selective. A trial of 18 325 patients, the largest in the field, demonstrated only modest (not statistically significant) excess of cardiovascular risk when lumiracoxib was compared with naproxen, but not when compared with ibuprofen.5 Importantly, there have not been any direct comparative (head-to-head) trials of one of the agents vs another, which is the only way to definitively establish likeness or difference between the drugs.
Notwithstanding these concerns, several epidemiologic studies have considered large populations of patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors.6-10 In general, these studies found an increased cardiovascular hazard for rofecoxib, especially at higher doses, but not for celecoxib. Some studies therefore concluded that celecoxib did not carry any risk for MI or stroke.
But in randomized trials, a signal for potential cardiovascular risk with celecoxib was present. As my colleagues and I described in a 2001 review11 of the Celecoxib Long-term Arthritis Safety Study (CLASS),12 the MI rate was 1.6% in the celecoxib group (at a dosage of 400 mg twice per day) and 1.2% in the diclofenac or ibuprofen group for the 1739 patients taking low-dose aspirin. This numerical excess, albeit not statistically significant, was also found in the 6229patients not taking aspirin in the trial. Notably, the study drug duration was only 6 months. Underlying this finding were 2 other mechanistic issues. In experimental models of coronary artery occlusion, celecoxib had been found to be prothrombotic.13 On the other hand, in patients with coronary artery disease, celecoxib has been associated with reduction of C-reactive protein and improvement of endothelial dysfunction.14 Based on data available in 2001 for celecoxib and rofecoxib, my colleagues and I concluded: "It is mandatory to conduct a trial specifically assessing cardiovascular risk and benefit of these agents. Until then, we urge caution in prescribing these agents to patients at risk for cardiovascular morbidity."11 Unfortunately, no such trials were ever initiated and the official warnings for the coxib drugs took years to materialize.
With celecoxib, only one trial has thus far shown cardiovascular hazard. While this clearly confirms a class effect, there has not yet been independent replication. Unlike rofecoxib, in which 3 independent randomized trials19 and a cumulative meta-analysis20 confirmed excess cardiovascular risk, a trial conducted in parallel to APC for the same indication has not shown any hazard for celecoxib. The celecoxib dose-response effect for cardiovascular events in APC is not shared by the data for rofecoxib.20 It will be important to have a full analysis of the APC data, with timing of the event curve divergence, and careful examination of the cardiovascular risk profile of patients with events. Until more detailed information is available, it appears that celecoxib use should be restricted. A welcome new precedent was set by the FDA and manufacturer with the agreement to stop marketing celecoxib to consumers while the review of all available data is ongoing.
Second, the NSAID benchmark safety has now been called into question. The pattern from multiple trials of coxibs, with different control NSAID comparators, has helped establish some useful findings. Naproxen appeared to be the only NSAID with some cardioprotective effect. Juni et al20 reviewed all of the trials studying this agent and suggested that it is associated with a 14% reduction of MI, which is less than that of aspirin at 23%. On the other hand, ibuprofen appears to act in the opposite direction of naproxen, with an approximate 10% increase in MI as judged from the very large lumiracoxib trial that fortunately included these 2 different NSAIDs as controls.5 From the body of data available, it appeared that naproxen may be the safest NSAID from a cardiovascular standpoint.
However, on December 20, 2004, the National Institutes of Health and FDA announced the premature cessation of the Alzheimer Disease Anti-inflammatory Prevention Trial (ADAPT).21 While the trial of approximately 2400 patients with an average of 3 years of follow-up (of a planned 5-7 years) was being reviewed for potential adverse cardiovascular events with celecoxib, an excess of cardiovascular events was found in the patients assigned to naproxen vs placebo. This was the first time in a placebo-controlled trial that naproxen has been associated with an excess of MI events. But the trial was interrupted and not designed to assess cardiovascular events for naproxen, and the events have not been adjudicated by cardiologists. Given the large body of evidence from multiple epidemiologic studies and randomized trials6, 20 supporting a modest degree of cardioprotection with naproxen, it seems premature to judge any possible untoward cardiovascular effect of naproxen until the final data from ADAPT become available.
Third, there are major concerns about how an entire drug class has gone awry with respect to unleashing significant cardiovascular hazard. A "house of cards" is defined as a flimsy situation that is in danger of collapsing or failing. From the outset, the coxib class of medicines seemed destined for potential collapse. These drugs were mass-marketed from the moment they were commercially available in the new world of direct-to-consumer advertising, with unrealistic expectations about pain relief, marked gastrointestinal protection, and safety. Rather than a sufficient waiting period after approval to firmly establish safety in the large, representative "real world" population, the unbridled promotion exacerbated the public health problem. This is so poignantly clear for an indication such as arthritis, which is one of the most common conditions requiring medication. Furthermore, one has to question the wisdom of allowing direct-to-consumer advertising for lifestyle medications that have no capability of preserving life or preventing major events such as MI or stroke. Here the paradox of actually promoting these events is all the more difficult to accept.
In recent weeks there has been considerable speculation on how the FDA authority and configuration can be bolstered to preempt a coxib-like problem in the future. There is ample evidence of the overemphasis and resource allocation for initial drug approval, with little priority for postmarketing surveillance.22 An independent drug safety agency or center that compartmentalizes the vital functions of approval and surveillance seems to be gathering broad support.23 Importantly, providing more authority to the FDA to shape and require the execution of vital trials is perhaps the most important lesson from the coxibs. Currently, for the FDA to mandate that a trial be performed in the postapproval phase of a drug, it has to confront the manufacturer that the drug in question may be withdrawn from the market. There is hardly a precedent for such a drastic step in the history of the FDA. Unfortunately, manufacturers of coxibs were not willing to initiate dedicated cardiovascular trials on their own accord. With early results of coxibs that brought out their prothrombotic potential, rapid initiation of follow-up randomized clinical trials was absolutely necessary. Furthermore, nearly half of "real world" patients with arthritis have coexisting cardiovascular disease,24 and essentially no trials addressed this vacuum of knowledge. Accordingly, legislation is needed to empower the FDA to require industry to conduct trials that are deemed necessary to ensure the safety profile of a drug. Had coxib trials been conducted 5 years ago in patients with established cardiovascular disease, when the benefit and risk were indeterminate, clinicians would have quickly learned the risk and potentially avoided a major cardiovascular calamity.
The combination of mass promotion of a medicine with an unknown and suspect safety profile cannot be tolerated in the future. An aggressive position going forward is necessary not only for ensuring the safety of prescription medicines but also to restore a solid foundation of public trust.
Corresponding Author: Eric J. Topol, MD, Desk F25, 9500 Euclid Ave, Cleveland Clinic Foundation, Cleveland, OH 44195 (topole@ccf.org).
