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Understanding Treatment Advances in Psoriatic Arthritis
Medically Reviewed by Ed Zimney, MD
Psoriasis doesn't just affect the skin. Many of its worst effects can come from psoriatic arthritis, a swelling of the joints that develops in some people with psoriasis. Learn about the signs and symptoms of psoriatic arthritis, how it is diagnosed, and the latest treatment options.
This HealthTalk program is supported through an unrestricted educational grant from Abbott Laboratories.
Announcer: This program is produced by HealthTalk and supported through an unrestricted educational grant from Abbott Laboratories. We thank them for their commitment to patient education. Our panelist today reports he has received prior funding from the sponsor of this program. The opinions expressed on this program are solely the views of our guest. They are not necessarily the views of HealthTalk, our sponsor or any outside organization. As always, please consult your own physician for the medical advice most appropriate for you.
Now, here's your host, Dick Foley.
Dick Foley: Hello and welcome to our program, Understanding Psoriatic Arthritis, from Diagnosis to Treatment. Psoriasis doesn't just affect the skin. Many of its worst effects can come from psoriatic arthritis, a swelling of the joints that develops in some people with psoriasis. Today, you'll learn about the signs and symptoms of psoriatic arthritis, how it is diagnosed, and some of the latest treatment options.
I'm very pleased to welcome Dr. Kenneth Gordon to our program today. Dr. Gordon is head of the division of dermatology at Evanston Northwestern Healthcare [in Evanston, Ill]. He is also associate professor of dermatology at Northwestern University's Feinberg School of Medicine [in Chicago].
Can you start right at the beginning for us, and tell us what exactly psoriatic arthritis is?
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Dr. Kenneth Gordon: Psoriatic arthritis is what we call an inflammatory arthritis. It means pain, breakdown of the joints and discomfort in joints that's related to the immune system affecting the way the joint functions. Psoriatic arthritis is one of a variety of what we call inflammatory arthritidies, and it is one that's most frequently associated with the skin disease psoriasis, which is characterized by red, scaly plaques on the skin.
Psoriatic arthritis comes in multiple types. It can affect small joints of the hands and feet; larger joints, like the elbows and the knees; and, increasingly common, the spinal cord and the back. So you can't say psoriatic arthritis is just one disease, but it's probably a compilation of multiple conditions, which affect the joints in different parts of the body.
Dick: You did mention the immune system. Is this disorder considered an autoimmune disorder?
Dr. Gordon: It's considered immune-mediated. That means that the immune system is the thing that's driving the inflammation, the problem with the joints. Autoimmunity is thought to be one subset of immune-mediated diseases. But unlike other autoimmune diseases, we don't know exactly what the immune system is reacting against in psoriatic arthritis.
Dick: So this is completely different than, or unrelated to, something like rheumatoid arthritis?
Dr. Gordon: That's a very interesting question, actually, because many of the symptoms and signs are very, very similar to rheumatoid arthritis. And, in fact, these two conditions can be misdiagnosed as each other over time. However, when you really look at the details of the two diseases, they are actually quite distinct.
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Dick: In terms of factors like gender and age and race, is there a patient profile? Who is that person who is most likely to get psoriatic arthritis?
Dr. Gordon: In predicting a person who may get psoriatic arthritis, the one thing that really suggests that a patient might get it is the presence of psoriasis. Unlike other kinds of inflammatory arthritidies like rheumatoid arthritis, it happens in about equal amounts in both men and women. Most others occur more frequently in women. And while older people are more likely to get psoriatic arthritis, it does happen in the young, not frequently. And finally, it occurs in all races, so there's no predilection for a person who is of one race.
Dick: Does the psoriasis have to be a severe condition in order to lead to psoriatic arthritis?
Dr. Gordon: That's a very common misconception. Many people believe that you have to have bad psoriasis in order to get psoriatic arthritis, and that's actually not true. We have many patients who have very minimal psoriasis who have very severe psoriatic arthritis, and vice versa. People with very severe psoriasis might have no psoriatic arthritis.
There is some thought that people with more severe psoriasis, as it becomes worse, might also have flares of their psoriatic arthritis, but there's no absolute correlation between the severity of the two diseases.
Dick: But some involvement of the skin and the condition of psoriasis is always present in those who develop psoriatic arthritis.
Dr. Gordon: Not necessarily. About 85 percent of people with psoriatic arthritis will have the skin disease psoriasis. Though in my experience when I've been challenged by people who say that they have a patient with psoriatic arthritis without psoriasis, on every person I've been able to find just a little bit of skin disease. But the common teaching is you can have the joint disease without the skin disease, but it's very uncommon.
Dick: And then looking at it the other way, roughly what's the percentage of people with psoriasis who will go on to develop psoriatic arthritis?
Dr. Gordon: That's another one of those questions where the answers vary depending on what study you look at. The early studies suggested about 7 to 10 percent of patients with psoriasis get psoriatic arthritis. Later studies have suggested anywhere between 30 and 40 percent. I think most people now believe around a quarter of the people with psoriasis will develop some level of psoriatic arthritis.
Dick: Is it a slow-developing disease, or can it be diagnosed rather early in its course?
Dr. Gordon: Again, this is one of those questions where the answer varies based on the patient. There are many patients who have very slow-developing disease that takes years to be diagnosed and actually never develops into anything particularly serious.
On the other hand, there are many, particularly young people, who have very, very aggressive disease where they'll get multiple joints inflamed early on and also get early permanent joint damage associated with high levels of inflammation. And so it really varies on the patient and their own presentation. And it's very difficult to predict how their disease will develop.
Dick: I think you've already hinted at it, Dr. Gordon, but what are the early signs and symptoms that a person with psoriatic arthritis might notice?