Financial Disclosure: Dr Topol reports no conflict of interest/relationship with any manufacturer of COX-2 inhibitors or NSAIDs.
Disclaimer: The views expressed herein represent the author's and are not intended to represent the institutions with which he is affiliated.
Author Affiliations: Department of Cardiovascular Medicine, Cleveland Clinic Foundation; Office of the Provost, Cleveland Clinic Lerner College of Medicine; Case Western Reserve University, Cleveland, Ohio.
1. US Food and Drug Administration. Bextra label updated with boxed warning concerning severe skin reactions and warning regarding cardiovascular risk. FDA Talk Paper. December 9, 2004. Available at: http://www.fda.gov/bbs/topics/ANSWERS/2 ... 01331.html Accessed December 21, 2004.
2. US Department of Health and Human Services. NIH halts use of COX-2 inhibitor in large cancer prevention trial. NIH News. December 17, 2004. Available at: http://www.nih.gov/news/pr/dec2004/od-17.htm. Accessed December 21, 2004.
8. Kimmel SE, Berlin JA, Reilly M, et al. Patients exposed to rofecoxib and celecoxib have different odds of nonfatal myocardial infarction. Ann Intern Med. Available at: http://www.acponline.org/journals/annals/myo_infar.htm. Published online December 7, 2004. Accessed December 20, 2004.
9. Graham DJ, Campen D, Cheetham C, et al. Risk of acute cardiac events among patients treated with cyclooxygenase-2 selective and non-selective nonsteroidal anti-inflammatory drugs [abstract]. Pharmacoepidemiol Drug Saf. 2004;13:S287-S288.
15. Bextra [package insert]. Available at: http://www.fda.gov/cder/foi/label/2004/21341lbl.pdf. Accessed December 21, 2004.
18. Harris G. Drug trial finds big health risks in 2nd painkiller. New York Times. December 18, 2004:A1.
19. Topol EJ. Rofecoxib, Merck and the FDA [letter]. N Engl J Med. In press.
21. FDA statement on naproxen. Available at: http://www.fda.gov/bbs/topics/news/2004/NEW01148.html. Accessed December 21, 2004.
22. Harris G, Schwartz J. Regulation redefined: the FDA shifts focus; at FDA strong drug ties and less monitoring. New York Times. December 6, 2004:A1.
David Graham said last week that his Catholic faith guided him in blowing the whistle on his employer, the Food and Drug Administration (FDA), for its failure to pull Merck's popular painkiller Vioxx off the market.
Merck voluntarily pulled the drug off the market in September after a study it conducted showed that Vioxx doubled the risk of heart attacks.
"To paraphrase this verse, I have done nothing more than my duty," Graham said.
Graham is married had has six children. His wife is a lawyer who home schools her children.
During his thirty-minute acceptance speech, and a short question-and-answer period that followed, Graham portrayed his action in speaking out publically against the FDA and the drug industry as a Christian duty of conscience.
Graham became something of a celebrity in Washington after going before the Senate Finance Committee and caustically ripping apart the FDA for failing to protect American consumers.
At that hearing, Graham estimated that between 88,000 and 139,000 people in the United States had suffered heart attacks or stroke as result of taking Vioxx and that as many as 40 percent of those, or about 55,000, died as a result.
But at the awards ceremony last week, he didn't use the 55,000 number, instead at one point referring to 40,000 dead, and at another talking about 30,000 to 40,000 dead.
While he was trying to convince his superiors to let him publish his study, Merck was voluntarily pulling Vioxx off the market.
Congress became interested in the drug safety problem only after Merck pulled Vioxx off the market.
The three big painkillers in this class – Vioxx, Celebrex and Bextra – combined made over $4 billion in profits this year.
"And who knows how many people had heart attacks because of them?" Graham asked.
Graham said that on the weekend before his fateful testimony before Grassley's Senate Committee, his bosses launched a three-pronged attack against his credibility.
It became clear from listening to Graham's talk that he blames the FDA, not the drug companies, for the drug safety problems afflicting the country.
Graham said that the big drug companies "have been lobbying like crazy" in recent weeks to prevent Congress from reorganizing the FDA.
"The last thing on earth drug companies want to see is strong post-marketing drug safety because if there is strong post-marketing drug safety, it is going to cost companies more money to research the drugs before they get to market, and they are going to run the risks of a drug being removed from the market," he said.
Under current federal law, the FDA must guarantee that drugs are safe and effective.
But when it comes to safety, the FDA takes that statistical model and turns it on its head, Graham said.
Graham said that a recent FDA Office of Inspector General survey found that two-thirds of FDA medical officers are not confident that the products that are approved are safe and that 18 percent felt that they have been pressured to change their conclusions.
The Joe A. Callaway award was established to recognize individuals in any area of endeavor who, with integrity and at some personal risk, take a public stand to advance truth and justice, and who challenge unsatisfactory conditions in pursuit of the common good.
The award was also given this year to Mark Livingston, a pharmaceutical quality control specialist who was involved in the launching of Wyeth Pharmaceuticals' Prevnar pediatric vaccine.
In the fall of 2003, Livingston filed a lawsuit in federal court alleging that Wyeth Pharmaceuticals compromised the manufacturing process of bulk vaccine to meet demand.
If deaths are similar to vioxx why no animal investigation by the fda like the human one? Do you think honest vets and clients would be buying these cox2 drugs for their patients and pets if they had all the withheld information?
Agency says drugmaker withheld data showing deaths with drug similar to Vioxx.
Novartis (up $0.23 to $50.33, Research) officials could not immediately be reached for comment.
Similar drugs for people are under heavy scrutiny after studies associated them with heart attacks and strokes. One of the drugs, Merck & Co. Inc.'s (up $0.33 to $32.28, Research) Vioxx, was pulled from the market because of safety risks.
Nimesulide, a cyclooxygenase-2 preferential inhibitor, impairs renal function in the newborn rabbit.
Prevot A, Mosig D, Martini S, Guignard JP.
Nephrology Unit, Department of Pediatrics, Lausanne University Medical Center, CH 1011 Lausanne, Switzerland.
Tocolysis with nonsteroidal anti-inflammatory drugs (NSAIDs) has been widely accepted for several years. Recently, the use of the cyclooxygenase-2 (COX2) preferential NSAID nimesulide has been proposed. However, data reporting neonatal acute renal failure or irreversible end-stage renal failure after maternal ingestion of nimesulide question the safety of this drug for the fetus and the neonate. Therefore, this study was designed to define the renal effects of nimesulide in newborn rabbits. Experiments were performed in 28 newborn rabbits. Renal function and hemodynamic parameters were measured using inulin and para-aminohippuric acid clearances as markers of GFR and renal blood flow, respectively. After a control period, nimesulide 2, 20, or 200 microg/kg was given as an i.v. bolus, followed by a 0.05, 0.5, or 5 microg.kg(-1).min(-1) infusion. Nimesulide administration induced a significant dose-dependent increase in renal vascular resistance (29, 37, and 92%, respectively), with a concomitant decrease in diuresis (-5, -23, and -44%), GFR (-12, -23, and -47%), and renal blood flow (-23, -23, and -48%). These results are in contrast with recent reports claiming that selective COX2 inhibition could be safer for the kidney than nonselective NSAIDs. These experiments confirm that prostaglandins, by maintaining renal vasodilation, play a key role in the delicate balance regulating neonatal GFR. We conclude that COX2-selective/preferential inhibitors thus should be prescribed with the same caution as nonselective NSAIDs during pregnancy and in the neonatal period.


text:
Sorbus thomsonii är en rosväxtart som först beskrevs av George King och Joseph Dalton Hooker, och fick sitt nu gällande namn av Alfred Rehder. Sorbus thomsonii ingår i släktet oxlar, och familjen rosväxter. Inga underarter finns listade i Catalogue of Life.

Källor

Oxlar
thomsonii

redpajama_set_name: RedPajamaWikipedia


OSHA expects the updated rule to save more than 600 lives annually and prevent more than 900 new cases of silicosis – an incurable and progressive disease – each year.
The U.S. Department of Labor's Occupational Safety and Health Administration (OSHA) has announced a final rule to improve protections for workers exposed to respirable silica dust. The rule will curb lung cancer, silicosis, chronic obstructive pulmonary disease and kidney disease in America's workers by limiting their exposure to respirable crystalline silica.
OSHA estimates that when the final rule on Occupational Exposure to Respirable Crystalline Silica becomes fully effective, it will save more than 600 lives annually and prevent more than 900 new cases of silicosis – an incurable and progressive disease – each year. The agency also estimates the final rule will provide net benefits of about $7.7 billion per year.
About 2.3 million men and women face exposure to respirable crystalline silica in their workplaces, including two million construction workers who drill and cut silica-containing materials such as concrete and stone, and 300,000 workers in operations such as brick manufacturing, foundries, and hydraulic fracturing. Most employers can limit harmful dust exposure by using equipment that is widely available – generally using water to keep dust from getting into the air or a ventilation system to capture dust where it is created.
Requiring employers to use engineering controls (such as water or ventilation) and work practices to limit worker exposure; provide respiratory protection when controls are not able to limit exposures to the permissible level; limit access to high exposure areas; train workers; and provide medical exams to highly exposed workers.
Providing greater certainty and ease of compliance to construction employers – including many small employers – by including a table of specified controls they can follow to be in compliance, without having to monitor exposures.
Staggering compliance dates to ensure employers have sufficient time to meet the requirements, e.g., extra time for the hydraulic fracturing (fracking) industry to install new engineering controls and for all general industry employers to offer medical surveillance to employees exposed between the PEL and 50 micrograms per cubic meter and the action level of 25 micrograms per cubic meter.
The final rule is written as two standards, one for construction and one for general industry and maritime, and is available here.
Employers covered by the construction standard have until June 23, 2017 to comply with most requirements. Employers covered by the general industry and maritime standard have until June 23, 2018 to comply with most requirements; additional time is provided to offer medical exams to some workers and for hydraulic fracturing employers to install dust controls to meet the new exposure limit.


text:
Q: Elasticsearch EC2 discovery fails with "invalid credentials" I'm trying to create an Elasticsearch cluster on EC2 and getting errors that I have supplied invalid credentials, but these are the exact same credentials I used when creating the instances via jclouds.
A sample error log I see from Elasticsearch:
[2014-03-03 21:32:26,109][INFO ][node                     ] [Baron Blood] version[1.0.1], pid[6832], build[5c03844/2014-02-25T15:52:53Z]
[2014-03-03 21:32:26,110][INFO ][node                     ] [Baron Blood] initializing ...
[2014-03-03 21:32:26,127][INFO ][plugins                  ] [Baron Blood] loaded [cloud-aws], sites []
[2014-03-03 21:32:30,736][INFO ][node                     ] [Baron Blood] initialized
[2014-03-03 21:32:30,736][INFO ][node                     ] [Baron Blood] starting ...
[2014-03-03 21:32:30,932][INFO ][transport                ] [Baron Blood] bound_address {inet[/0:0:0:0:0:0:0:0:9300]}, publish_address {inet[/10.154.175.62:9300]}
[2014-03-03 21:32:31,228][WARN ][org.apache.http.impl.client.DefaultHttpClient] Authentication error: Unable to respond to any of these challenges: {}
[2014-03-03 21:32:31,388][INFO ][discovery.ec2            ] [Baron Blood] Exception while retrieving instance list from AWS API: AWS was not able to validate the provided access credentials
[2014-03-03 21:32:46,415][WARN ][org.apache.http.impl.client.DefaultHttpClient] Authentication error: Unable to respond to any of these challenges: {}
[2014-03-03 21:32:46,425][INFO ][discovery.ec2            ] [Baron Blood] Exception while retrieving instance list from AWS API: AWS was not able to validate the provided access credentials
[2014-03-03 21:33:00,939][WARN ][discovery                ] [Baron Blood] waited for 30s and no initial state was set by the discovery
[2014-03-03 21:33:00,939][INFO ][discovery                ] [Baron Blood] adstage-es-log/KolEM00zT9mYvYn3mDkrow
[2014-03-03 21:33:00,946][INFO ][http                     ] [Baron Blood] bound_address {inet[/0:0:0:0:0:0:0:0:9200]}, publish_address {inet[/10.154.175.62:9200]}
[2014-03-03 21:33:00,998][INFO ][node                     ] [Baron Blood] started
[2014-03-03 21:33:01,454][WARN ][org.apache.http.impl.client.DefaultHttpClient] Authentication error: Unable to respond to any of these challenges: {}
[2014-03-03 21:33:01,463][INFO ][discovery.ec2            ] [Baron Blood] Exception while retrieving instance list from AWS API: AWS was not able to validate the provided access credentials
[2014-03-03 21:33:01,466][INFO ][cluster.service          ] [Baron Blood] new_master [Baron Blood][KolEM00zT9mYvYn3mDkrow][ip-10-154-175-62][inet[/10.154.175.62:9300]], reason: zen-disco-join (elected_as_master)
[2014-03-03 21:33:01,516][INFO ][gateway                  ] [Baron Blood] recovered [0] indices into cluster_state

My elasticsearch.yml file seems, based on the documentation, to be correct:
cluster.name: adstage-es-log
cloud.aws.access_key: MY_ACCESS_KEY
cloud.aws.secret_key: MY_SECRET_TOKEN
cloud.aws.region: us-east
discovery.type: ec2
discovery.ec2.ping_timeout: 30s

Also, because someone will ask, security group is wide open on these boxes. Using Elasticsearch 1.0.1 and ec2 plugin 2.0.0.RC1.
So far I haven't found anything indicating what could be causing this. Any ideas on how to address this issue?