Dr. Gordon: Well, there are a bunch of different signs and symptoms that can accompany the disease, but the things that we look at most frequently are pain, joint swelling and stiffness in the joints. And the stiffness in the joints is generally early in the morning as a person wakes up. Now, everyone can feel aches and pains in the morning when they wake up. I know I have that in the morning sometimes as I get a little bit older.
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But people who have that stiffness that persists for 30, 45 minutes or even an hour in the morning and then begins to loosen up is really a sign that there's something going on [that's] inflammatory in their joints. And that can be a hint for psoriatic arthritis, and it can occur not only in the small joints of the hands and feet, which is the classic presentation, but in bigger joints and also in the spinal column and in the back.
Dick: Now, once those symptoms appear and can be clearly noticed and identified, does that mean this disease has already done some damage to the joints?
Dr. Gordon: Not necessarily. People can have symptoms that would potentially go on to permanent damage to the joints, but it doesn't necessarily mean that's happened in a clinically significant way early on. When people get stiffness that they can't overcome, or in, for example, a patient I saw today, a gentleman who can't move his neck all the way in normal range of motion, those are permanent changes that might happen that won't necessarily be able to be repaired.
But just because someone has early damage doesn't mean that that damage is going to be permanent if they can get the proper intervention.
Dick: In your specialty of dermatology, are you the specialist who would most often diagnose psoriatic arthritis?
Dr. Gordon: It's very interesting because since most of the patients who develop psoriatic arthritis have psoriasis. And in most of those patients, the psoriasis will present first - the patient will have the skin disease before they'll have the joint disease. Generally, the person who has the first chance to make the diagnosis is the dermatologist.
A patient will come in and have psoriasis, and it's been my practice and hopefully the practice of most dermatologists in this day and age to say, "Do you have any pain in your joints, stiffness in your joints?" We get a sense that the person has something wrong with the joints. And if we don't feel comfortable making the diagnosis, get the patient to a physician, primarily a rheumatologist, who is adept at making the diagnosis and feels comfortable doing so.
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Dick: So that would be the next specialty referral, to a rheumatologist?
Dr. Gordon: In general, [that would be the next specialty referral]. In my personal practice if a person has very severe psoriatic arthritis, I usually can make the diagnosis. I will go to a rheumatologist for assistance in care, but the patient can get the diagnosis at that point.
In patients with very mild disease, we frequently can make a suggestion, but even a rheumatologist can have difficulty making that diagnosis at that time. It's with the patients who are in sort of a hazy area there that we definitely need to have cooperative systems to make the proper diagnosis.
Dick: You talk about the risk of misdiagnosis and that sometimes psoriatic arthritis might be confused with or even diagnosed as rheumatoid arthritis. Are there any other avenues where we're led astray by this disease and think it may be something else?
Dr. Gordon: It's not uncommon to have psoriatic arthritis misdiagnosed as other diseases. I can tell you of a number of patients, for example, who've been called having tendonitis or Achilles tendonitis or plantar fasciitis - which are conditions of the feet that can be very painful - who have psoriasis, and these are things that can mimic psoriatic arthritis. When they actually had psoriatic arthritis we were able to treat them rather easily. Many patients who are diagnosed as having osteoarthritis or wear-and-tear arthritis over the years can be misdiagnosed as well.
So I think it's important to look at the patient from the standpoint of inflammatory arthritis versus noninflammatory arthritis, as well as, do they have skin disease? That will help to make the diagnosis more readily apparent.
Unfortunately, even those criteria are not always easy to make a final diagnosis for a dermatologist. So we frequently have to cooperate with our rheumatology colleagues to have better luck with making a diagnosis.
Dick: Do you find among your patients that some of them just have this great stoicism and put off a real recognition of their symptoms, and therefore don't get to a specialist soon enough?
Dr. Gordon: Oh, that's without a question. And I think that's a very important issue to bring up. Especially with the arthritis, it's important to try to make the diagnosis as early as possible. With the skin disease of psoriasis, I can treat a patient, and five years down the road if they decide not to get care, their skin, if I treat it appropriately, will still go back to normal.
In a patient with psoriatic arthritis, if a patient chooses not to get therapy appropriately because they had more important things to do in the world, I can't hold that against a patient. Oftentimes, what will happen is the patient will have persistent joint disease, and that can lead to more disability in terms of permanent joint damage, inability to use that joint over time, which can lead to greater issues later on in life.
Dick: And that brings us, of course, to the whole issue of disease progression. Once a diagnosis has been made, a diagnosis of psoriatic arthritis, are there particular markers that you can use to measure the progression of the disease, how fast it may be moving ahead?
Dr. Gordon: There are actually two questions in that question. One is, can we predict who's going to get progressive disease? And secondly, can we identify how fast is someone going onwards in their downward course?
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The first is actually one of the great challenges we have right now. There are certain indications that really suggest progressive disease, that someone is going to go on to joint damage. I should add right here that not everyone with psoriatic arthritis has permanent joint damage. It's actually a minority of patients, not even a majority of patients who do [have permanent joint damage]. The big issue is identifying who will go on.
Now, clearly people who have very aggressive disease, many joints that are inflamed [and] might take two or three hours for the joints to get rid of their stiffness in the day, those patients really have a strong suspicion of going on to get permanent joint damage. And for those, the question is how fast they'll go. It's really difficult to predict, but the general assumption is the people who have more inflammation have a high risk for getting real structural damage that will make an impact on their life, so those are the people we're most aggressive with.
That said, there are some people who have limited amounts of involvement in terms of the inflammation, who years later when you look at their joints on an X-ray will have significant changes. So, no, we don't have a predictive symptom that really tells us with 100 percent accuracy who's going to go on to more significant damage in their joints.
Dick: Not surprisingly, the pain and stiffness are the most common symptoms of psoriatic arthritis. Are there any other less common symptoms that people ought to be on the lookout for?