A: This is it as a policy ready for copy&paste:
{
  "Version": "2012-10-17",
  "Statement": [
    {
      "Sid": "Stmt1404060922000",
      "Effect": "Allow",
      "Action": [
        "ec2:DescribeAvailabilityZones",
        "ec2:DescribeInstances",
        "ec2:DescribeRegions",
        "ec2:DescribeSecurityGroups",
        "ec2:DescribeTags"
      ],
      "Resource": [
        "*"
      ]
    }
  ]
}

A: Turns out the issue was that I had incorrect permissions set for my AWS account since we're using IAM. Was able to get past this issue by making sure my account had the following permissions:

*

*ec2:DescribeAvailabilityZones

*ec2:DescribeInstances

*ec2:DescribeRegions

*ec2:DescribeSecurityGroups

*ec2:DescribeTags

A: To add a concrete example to Gordon's helpful answer, here is a working IAM permissions policy:
{
  "Version": "2012-10-17",
  "Statement": [
    {
      "Effect": "Allow",
      "Action": "ec2:Describe*",
      "Resource": "*"
    }
  ]
}

redpajama_set_name: RedPajamaStackExchange


A single-chip IC device has an on-board CPU, an I/O bus controller, and a memory controller all implemented in semiconductor devices on the chip. The CPU, I/O bus controller, and memory controller are interconnected on the IC chip by a parallel data and address bus formed by the IC manufacturing techniques of deposition, patterning, and etching. In a preferred embodiment the on-board local bus has 32 address and 32 data lines. Also in a preferred embodiment the I/O bus controller has 32 data and address paths off the die for connection to a multiplexed I/O bus. The memory controller in the same embodiment has 32 data and 11 address paths off the die to a memory bus with 43 data and address lines. The I/O bus controller is configured to rout memory requests from peripheral devices through the memory controller directly to system memory.
The present invention is continuation patent application of patent application Ser. No. 08/769,582 filed on Dec. 18, 1996, attorney docket number P228FWC2. The disclosure of application Ser. No. 08/769,582 is incorporated herein in its entirety by reference.
The main circuit board of a typical desktop computer is commonly known as a motherboard. FIG. 1 is a simplified block diagram of IC's and interconnections as conventionally implemented on such a motherboard. Its major components include a central processing unit (CPU)  27 for performing computations and managing computer operations according to stored routines, system memory comprised of dynamic random access memory (DRAM) chips 37 for storage of data, and a multiplexed, or combined address and data, input/output (I/O) bus 39 for the connection of I/O devices, such as disk drive controller boards, video co-processor boards, sound boards, fax/modem boards, etc.
A discrete memory controller  33 regulates the flow of signals between system memory and CPU 27 typically over a local bus 45 comprising separate data paths 29 and address paths 31. When the CPU needs information stored in system memory, it makes an off-chip request to external memory controller 33, which fetches the data stored in the address specified by the CPU. The memory controller is usually tailored to a particular type of bus structure, such as the Industry Standard Architecture (ISA) bus, MicroChannel bus, TurboChannel bus, etc. A memory bus 41 connects the memory controller to system memory.
A discrete, multiplexed I/O bus controller  35 regulates the flow of signals between devices on I/O bus 39, such as device 47, and CPU 27. The CPU can make requests to I/O controller 35 to access an I/O device, or an I/O device can initiate an access. The I/O bus is the connection between the I/O bus controller and the I/O devices. It is comprised primarily of a set of circuit paths terminating at several connectors for the installation of I/O devices. I/O bus controller 35 and memory controller 33 are connected in parallel, so that in addition to the regulation of signals between themselves and the CPU, they also serve as a "bridge" that routes memory access requests from I/O devices to system memory.
In a desktop computer with a 32 bit CPU, such as the Intel 80486DX, 32 address pins and 32 data pins are required on the chip, so that addresses and data can be communicated on separate paths. Therefore, the CPU has a total of 64 address and data pins. On the other hand, typical DRAM chips have 32 data pins, but only 11 address pins. When the CPU tries to access a particular address in memory, the memory controller separates the address into row and column portions, then sequentially communicates the two address components to system memory. The memory controller consequently requires 64 address and data pins for connecting to the CPU, and 43 address and data pins for connecting to system memory. To help reduce pin count, multiplexed I/O bus  39 alternately carries address and data multiplexed on the same 32 pins and paths. I/O controller 35 consequently requires 64 address and data pins for connecting to the CPU, and 32 pins for connecting to the I/O bus and peripheral devices. The number of address and data pins among the discrete CPU, memory controller, and I/O controller add up to a high total of 267. Of course, additional control pins are typically needed as well. Because the size of a chip's package is largely dictated by the number of pins (leads) it carries, the large number of pins required by a conventional computer design require relatively large chip packages.
The performance penalty imposed by the slow system memory can be alleviated to some extent by the use of a cache memory  43 comprised of much faster static RAM (SRAM) chips. The SRAM, also controlled by the memory controller, holds the most frequently used information so that it can be supplied to the CPU much quicker than the DRAM system memory can normally operate. Although very fast, SRAM has a much lower memory density than DRAM, so that a significant area on the motherboard is occupied by SRAM chips of just one to two hundred kilobytes. In comparison, DRAM chips occupying a similar sized area can easily hold more than thirty megabytes. SRAM is also significantly more expensive than DRAM.
FIG. 2 is a schematic diagram of an integrated microprocessor according to an embodiment of the present invention.
In a preferred embodiment of the invention as shown in FIG. 2, a microprocessor  10 comprises a CPU 11 compatible with the Intel 80×86 family of 32 bit processors, and a bridge 25. Bridge 25 comprises a memory controller 12 and a multiplexed I/O bus controller 13. The circuitry architecture for controllers to multiplex data and address words on common bus conductors is well known in the art, and not shown in detail. Memory controller 12 in this embodiment has a data buffer 26. Data buffer integrated circuitry is also known in the art and not described here in detail. CPU 11, memory controller 12, and multiplexed I/O bus controller 13 are all located on the same IC physical device, and are interconnected with a very short internal bus 14 comprised of address lines 15 and data lines 16. Bus structure 14 is implemented in the same manner as interconnects are typically provided in IC circuitry manufacture, that is, by metal deposition, lithographic patterning, and etching.
In this description, single-chip device  10 is termed an integrated microprocessor, because the functions generally performed by the circuitry thereon are functions typically performed by discrete microprocessors. Other terms of description might be preferable in some embodiments, and the terminology is not meant to be limiting.
DRAM system memory  18 and multiplexed I/O bus devices 19, such as a video co-processor, modem, or any other peripheral device, are directly connected to microprocessor 10 in this embodiment, rather than through a separate chip or chip set.
System memory  18 is connected to memory controller 12 within microprocessor 10 with a memory bus 20. Memory bus 20 comprises memory address lines 21 and memory data lines 22. Because DRAM is relatively slow, an optional cache memory 24 comprised of much faster SRAM can be added to boost performance. Cache memory 24 stores and makes available to CPU 11 the most frequently used information. Cache memory 24 also connects to memory controller 12 through memory bus 20. Multiplexed I/O bus device 19, exemplary of many I/O devices, is connected to multiplexed I/O bus controller 13 within microprocessor 10 through a multiplexed I/O bus 23. Necessary control lines on internal bus 14, memory bus 20, and multiplexed I/O bus 23 are not shown in the interest of clarity.
Because memory controller  12 is built into microprocessor 10, its functions can be tailored and optimized to support the memory addressing requirements and capabilities of CPU 11. The CPU can provide memory controller 12 advance information about its addressing needs, so that memory controller 12 can obtain the data ahead of time. When CPU 11 needs the information, memory controller 12 will be able to provide it immediately, without having to make CPU 11 wait for the controller to fetch it from system memory 18. Unlike conventional designs, CPU 11 does not have to go off-chip to access memory controller 12, so that its address and data cycle delays can be reduced by a factor of as much as ten or more from those of a conventional design. This saving may amount to as much as two clock cycles, and greatly enhances memory performance. It may also obviate need for expensive cache memory 24, so that board size and cost can be greatly reduced without a reduction in performance. Performance can also be enhanced by using burst mode data transfer, wherein several data words can be communicated following only one address cycle.
When multiplexed I/O bus device  19 issues a memory access request, bridge 25 routes it to system memory 18. Because bridge 25 is integrated into microprocessor 10, the interface overhead between multiplexed I/O bus controller 13 and memory controller 12 is significantly reduced, i.e., the address and data cycle delays are greatly shortened. As a result, system performance is further enhanced.
Microprocessor  10 in this embodiment has thirty-two (32) multiplexed address and data pins for connecting to I/O bus 23, and eleven (11) address pins and thirty-two (32) data pins for connecting to system memory 18 and optional cache memory 24. Therefore, consolidating CPU 11, memory controller 12, and I/O bus controller 13 into a single device has reduced the address and data pin count from a conventional two hundred sixty-seven (267), as described in the Background section, to only seventy-five (75). Because the package size of a chip is mostly dictated by its pin count, the package size of integrated microprocessor 10 is much smaller than the combined sizes of conventional, discrete chips.
Replacing several discrete chips with the single integrated microprocessor according to an embodiment of the present invention eliminates a large number of interconnection traces. Further, interface overhead is reduced, while performance is increased. Component size and population, as well as trace routing congestion, are significantly reduced on motherboard  17. The fewer traces can be made shorter, which reduces signal propagation delays, capacitance, and electromagnetic radiation. As a result, motherboard 17 is greatly simplified, so that it is much easier and less expensive to design. It can be made much more compact and less expensive to manufacture. This ultimately results in smaller and less expensive desktop and notebook computers.
said I/O bus controller means configured to route memory requests from I/O devices through said memory controller means directly to said one or more random access memory devices.
2. A single-chip device as in claim 1 wherein said memory controller means further comprises a data buffer.
3. A single-chip device as in claim 1 wherein said local bus means is configured to communicate 32-bit data and address words in parallel fashion.
4. A single-chip device as in claim 1 wherein said first external leads are configured to communicate either address or data in up to 32-bit length in parallel.
5. A single-chip device as in claim 1 wherein said second external leads are configured to communicate 32-bit data words and up to 12 address bits.
said I/O bus controller means configured to route memory requests from I/O devices through said memory controller means directly to said system memory.
7. A computer motherboard as in claim 6 wherein said memory controller means further comprises a data buffer.
8. A computer motherboard as in claim 6 wherein said local bus means is configured to communicate 32-bit data and address words in parallel fashion.
9. A computer motherboard as in claim 6 wherein said first external leads are configured to communicate either address or data in up to 32-bit length in parallel.
10. A computer motherboard as in claim 1 wherein said second external leads are configured to communicate 32-bit data words and up to 12 address bits.
11. A computer motherboard as in claim 6 wherein said system memory comprises DRAM system memory and SRAM cache memory each communicating on said memory bus means.


text:
Q: Fill a textbox with varaible text depending on Radio Button selection combo (VBA Excel) I need some help with getting the right code to do the following:

*

*I have 4 groups of radio buttons inside a frame in a userform

*Each group is a simple Yes/No radio button

*I have a textbox that I want to autofill with a score range of A-D depending on the # of "yes" radio buttons selected.

*The "No" checkboxes really shouldn't do anything in regards to the textbox

*

*Userform Name = TP_UF

*Frame Name = fun_opt_frame

*Option Button Name for "Yes" = fun_score_yes1-4

*Textbox Name = fun_scorebox

Logic:

*

*4 Yesses = A

*3 Yesses = B

*2 Yesses = C

*1 Yes = D

It doesn't matter what order the yesses are selected, its a total count. I tried using code using the frame but not sure if that is the best way. The frame for these radio buttons isn't needed for any reason other then to perhaps make it easier to code. So I could throw out the frame if it's not necessary to get this working.
I am not sure where to start here. Any help would be appreciated.
pic

A: The quickest and easiest way for you to understand is - I guess - the following code. You have to put the code into the class module of the userform.
Option Explicit

Dim opt1 As Byte
Dim opt2 As Byte
Dim opt3 As Byte
Dim opt4 As Byte

Private Sub opt1Yes_Click()
    opt1 = 1
    EvalOpt
End Sub
Private Sub opt1No_Click()
    opt1 = 0
    EvalOpt
End Sub
Private Sub opt2yes_Click()
    opt2 = 1
    EvalOpt
End Sub
Private Sub opt2No_Click()
    opt2 = 0
    EvalOpt
End Sub
Private Sub opt3yes_Click()
    opt3 = 1
    EvalOpt
End Sub
Private Sub opt3No_Click()
    opt3 = 0
    EvalOpt
End Sub
Private Sub opt4yes_Click()
    opt4 = 1
    EvalOpt
End Sub
Private Sub opt4No_Click()
    opt4 = 0
    EvalOpt
End Sub

Private Sub EvalOpt()
Dim sumOpt As Byte
Dim res As String
    sumOpt = opt1 + opt2 + opt3 + opt4
    Select Case sumOpt
    Case 1: res = "D"
    Case 2: res = "C"
    Case 3: res = "B"
    Case 4: res = "A"
    Case Else: res = ""
    End Select
    Me.fun_scorebox.text = res
End Sub

I assumed the option buttons are named opt1Yes, opt1No, opt2Yes, opt2No etc.
A more advanced solution would probably be to use classe modules and "collect" the option buttons in such a way.