Dr. Gordon: It's difficult to say because it's not so much the symptoms are different but the location of the symptoms that can differ. Typically, the pain, the stiffness and the swelling are the hallmarks of inflammation in the joints, including heat to touch. That always does show up.
What is important, and what's oftentimes missed, is the number of different places that psoriatic arthritis can occur. It can occur in the neck. It can occur in the lower back. In those areas, pain and stiffness are really all you can see. You can't really see swelling in those areas.
In small joints, for example, the foot, you can see swelling of the entire toe with relatively minor amounts of inflammation. It's called a "sausage digit" because the toe looks like a sausage when it's done.
So it can occur in any joint, and it can also occur in tendons. For example, you can get a swollen Achilles tendon in the back of the ankle. So it's not really the symptoms that differ so much but the multiple different areas where the disease can show itself.
Dick: I see. Tell us about something called "nail pitting." Does it relate to psoriatic arthritis?
Dr. Gordon: Nail pitting is a sign of psoriasis in the fingernail or the toenail, and it's a sign that the person has the disease in the nail matrix, which is underneath the nail folds. If you look at your nail, you can see at the very, very bottom of it a little white area called the lunula, but that's the nail matrix. And that goes all the way back underneath the skin.
Nail pitting has been associated with a higher rate of psoriatic arthritis. Nail pitting is a common sign in patients with psoriasis. It might occur more commonly in psoriatic arthritis. It's the impression of most dermatologists that that's not a sign that you hang your hat on to make a diagnosis. Rheumatologists, for some reason, think more highly of that as a diagnostic criteria. Dermatologists don't think it's that helpful.
Dick: If this condition of psoriatic arthritis is left, say, virtually untreated or intervention does not occur early enough or maybe is not aggressive enough, does damage always occur to the joints, and is that damage ever reversible?
Dr. Gordon: The question about whether the damage happens invariably is no, it doesn't happen invariably. In fact, people think now that it's actually a minority of patients that have permanent joint damage who have psoriatic arthritis. What we looked at when we thought only 5 to 7 percent of patients had psoriatic arthritis, those people had very severe disease. As we've learned, more patients actually have the disease but in a milder form. Many of those patients, as we expand the diagnosis, don't go on to joint damage.
The problem, however, is in those patients who do [go on to develop joint damage]. Because once the permanent joint damage happens, there's no way to turn it around. That is permanent. The bone has changed. The joint space has changed. There's no way to really fix that, and that's why we want to have as much appropriate intervention as we can as early as possible in patients who are going to go on to progressive disease, to try to prevent those permanent changes from happening. And those permanent changes can really lead to significant disability, inability to use their hands, inability to walk properly and inability to turn and do normal things that are required, if you have damage in your back.
Dick: That's the specific damage. It's the damage to the bone and to the spaces in the joint. Does what happens to the bone resemble something like osteoporosis?
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Dr. Gordon: It's not similar to osteoporosis. It's actually a breakdown of some bone and a proliferation of other bone. And it's very different from osteoporosis because osteoporosis is general loss of bone density. What you see in psoriatic arthritis is a breakdown in the bone, with the bone density being intact. [It] doesn't mean the two of them actually can't co-exist, as they frequently do, but they are different conditions.
Dick: We talked a little bit before about who is more appropriate to treat psoriatic arthritis. Couldn't that be a key to it - the dermatologist treating the patient with psoriasis recognizing that this patient may have some arthritic involvement and making that referral to a rheumatologist?
Dr. Gordon: I think it's extremely important to have the dermatologist to at least get the idea that this patient has something wrong with their joints. If you would have asked me five years ago if dermatologists asked every patient with psoriasis, "Do you have joint pain, or stiffness or any symptoms that might suggest psoriatic arthritis?" I would say a very small number of dermatologists would have actually asked their patients about joint disease.
As recognition of psoriatic arthritis has become more recognized as something that we really must do as dermatologists, I think more dermatologists are asking the initial questions. Is it 100 percent? [It's] ftar from it. But I think there's a much larger number of doctors doing it, and that is so critical.
Because even if a dermatologist isn't going to treat the joint disease, its presence in the patient with psoriasis might lead you in terms of what therapy you would select. And I think it's also of critical importance, if you don't feel comfortable making the diagnosis, at least referring the patient on to a rheumatologist to be able to appropriately get the diagnosis so therapy can be instituted. Both of those two issues have become critical for dermatologists, and I think dermatologists are doing a better job at handling it.
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Dick: Are only specific joints in the body at risk, or could it be any and all joints?
Dr. Gordon: Typically, we think of the classic being small joints. But as time has gone on, we're beginning to recognize that more and more joints can be affected. And pretty much all of the joints you think about being arthritic joints - on the extremities and in the spine - have at least at some point been involved in psoriatic arthritis.
Dick: Could it involve knees and hips as well?
Dr. Gordon: Yes, it does [involve the knees and hips] - not infrequently.
Dick: And would that ever lead to the necessity of a joint replacement?
Dr. Gordon: Actually, joint replacements are not infrequent in hips, knees, but also in small joints that sometimes require joint replacements, and fingers. But yes, a number of my patients have had knee replacement or hip replacement because of psoriatic arthritis.
Dick: When you see a psoriatic arthritis patient for the first time, how do you go about establishing treatment goals for that patient?
Dr. Gordon: Well, I think there are a number of things that are important in identifying what we want to do. If a patient's seeing me, it means, clearly, they have the skin disease as well. There aren't too many patients who seek me out because they have joint disease without skin problems.
So when I look at the patient and say, "You have skin disease, and it's significant enough skin disease that I would want to treat you with a systemic medication," - that is, a pill or a shot, rather than just creams or with phototherapy, standing in a booth that gives special wave lengths and ultraviolet light - in those patients, it's important to identify the psoriatic arthritis because that comes into play in choosing therapy.