A: I ended up going about this differently and I got it working using a counter. Thanks for the help! Posting code here in case anyone else needs it.
    Option Explicit

    Private Sub OptionButton1_Change()
    set_counter
    End Sub

    Private Sub OptionButton2_Change()
    set_counter
    End Sub

    Private Sub OptionButton3_Change()
    set_counter
    End Sub

    Private Sub OptionButton4_Change()
    set_counter
    End Sub

    Private Sub OptionButton5_Change()
    set_counter
    End Sub

   Private Sub OptionButton6_Change()
   set_counter
   End Sub

   Private Sub OptionButton7_Change()
   set_counter
   End Sub

   Private Sub OptionButton8_Change()
   set_counter
   End Sub

   Private Sub set_counter()
    Dim x As Integer, counter As Integer
     Me.TextBox1.Value = ""
     counter = 0
     For x = 1 To 8 Step 2
       If Me.Controls("OptionButton" & x).Value = True Then counter = counter + 1
     Next x
        Me.TextBox1.Value = Choose(counter, "D", "C", "B", "A")
   End Sub

  Private Sub UserForm_Activate()
    Me.TextBox1.Value = ""
  End Sub

  Private Sub UserForm_Click()
    Dim x As Integer
      Me.TextBox1.Value = ""
      For x = 1 To 8
         Me.Controls("OptionButton" & x).Value = False
      Next x
  End Sub


I will be having a series of posts featuring my new favorite jersey from Zip Tanks this next month .... and the company/ CEO behind it.
The CEO of Zip Tanks is a young female entrepreneur (and close friend of mine) conquering the world with one innovative product at a time.
I not only enjoy her company's product, but I admire the perseverance that she has demonstrated throughout her career.
To learn more, stay tuned to see 3 different looks styling this jersey and a background on this company's unique founding members and history!


text:
University of Surrey · Faculty of Health and Medical Sciences
Applicants are expected to hold a good honours degree (upper second) in an appropriate discipline, but prior experience in research or health and social care may be acceptable.
January, April, July, October
The University of Surrey has been leading health-related research for over 30 years and the School of Health Sciences has been central to this. Positioned within the Faculty of Health and Medical Sciences alongside the Schools of Biosciences and Medicine, Veterinary Science and Psychology, we are all united under a 'One Health' theme.
With innovation, research and passion at its heart, the School aims to deliver the UK's most dynamic, effective and caring healthcare professionals. We also work with professionals in fields allied to healthcare and medicine who wish to pursue doctoral-level study.
We have a strong track record in interdisciplinary research and our submission alongside biosciences in the 2014 Research Excellence Framework (REF) saw 93 per cent of our research rated world-leading or internationally excellent. We were also ranked 2nd by the Complete University Guide 2018 and 3rd by the Guardian University Guide 2017 for our undergraduate programmes.
We collaborate closely with healthcare providers, government, corporate businesses and the third sector to improve the delivery of healthcare nationally and internationally. We have over 800 active partnerships, including our partnership within Surrey Health Partners (SHP) which is a clinical academic partnership between the University of Surrey and four NHS Foundation Trusts.
Our academics are engaged in leading healthcare research that drives and reflects change in clinical practice and medicine, and embraces evidence-based practice, policy and education.
We are changing the future of healthcare by developing eHealth applications, including those developed at the University's 5G Innovation Centre (5GIC), which is now testing the future generation of innovative health technologies.
You will be joining a thriving doctoral community of postgraduate research students who meet weekly and offer peer-support in informal student-led support groups with guest speakers and facilitators both from within the University and externally.
admissions@surrey.ac.uk
Similar courses from University of Surrey
Veterinary Medicine and Science

redpajama_set_name: RedPajamaCommonCrawl


For more information on joining one or more of the Collectors Circles, please call 314.655.5390 or email collectors.circle@slam.org.
Friends of African American Art (FAAA) is for those who wish to expand their awareness of African American art of the past and present. This collaborative group is devoted to advancing the presence and profile of African American art within the Museum and in the community by educating a new generation of art connoisseurs. In-depth seminars, private receptions, and guided tours will give you up close and personal experiences with curators, scholars, artists, and collectors.
FAAA is advised by Melissa Wolfe, Curator of American Art; and Renée Brummell Franklin, Director of Audience Development.
Friends of American Art and Design (FAAD) is for Members interested in refining their understanding of the arts of America. This discerning group seeks to develop appreciation of a wide range of American Art, from painting and sculpture to the decorative arts and architecture. Programs include visits to private collections and galleries, architectural tours, lectures by scholars and other experts from around the country, and behind-the-scenes tours and events hosted by the Museum's curators.
FAAD is advised by David Conradsen, Grace L. Brumbaugh and Richard E. Brumbaugh Curator of Decorative Arts & Design; and Melissa Wolfe, Curator of American Art.
Contemporary Art Society (CAS) is for those who are concerned with cultivating their knowledge of contemporary art as well as for those who already have a highly-honed understanding of it. This dynamic group facilitates an appreciation by exploring current trends in the art world as well as their ongoing impact on the history of art. Programs range from private lectures and receptions with curators, artists and scholars, to off-site visits at other arts institutions and private collections.
CAS is advised by Hannah Klemm, Assistant Curator of Modern and Contemporary Art.
For the 2018–2019 season, CAS is sponsored by Christie's.
Friends of Photography (FOP) is for those who value the history and art of photography. This dedicated group strives to enhance knowledge of the medium and promotes an appreciation of the collection and display of photographs. Programs range from private exhibition tours and scholarly lectures, to artist presentations and collection visits.
FOP is advised by Eric Lutz, Associate Curator of Prints, Drawings and Photographs.


text:
Q: Open Custom TabPage in Designer of Visual Studio I have created a custom class which inherits from System.Windows.Forms.TabPage, and is actually a TabPage with many buttons and different stuff in it. I created this because I wanted to have the user add dynamically as many tabs as he would like at runtime.
The problem I have here is that I can't find a way to have the Visual Studio designer let me design that custom TabPage easily, without me having write all the needed code manually (the way I've been doing it until now).
Is that even possible?