If a patient has mild psoriatic arthritis but significant skin disease, I might choose a therapy that would treat both problems initially, rather than just trying to shoot one or the other.
On the other side, if a person has significant joint disease, and I want to try to prevent development of permanent joint damage, and mild skin disease, in that case I would also choose something systemic that has what we call disease-modifying abilities, rather than something that would just treat symptoms. So I think looking at both diseases is important.
If you have mild psoriatic arthritis, or nonprogressive disease that's been going on for a long time, you can just treat symptoms. Likewise, if you have just mild skin disease, you can just treat with a topical therapy, for example. But you have to look at both issues prior to making that therapeutic decision.
Dick: We promised our listeners that we would talk about the full range of treatment options. What are those treatments that you would consider to be the first line of treatment that might include anti-inflammatories or steroids? Tell us about those and when you choose them and how they work.
Dr. Gordon: Basically, all the medications for psoriatic arthritis work through decreasing the inflammation in the joints. Since the disease is driven by inflammation, that makes sense.
There are two different classes of drugs for psoriatic arthritis: those that are called disease-modifying and those that are considered non-disease-modifying.
Disease-modifying means you can show change in the natural history of the disease, that the disease, if you use this medication, will have less permanent damage over time. In a patient with very mild disease that doesn't have a lot of symptoms and is not looking like it's going to cause significant damage over time, typically the way to treat is to treat with things that might improve symptoms, but you don't have to worry so much about disease modification. And those medications, primarily, are the nonsteroidal anti-inflammatory drugs (NSAIDs), medications like naproxen or ibuprofen, medications that we're all familiar with for aches and pains to headaches.
The next line of therapy is frequently medications like systemic corticosteroids or a medication like sulfasalazine, which are medications that impact the inflammation as well but probably don't have a big impact on the progression of joint damage over time.
Dick: But systemic corticosteroids [is the next line of therapy] rather than topical?
Dr. Gordon: Yeah, topical corticosteroids for psoriatic arthritis won't help. Some people use injected corticosteroids. You take the medication and inject it directly into the joint space, and that can be extremely helpful.
Dick: Before we leave those two classes of medications entirely, what about side effects? And can people use them over the long haul?
Dr. Gordon: In fact, people can use the medications over the long haul. Clearly, there have been some issues with variations on the nonsteroidal anti-inflammatories, and that would be the COX-2 inhibitors [such as Vioxx (rofecoxib)] that we've heard so much about in the last couple of years. But generally, people tolerate these medications quite well over time.
Systemic corticosteroids do have other effects that can be big problems. Mostly, we think about people who are more susceptible to infection as well as thinning of the bones, for example, if you have diabetes or hypertension.
And from a skin standpoint, we worry very much about people who have cutaneous psoriasis. If you get high doses of these things and then come off it, you can actually oftentimes have a very severe flare of psoriasis. So from a dermatology standpoint, I would not use systemic corticosteroids very conveniently. I would rather in that case use one of the disease-modifying medications, which I think actually over time have a smaller side-effect profile than do systemic corticosteroids.
The primary disease-modifying agents that have been used over the last decade are methotrexate, which is a medication you take once a week. It's a chemotherapeutic agent that we found that in small doses once a week can have significant effects in both psoriasis and psoriatic arthritis.
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The other class of medications is what we call the biologics, which are primarily anti-TNF agents, molecules that attack a single molecule and can make a major impact on disease in that way. And those are generally given as shots, either intravenously in the case of a medication called infliximab [Remicade], or a patient can give themselves a subcutaneous injection in the case of etanercept [Enbrel] or adalimumab [Humira]. And those, I think, are the choices for people who have more progressive disease, or are not controlled sufficiently with the nonsteroidal anti-inflammatory medications.
Dick: We'll discuss those in somewhat more detail in a moment and by name. But when we're talking about the NSAIDs and the corticosteroids, [are there] any age restrictions on those? Are they better, more efficacious in younger patients than older?
Dr. Gordon: Well, the efficacy doesn't vary that much based on age. The safety does [vary]. And I think that's where you have to take into account that people who are a little bit older tend to have more difficulty with almost any medication.
In particular, people, with the nonsteroidal anti-inflammatories, can get more stomach problems and also kidney problems associated with older age. Likewise, people with systemic corticosteroids will have problems with diabetes, more hypertension, more bone loss because of much more acute problems. So people who are older will have more difficulties with these medications than people who are young though I think the efficacy doesn't vary quite so much as the safety issues.
Dick: Do you have to be mindful of those folks who may have some other conditions along with their psoriatic arthritis?
Dr. Gordon: I think you clearly have to be mindful with any medication. And the other thing to keep in mind is some of these medications have drug interactions with other medications that people, especially older people, might be on.
Dick: Let's tackle this group of medications, the newer ones that are commonly referred to as the biologics. Tell us how they differ from the older therapies. I know that disease-modifying is a part of all this, but let's start with them by name and have you just describe them for us. Let's start with Enbrel.
Dr. Gordon: In psoriatic arthritis, there are really three biologic agents. In psoriasis, there are actually a couple more that work a slightly different way. But since we're talking about the joint disease today, we'll stick with what we call the anti-TNF agents, of which Enbrel was the first one approved for psoriatic arthritis and probably the one that's used most commonly today.
TNF is a molecule called tumor necrosis factor alpha. And TNF is a molecule that's very, very important in promoting inflammation. So if you inactivate this molecule, you can decrease the amount of inflammation, which, as we said before, is driving the joints to become abnormal in the first place. So the principle behind it is these molecules, the biologics, can specifically attach to their target, in this case TNF, eliminate it without having impact on, for example, other organ systems in the body.
That's the goal of using a biologic agent. The TNF agents can selectively pick out this one molecule that's very important, eliminate it, and the patients will get better without having effects on the stomach or the liver or the kidneys.
Dick: How is Enbrel administered, and how long can a patient continue to take it?
Dr. Gordon: Okay. Enbrel is a medication that's given as a subcutaneous injection once a week, a dose of 50 milligrams once a week. In psoriasis, patients can go up to twice a week for a three-month period and then down to once a week. But typically, for arthritis, there is no significant benefit that we've seen for giving higher doses.
Enbrel, which is often known by its generic name of etanercept, as far as we know can be given continuously. There don't seem to be cumulative side effects from use of the medication. We do worry, for example, about a higher risk of infection, primarily infections like tuberculosis. So everyone who goes on any of these agents should get a TB test prior to starting the medication.
But, in general, all these agents, and Enbrel in particular, are extremely well-tolerated, and patients don't seem to have a lot of side effects from the medication.
Dick: And I assume those patients who are comfortable doing so can self-inject?
Dr. Gordon: Yes. In my practice, I've yet to find a patient who is doing well with the medication who hasn't been able to self-inject. But there are some patients who will have issues with it, and they can usually find someone - a family friend or a spouse or a partner - who will be willing to do the injection for them. Or in some extremely rare cases, the patient might request the physician's office to do the injection.
Dick: Remicade is the next one on my list. How different is it from Enbrel, and how does it work?
Dr. Gordon: Well, Remicade works in the same way as Enbrel does. It's also known by its generic name of infliximab. The difference between infliximab and the other two agents is this is a medication that is given as an intravenous infusion. So it's done either in a doctor's office, at a hospital infusion center or some other kind of outpatient facility in which you can have an intravenous infusion, which usually takes anywhere between two and three hours.
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It's usually given three times over a six-week period to start with and then generally about every eight weeks thereafter for maintenance therapy. Infliximab also is extremely well-tolerated. A few patients will get sick while getting the intravenous infusion. They'll feel either light-headed or nauseated and not feel really well for the day following the injection. But the great majority of patients tolerate the infusion just fine. Usually, they want to have a magazine or TV while they're sitting there getting infused.
But it [Remicade] tends to work extremely well. All of the agents that we'll talk about have pretty similar effects on the joints. The difference actually lies in the effects on the skin, where infliximab probably has the most benefit for the skin. Adalimumab, or Humira, is somewhere in between. And etanercept, or Enbrel, still a very effective agent for the skin, probably isn't quite as good as the other two for skin disease.
Dick: That leads us then to a discussion of Humira, which is the third of these biologics. When would that one be chosen and why?
Dr. Gordon: Humira is a medication that is given as a subcutaneous injection every other week. It can be increased to every week if a patient isn't having the appropriate response. It has about similar efficacy as etanercept and infliximab for the joints, and probably works a little better for the skin than Enbrel does and not quite as well as Remicade, but is also given as a subcutaneous injection so the patient can do it at home as well.
One thing that's important to know about differences in how well these medications work for the skin, all three of them work as well if not better than most of the things we have available for skin disease in our armamentarium. So all three of them are excellent medications for skin disease.
And the important thing to remember is if, for example, you don't respond appropriately to one of these three drugs, it doesn't mean that you're not going to respond to another one. We frequently move patients between these three medications to see the one that's best for an individual patient, rather than trying to say if one of them doesn't work, you won't use the others.
And I should also add that Enbrel is the only one of the three that's approved by the FDA for the treatment of psoriasis, not just psoriatic arthritis.
Dick: When a patient then puts the question to his or her physician, "Am I candidate for biologic therapy?" how is that answered?
Dr. Gordon: It is one discussion that I have with the patient, and I try to give the potential costs and benefits of the medication to the patient. The first thing that I think has to be reviewed is, does the patient really need systemic therapy, or do they need to have aggressive therapy for their joint disease and their skin disease? As I mentioned before, someone might have slowly progressing joint disease, which can be treated with medication like nonsteroidal anti-inflammatories, and might have limited skin disease, which could be treated with topicals. For that reason, I wouldn't think that patient would be a candidate for biologic therapy.
However, in people who have progressive disease that either suggests permanent joint damage or are having permanent joint damage as recognized by X-ray findings or by clinical examination, those people are clearly candidates for biologic therapy, and the skin disease doesn't necessarily come into play.
On the other side, if someone has very mild joint disease but has very aggressive skin disease and needs systemic therapy, in those cases biologic therapy is also appropriate.
Dick: Is it the X-rays that you mentioned and the clinical examination that guide the physician toward that decision on biologics or systemic therapy?
Dr. Gordon: I think that it plays a large role. Clearly, physical examination and history of disease - the questions that you discuss with the physician early on if you have the condition - are the things that really direct what kind of therapy a person goes to. In many cases, X-ray findings might help with the diagnosis and might even suggest how rapidly the disease is progressing. But by the time you have significant X-ray findings, to a certain extent it's already too late, so you'd want to, hopefully, treat prior to having significant X-ray findings.
Dick: I'm sure that our listeners would love to hear your comments on the safety of biologics in general. You mentioned TB screening. [Is there] any connection with other illnesses or malignancy? I know there was a JAMA (Journal of the American Medical Association) article recently on Remicade and Humira. [Please give us] your comments on that area.
Dr. Gordon: When you're thinking about medications for psoriatic arthritis, the first thing to remember when looking at safety and studies, including the one that was published in JAMA just last week, is, what is the safety in comparison to other appropriate treatments?