A: Rather than designing the tab page itself, consider designing a 'UserControl', and then inserting that onto the tab page, with its Dock property set to Full.
You can use the VS designer on a UserControl to arrange its children.
Then the programmatic bit just consists of constructing the UserControl and adding it to the TabPage's controls list.


Many individuals and families are living a stressful and ineffective life.
Counseling is out of reach financially for many.
Insurance companies delay or deny services.
Providers are left unpaid or underpaid for services.
Individuals and Providers are left unsupported, alone, and in despair.
Individuals and families are giving up on counseling.
Providers are leaving the industry.
Negativity, suffering, and violence is on the rise.


text:
Home> Altera
MediaTek Subsidiary to Acquire Intel Enpirion Business for $85 Million
by Dr. Ian Cutress 17 comments
Today an agreement between MediaTek subsidiary Richtek and Intel has been made for Richtek to acquire Intel's power management solutions and controller product line known as Enpirion. The agreement will enable the sale of the division, subject to regulatory approval, for $85 million, and is expected to close in Q4. Intel's Enpirion business has been part of the company under the Programmable Solutions Group, formerly known as Altera, which was acquired by Intel in December 2015 for $16.7 billion. Altera had previously acquired Enpirion in May 2013 for $140 million, indicating a net loss over the seven years. The Enpirion PowerSoC product line has been a series of system-on-a-chip DC-to-DC power converters, enabling higher power density and lower electrical noise compared to discrete power converter equivalents...
Bittware 4x100G FPGA Card, Uses Intel 10nm Agilex and oneAPI
This week at the annual Supercomputing HPC show, we're going to see a number of high-profile enterprise announcements across a wide array of industries that support server and high-performance...
8 by Dr. Ian Cutress on 11/17/2020
Intel Launches Stratix 10 TX: Leveraging EMIB with 58G Transceivers
One of the key takeaways from Hot Chips last year was that Intel's EMIB strategy was going to be fixed primarily in FPGAs to begin with. Intel instigated a...
Intel Displays 10nm Wafer, Commits to 10nm 'Falcon Mesa' FPGAs
On the back of Intel's Technology and Manufacturing Day in March, the company presented another iteration of the information at an equivalent event in Beijing this week. Most of...
Hot Chips: Intel EMIB and 14nm Stratix 10 FPGA Live Blog (8:45am PT, 3:45pm UTC)
Today at Hot Chips we have a lot of interesting talks going on. First up is a talk on Intel's latest 14nm FPGA solution: Stratix 10 implementing HBM using...
Intel Announces Cyclone 10 FPGAs for IoT Devices
Intel this week has announced its new portfolio of FPGAs designed for small form-factor and/or low-power Internet-of-Things devices, specifically in the fields of automotive, industrial, audio/visual and vision applications...
Intel to Acquire FPGA-Specialist Altera for $16.7 Billion
Today Intel has announced that they are buying Altera in an all-cash deal of $16.7 billion. The deal, having been rumored for a while now, will see Intel pick...
FPGA news roundup: Microsoft "Catapult", Intel's hybrid and Xilinx OpenCL
There has been some activity in the FPGA realm lately. First, Microsoft has published a paper at ISCA (a very well-known peer-reviewed computer architecture conference) about using FPGAs...
23 by Rahul Garg on 6/21/2014
Intel to Fab Altera FPGAs with ARM IP
In a story posted today on EETimes, Altera announced at the ARM Developers Conference that they have entered into a partnership with Intel to have their next generation 64-bit...
44 by Jarred Walton on 10/30/2013
A Look at Altera's OpenCL SDK for FPGAs
FPGAs offer the promise of reconfigurable computing: Reconfiguring the hardware to match your application needs. This reconfigurable approach is often more efficient than general purpose processors such as CPUs...
56 by Rahul Garg on 10/9/2013


Next month Damon Krukowski will be heading out on a solo talking tour to discuss and promote his forthcoming book The New Analog.
The book will be released on the 22nd April (Record Store Day - but suspect there'll be copies to buy at the dates before that) and during the tour he will be speaking to such vocal and opinionated luminaries as Amanda Palmer, former Steve Albini and Ian Svenonious (author of Supernatural Strategies for making a Rock 'n' Roll Group).
The book is less a study of older formats' current popularity and more a survey of the struggles between permanence and ephemera, as well as artists' visions and the consumer marketplace, playing out over decades of technological and industry changes.
Krukowski's writing is witty and generally accessible, though his detours into recording minutiae and avant-garde ideas about sound and art may lose some readers.
As a fan of both minutiae and avant-garde ideas I'd consider the last paragraph a selling point!


text:
LeRoy (Roy) Vinthers (born c. 1931) is a Canadian curler from Vancouver, British Columbia. He is a former British Columbia provincial champion skip, and was the runner-up at the 1977 Macdonald Brier, Canada's national men's curling championship. Vinthers grew up in Inglis, Manitoba.

Playing career
Vinthers played third for the Harry McConachie rink at the 1954 provincial championship. The team finished third.

Vinthers began skipping in 1959. He and teammates Leo Hebert, Howie Christopherson and George Ingram won the $9,000 Totem Bonspiel in 1959. The team played in the 1960 BC Championships, where they were eliminated in the first round of the "B event".

In 1961, Christopherson took over as skip with Vinthers at third with front end George Ingram and Charlie Gardner. The team won the Pacific Coast playdowns putting them into the BC final. The provincial championship was a best of three series between the Pacific Coast champion Christopherson rink and Interior champion Reg Stone. Team Christopherson won the first match 11-4, but lost the next two, 12-6 and 10-9. In 1964, with Vinthers skipping, his rink lost in the Pacific Coast final to Lyall Dagg, who went on to win the World Curling Championships that year. In 1965, Vinthers took over as skip of the Dagg rink, with Dagg unable to curl due to "pressure of business". However, Vinthers was unable to lead the rink out of the 1965 Pacific playdowns, losing to Jack Arnet in the Pacific Coast finals. In 1966, Vinthers began curling out of Kamloops, where he lived for five years, then lived one year in Edmonton and three in Winnipeg. He moved back to the Vancouver area in 1973.

In 1976, Vinthers teamed up with former teammates Leo Hebert and Barry Naimark who had played for Lyall Dagg as well as second Greg Pruden. Naimark joined the team for playdowns after the team's regular lead, Al Richards couldn't compete due to getting a new job. The team won the 1977 BC Men's championships defeating the Al LaChance rink of Kamloops 5-3 and 6-4 in the best of three final. LaChance had been Vinthers' barber while living in Kamloops. This qualified the rink to represent British Columbia at the 1977 Macdonald Brier in Montreal. The team had a great start at the event, winning their first eight games, but lost their remaining three games, including a match against Quebec's Jim Ursel rink. That game proved to be pivotal as Quebec ended up winning the Brier with a 9-2 record, one more than B.C. who finished tied in second place.