What I mean by that is when a person comes in to me looking for care for psoriatic arthritis or severe psoriasis with psoriatic arthritis, the safety of any medication is not viewed as safety against a placebo or safety against nothing. Because if a patient is a candidate for these therapies, what we're looking at is choices between biologic therapy or, for example, methotrexate or cyclosporin, medications that are known to have multi-organ toxicities, and in the case of both methotrexate and cyclosporin, a connection with the risk of infection and risk of cancer. So to say that we're looking at these medications versus nothing is an inappropriate way to look at safety.
Now, once we've established that a patient needs a systemic therapy - a biologic or a more traditional systemic therapy - and we look at the safety, we can say, what are these medications connected to? Clearly, the connection with infections like TB is known, and I don't think [that] surprises anyone.
The other issues that are associated, at least in this JAMA article, would be cancer. And in that case, I think there are a couple of things in that article which are difficult to interpret. There are statistical issues, which I think, while not invalidating the studies, draw them into question. Those are very complex issues, but the answers in the study are not necessarily something that I think are hard and fast.
But I think it's also important to know that we don't know what happens with psoriatic arthritis, and so the study does not necessarily apply to psoriatic arthritis patients. That said, can I completely eliminate the association with cancer and biologic agents? The answer is I cannot [completely eliminate the association].
On the other hand, what you had were very rare events. And when you increase the risk, they were also quite rare. When I'm making a decision with a patient who has severe debilitating disease and might go on to severe disability over time, we have to incorporate the concept, which of these agents will be least likely to have multiple side effects? When you think about it that way the biologics come out actually looking pretty good because they don't have effects on the liver like methotrexate does.
Dick: As long as you've touched on side effects again, are there any others of those that you would consider to be notable?
Dr. Gordon: I think the biggest side effect that we're concerned about with the biologics, in terms of Enbrel [etanercept] and Humira [adalimumab], are local injection site reactions where people get reactions where they take the injections. Those are generally pretty mild.
In people who have multiple sclerosis or congestive heart failure, they're medications you probably don't want to use because there is a suggestion that they can make those conditions worse. But in patients who don't have the disease, it's unlikely to initiate them. It just makes them worse. So you have to ask for neurologic symptoms and heart symptoms for patients prior to starting biologics.
And then the other thing which is specific to Remicade [infliximab] is the tolerance of the infusion. Some people get sick from the infusion. It's a small minority of patients, and most of the infusion reactions, as we call them, are quite mild, but it is something that you take into account when choosing to use Remicade.
Dick: I'm sure convenience, from the patient's standpoint, is one of the factors in determining which agent would be right for them. Some probably would just much prefer to be able to self-inject at home than to go to a center for an infusion.
Dr. Gordon: There's absolutely no question about that. I agree entirely that patients would prefer to give themselves an injection, in most cases.
There are two other elements which are important. Obviously, convenience is important but also insurance issues and the coverage of the medication. Since Remicade is given in a physician's office, it is typically covered, for example, by Medicare. Even with the best Medicare, Part D, coverage the other injectables, which are done at home, might not have as good coverage. And given the fact that these medications are quite expensive, that decision may really play on what the patient's insurance coverage will do.
That's another issue that when selecting medications is very important. I might say that we've talked a little bit about methotrexate being the alternative medication. Well, as far as medications go these days, methotrexate is very inexpensive, and so that is another reason why someone might opt to use methotrexate instead of a biologic.
Dick: Now, we did hear you use the term "chemotherapy" in connection with methotrexate, and I think people almost automatically think of hair loss with chemotherapy. Does that happen with the smaller doses of methotrexate?
Dr. Gordon: Can it happen? Yes. Does it happen very commonly? No. We're much more concerned about issues with hepatic toxicity, liver toxicity. Hair loss and other changes like that are very uncommon with methotrexate in doses we use though I have to say it can happen. People can get mouth sores that are associated with much higher doses of methotrexate when used in chemotherapy, but the hair loss and the mouth sores are relatively uncommon in the doses that we're using.
Dick: Given all the issues that we discussed relative to the biologics, are they coming into more and more common use? Do you use them more and more in your practice, for instance?
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Dr. Gordon: In my practice, we've always used biologics quite a bit since they've become available, and that's because my practice is a referral center for people with severe disease who have failed other treatments. That said, I think that when you look at medications and how they're used over time, biologics are coming into increasing acceptance in general practice of dermatology and rheumatology, and more and more people are using them.
As with any new medication, it's difficult if you don't have experience either in clinical research or with early use of the medication. It's always intimidating to use a new medication. But then when you think about the biologics, they're not so new anymore. They've been around for seven, eight years in clinical practice and longer than that in clinical trials. So I think more and more people are taking the step to use them. And once they've used them a couple times, I think most people are finding they're very easy to use for both the patient and the physician, with good results.
Dick: The goal that is common to every patient and provider, of course, is the best possible management of the disease. And it leads me to wonder if the biologics can be taken by patients who may also be treating other conditions, such as hypertension or depression for instance.
Dr. Gordon: I would actually agree with that tremendously, that in patients with other conditions biologics are frequently the drug of choice simply because they have very few drug interactions, which is very helpful, especially in the elderly population. And they don't seem to interact with conditions like diabetes or hypertension.
That said, for example, patients with diabetes can be more susceptible to infection, and that's one of the issues with all the medications for the treatment of psoriatic arthritis. All of them, including biologics and non-biologics, can make a person more susceptible to infection, so that all has to be taken into account.
Dick: But there's a high awareness of that risk among physicians, I would assume?
Dr. Gordon: Oh, yes. I would think at this point almost all physicians are quite aware. I have patients come up [and] say, "I have heard about these wonderful medications," who have very mild disease, and I have to convince them not to use the medications. These are real medications that do have interactions with the immune system and so have to be taken seriously.
But, that said, they are oftentimes really life-changing medications that can make a person who has previously been disabled, either emotionally or physically, by their joint or skin disease into someone who really has a different lifestyle.
Dick: What about complications with pregnancy or for the young woman who might wish to become pregnant?
Dr. Gordon: Most of the biologics are Class B, which means that there's no evidence that there's any kind of issue with pregnancy but that no clinical studies have been done to study pregnancy.
In fact, it's my opinion - this is just my opinion - that with young women who are thinking of getting pregnant or could potentially get pregnant who have psoriatic arthritis or psoriasis, I would prefer to use a biologic agent rather than, for example, methotrexate, which is contraindicated in pregnancy and actually is known to potentially have effects on a pregnancy. So in case an accident can happen, as it does, I would rather a patient get pregnant while on Enbrel or Humira or Remicade rather than getting pregnant on methotrexate. Though I have to say, I strongly don't suggest getting pregnant while on any of these medications. We would all prefer to stop them prior to starting a pregnancy.
Dick: We have a couple of questions that listeners have sent us via e-mail. Jill in Maine sent us this question: "Are there any nondrug treatments for psoriatic arthritis?" And I guess we must assume that she's looking at things like lifestyle or diet or physical therapy, that sort of thing.
Dr. Gordon: All the alternative therapies that are out there can be, in many ways, useful adjuncts to medical therapy for psoriatic arthritis. I personally know of no good evidence for alternative therapies like acupuncture or diet therapy for the disease. That said, there are patients of mine who say, "You know, I got better when I started acupuncture," and I can't argue with that.
However, with psoriatic arthritis, the one worry we have is letting it go too long prior to getting optimal therapy. So what I would suggest in those cases is if you choose to use these therapies, that's fine, but don't go two years without getting traditional therapy knowing that you might have progressive disease.
As long as the alternative therapy is not having any side effects, I don't have any problem. I just want to point out that many alternative therapies, though, do have side effects. They're just not thought of as very significant. And things like physical therapy, occupational therapy, exercise, a good diet, all those I have to espouse as a physician because they're good for you.
Dick: Here's an e-mail from John in Atlanta. He says, "I understand there are a number of different kinds of psoriatic arthritis. Can you distinguish between them and tell us a little bit about how they're different?"
Dr. Gordon: Well, the concept of the different kinds has changed over time. We used to think of different types based on what parts of the body they involved. That whole concept has changed to a certain extent. We think that psoriatic arthritis is pretty much a single pathophysiologic disease with a spectrum of severity and a spectrum of involvement. Some people can have one area of the body more affected than another, just like in any other kind of disease that you can think of.
9 Things You Only Understand if You Have Psoriasis
But I think we generally are now considering psoriatic arthritis to be a common pathway disease and that it's just where it affects more than having different types of psoriatic arthritis.
Dick: Brenda in Portland wants to know, "If psoriatic arthritis has been shown to cause extreme fatigue, do you prescribe rest for that fatigue, or do you treat it in some other way?"
Dr. Gordon: It's a very interesting question because it's been suggested that treating the psoriatic arthritis is the best way to treat the fatigue associated with the disease. And, in fact, recently we have published a paper, myself and a number of co-authors, looking at fatigue and psoriasis, the skin disease. And we were actually able to show a change in that fatigue - not only in the skin disease but in the fatigue associated with it - by the use of a biologic agent, in this case, Enbrel.
So I think most people consider that the best way to treat the fatigue, while always getting good rest is good for you, is to actually treat the underlying disease as the best way to go about treating the sequelae of it, of which fatigue and even depression can be elements.
Dick: Oh, [that applies to] even depression as well?
Dr. Gordon: Yes, [it applies to depression as well], particularly with the skin disease.
Dick: A patient might want to know also if there are any activities that he or she should modify or avoid, or lifestyle changes that one should make, after having been diagnosed with psoriatic arthritis.
Dr. Gordon: That's a very common question about modification of activity with psoriatic arthritis. And with most of the people I speak to and most of my patients, I feel that the modification of activity should be to increase activity if possible. A good exercise program under the supervision of a physician is probably a good idea in patients with psoriatic arthritis.
Some people would argue, "I don't want to exercise as much because my joints hurt." But generally, the exercise will help. We don't suggest not exercising or not going to the gym or not being active but actually would suggest being more active.
Dick: [Are there] any specific diet changes that you've noticed that seem to make a difference?
Dr. Gordon: It's very interesting with diet. There are a number of patients who tell me, "Strawberries make my arthritis or my psoriasis worse." And being the brilliant physician I am, I say, "Then don't eat strawberries."
There have been lots of studies looking at specific foods to see if there is anything on a population basis that can make an impact, for both psoriasis and psoriatic arthritis. And the answer is, on a population basis, looking at all the patients, we can't find anything in the diet that might make a big difference.
That doesn't exclude an individual patient who might be able to identify things. And when that patient identifies something, I agree with them because overall they're usually right. But it's usually the patient who tells me what foods are making things worse, not me telling the patient. The one thing I worry about is, in many alternative medicine clinics, for example, they will say, "Well, milk will make your arthritis worse," and then the patient associates it. It's usually a patient making an individual assessment and observation, not someone having told them that there's something wrong and then they eliminate it and they think that there's some issue with that foodstuff. It's a subtle difference, but it's usually the patient identifying it versus someone else recognizing it.
Dick: How about coffee and alcohol?
Dr. Gordon: Alcohol has been connected with the worsening of inflammatory disease. There's some question whether it's the chicken or egg with alcohol - that alcohol will make it worse, or do people who have worse disease drink more alcohol? And that's a very difficult issue to decipher. Generally, we recommend not to drink alcohol in excess, particularly in people on methotrexate, where the side-effect profile becomes much worse if they drink alcohol.
Coffee, caffeine - again, [there are] very limited amounts of information. [It's] probably best not to have too much caffeine, but it's not something I can definitely say that is clearly proven to make arthritis worse.