The next season, Vinthers won the $18,500 1977 Labatt's Bonspiel. While Vinthers faltered in zone play that year, he did see action at the 1978 Macdonald Brier in Vancouver, as a spare for Northern Ontario, replacing John Ballantyne who couldn't play one day due to muscle spasms.

Vinther's last major spiel win was in 1980 when he won the $29,000 Peace Country Curling Classic.

Personal life
At the time of the 1977 Brier, Vinthers was employed as a terminal manager for Canadian Auto Carriers.

References

Living people
1930s births
Canadian male curlers
Curlers from Vancouver
Sportspeople from Kamloops
Curlers from Edmonton
Curlers from Winnipeg
People from Parkland Region, Manitoba


The Bennington area is served by the Southwest Vermont Supervisory Union. We have six elementary schools, one middle school, and one high school.
Want to learn more about our schools? Visit our district website.


text:
var express = require('express');
var app = express();
var path = require('path');
var sentiment = require('sentiment');

app.set('view engine', 'ejs');

app.use(express.static(path.join(__dirname, 'public')));

//twitter stuff.
var util = require('util');
var twitter = require('twitter');

var twit = new twitter({
consumer_key: '',
consumer_secret: '',
access_token_key: '',
access_token_secret: ''
});

app.get('/', function(req, res) {
    twit.search('#tybg', function(data) {
        var stringTw = JSON.stringify(data);
        var JSONTw = JSON.parse(stringTw);

        //console.log(util.inspect(data));
        //console.log(util.inspect(data));
        //console.log(util.inspect(JSONTw));

    var test = "#burlyrides";

	var fakeTwitter = [
    { id: 1, name: "coolguy99", lat: 44.482870, lon: -73.216312, text: "I love everything. Cool stuff all around." },
    { id: 2, name: "IhateBees", lat: 44.472496, lon: -73.218198, text: "I hate bees more than I hate everything else." },
    { id: 3, name: "EverythingIsPain33", lat: 44.477730, lon: -73.195035, text: "I hate myself and I want to die." },
];

/*
  	var sent1 = sentiment ("I love everything. Cool stuff all around.");
	var sent2 = sentiment ("I hate bees more than I hate everything else.");
	var sent3 = sentiment ("I hate myself and I want to die.");
*/

	res.render('rideclub_proto', {
        data : data,
        stringTw : stringTw,
        JSONTw : JSONTw,
        test : test,
		fakeTwitter : fakeTwitter

        });
   });

});

app.listen(3000);
console.log('What? Working?');

redpajama_set_name: RedPajamaGithub


text:
beautiful style
PARIS + par Art Basel
Richard Mille is the new official sponsor of the Monaco Yacht Show
The best Christmas films to watch in 2021
Dior presented a new men's collection
Breguet has released a new watch model exclusively for Russia
Style and provocation: Rihanna presented a new collection Savage x Fenty
Russian luxury goods market during a pandemic
Business breakthrough: an international success story of Kaspi.kz
The story of success of Indian entrepreneur Amira Shah: how to turn a private company into a billion-dollar business
Swarovski announced the reduction of 600 employees
Healthy style
Top 25 most influential psychologists in the world
The new season of Formula 1 is open: Grand Prix 2020 took place in Austria
International Bicycle Day: how bicycles make our lives better
It is time to start: a list of the best equipment for cycling
This New Electric 'Flying Car' Can Be Piloted With a Driver's License – and It Will Fit in Your Garage
Red carpet, Italian style, All the stars at the 2022 Venice Film Festival
Monaco Yacht Show 2022: the official list of superyachts is announced
The Monaco Yacht Show launches its Adventure Area
NEXT Yachting – It's the start of something new
MYS 2021: The epicentre of a booming yachting industry
Luxury watch brands delay new releases due to the COVID-19 pandemic
Luxury watch brands delay new releases due to the COVID-19 pandemic - Beautiful Lifestyle Magazine
Share on odnoklassniki
The leaders of the watch industry decided to postpone the release and presentation of new products due to the COVID-19 pandemic. Rolex and Patek Philippe were the first to announce their decision. Even before the official cancellation of Baselworld 2020, these brands decided to not participate in the exhibition, and later postponed the presentation of new products without setting a date.
For the first time in history, Patek Philippe has announced the launch of online sales of its products. In Russia, customers can order products by Patek Philippe on the Mercury website.
Meanwhile, the Bulgari brand is set to present new products in 2021. According to a statement by Bulgari's CEO, Baselworld 2021 might be able to reunite the watch industry after today's separation due to the COVID-19 pandemic.
News, Watches
Elegant St. Valentine's Day Gift by Bvlgari
Read completely »
Spring at Valentino's: Valentino spring 2020 collection
Peter Pilotto 2020 spring collection
I agree to the privacy policy and personal data processing policy.
Read our security policy.
Thank! You subscribed
Beautiful Lifestyle Magazine – modern encyclopedia about lifestyle and quality.
Beautiful Lifestyle – it is a magazine about fashion, jewelry and watches, beauty and spa, elite cuisine and travel, design and culture, business and sustainable investments, in a word, a beautiful lifestyle.
For questions pertaining to cooperation and advertising on Beautiful Lifestyle web portal please contact info@beautiful-mag.com.
This New Electric 'Flying Car' Can Be Piloted With a Driver's License – and It Will Fit in Your Garage September 16, 2022
Red carpet, Italian style, All the stars at the 2022 Venice Film Festival September 11, 2022
PARIS + par Art Basel August 20, 2022


Aloha, you beautiful strummers of Cool Hand Ukes.
I can't add anything to Abi's brilliant newsletter last week, but just wanted to send you the two songs we will look at next week for fingerpicking.
The first is Hallelujah, and I suggest a Travis Picking (4 1 3 2) pattern. This will all make perfect sense when we meet and is very easy. Just practice picking 4 1 3 2 in whichever chord you like, and moving between chords if you are able.
The other is House of the Rising Sun, for which I suggest a 4 3 2 1 2 3 pattern throughout. Again, we will practice when we next meet on 24th February, and all will make sense.
Love and peace – and happy picking.


As a small streamlined business we are able to deliver to quality products at a great price. Although we deliver Australia wide our business offers super quick and reliable service to Melbourne and especially the Bayside area as we are located in Highett. We also deal with a large range of Tradesman so if you are looking for a quality job done we can connect you without delay.
This product is part of our large selection of Hand tools, please click below to get more information on our suppliers website.