Dick: Would you say that psoriatic arthritis patients are better off today than they were, say, 10 years ago, strictly in terms of treatment options?
Dr. Gordon: Oh, I think that psoriatic arthritis patients today are tremendously better off, if nothing else because there are more treatment options. Ten years ago, in a patient who was on methotrexate but didn't tolerate the medication for whatever reason or had liver problems associated with it, we didn't have any alternative to turn to. We also have medications now, primarily the biologics, that can slow the progression of disease more effectively than anything we've had in the past and allow people to live lives without disability associated with the disease for a much more extended period of time, and hopefully forever. But we need to wait a few more years before we can make that claim.
But I think that the number of alternatives and how well these medications work make a tremendous impact on the well-being of patients with psoriatic arthritis today.
Dick: So these patients really should, under the best of circumstances, be able to avoid the most serious effects of this disease?
Dr. Gordon: We're hopeful that that's the case. I can't say that with 100 percent certainty, but that's clearly the direction we want to go, and I believe we've made progress on that.
Dick: I wonder if you have one take-home message that you would like to leave with our listeners today.
Dr. Gordon: I think that's exactly the message I'd want to leave to listeners, and that is, things have progressed in our treatment of psoriatic arthritis in the last number of years. With new medications and with new options and with better ideas about management with the old medications as well, we can make an impact on individual lives not only today and tomorrow but into the future. That's the message that is so important, that getting care and understanding that we can make an intervention now that we might not have been able to do in the past means that you can have a healthier life over time. I think that's the central theme of what we need to do to help people who have psoriatic arthritis - go get intervention because it might make a big difference over time.
Dick: We've been talking today with Dr. Kenneth Gordon from Northwestern University about psoriatic arthritis. We certainly want to thank you, doctor, for joining us today and sharing your knowledge with us.
Dr. Gordon: Well, thank you very much for having me on.
Dick: And from our studios here in Seattle, I'm Dick Foley. We wish you and your families the best of health.
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If you're looking for flight deals to Myrtle Beach from Calgary, WestJet is your trusted source. Not only do we fly to Myrtle Beach International Airport, but we also travel to more than 150 destinations in Canada, the U.S., Mexico, Central America, the Caribbean and Europe, so you can be sure we'll get you where you want to go with ease. Beyond the irresistible destinations on offer, countless travellers choose WestJet time and again for our remarkable customer care, as well as our commitment to safety and comfort. Put service and value first for your next trip by flying with WestJet.
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text:
The Rumford Chemical Works and Mill House Historic District is a historic district encompassing the remnants of the Rumford Chemical Works, a historical chemical plant in East Providence, Rhode Island, founded by Eben Horsford and George F. Wilson.

The Rumford Chemical Works are now home to several businesses including Avenue N American Kitchen, the Punch Kettlebell Gym and the Seven Stars Bakery as well as rental apartments and lofts.

History

Rumford Chemical Works was founded by Eben Horsford, who was the Rumford Professor and Lecturer on the Application of Science to the Useful Arts at Harvard University, and entrepreneur George F. Wilson. In 1854, Wilson formed George F. Wilson & Co., a chemical merchandising firm in Providence, Rhode Island. That same year, Wilson approached Eben Horsford with the goal of expanding to develop and manufacture chemical products. Their first plant, in Pleasant Valley, Rhode Island, manufactured calcium sulfite. Horsford's first patent used calcium sulfite to neutralize chlorine in bleached fabrics.

In 1856 the plant was moved from Pleasant Valley to Seekonk, Massachusetts. The same year, Horsford received a patent for production of "pulverulent phosphoric acid" (calcium acid phosphate), an ingredient for baking powder. In 1859, the company was incorporated in Massachusetts as the Rumford Chemical Works. Its name honored Sir Benjamin Thompson, Count Rumford, who had established the chair held by Horsford at Harvard.

After the boundary line between Massachusetts and Rhode Island was recalculated in 1861, the East Seekonk area became East Providence, Rhode Island. The Rumford Chemical Works was chartered again in Rhode Island in 1862.

The company eventually built an extensive complex of buildings centered on the junction of Newman and Greenwood Avenues with North Broadway.  Its main section originally extended eastward from this junction to a pond which has since been filled in and built over with apartments.

The company's most successful product was Rumford baking powder. Hulman & Company acquired the Rumford Chemical Works in 1950 and still makes Rumford baking powder, now at its facility in Terre Haute, Indiana.

National Register of Historic Places
The surviving parcel, roughly , includes a few wood-frame buildings which may date to the 1857 move and a large three-story brick warehouse built in 1895.  A wood-frame office building stands across North Broadway from the main complex, and a series of duplexes built as worker housing line North Broadway.
The district was listed on the National Register of Historic Places in 1980.

See also
National Register of Historic Places listings in Providence County, Rhode Island

References

External links
 ACS Development of Baking Powder
 Rensselaer Guides to Institute Records and Manuscript Collections - Rumford Chemical Works (1853-1951)
 Rensselaer Guides to Institute Records and Manuscript Collection - Rumford Chemical Works records, 1861-1947
The Horsford 1887 Almanac and Cook Book from Science History Institute Digital Collections
The Rumford Cook Book (circa 1910) from Science History Institute Digital Collections
The Horsford Cook Book (circa 1877) from Science History Institute Digital Collections

Historic districts in Providence County, Rhode Island
Buildings and structures in East Providence, Rhode Island
Historic districts on the National Register of Historic Places in Rhode Island
National Register of Historic Places in Providence County, Rhode Island

redpajama_set_name: RedPajamaWikipedia


How to start using a credit card?
Hi! I've got my credit card (Bank Of America Partially Secured) with a limit for $500.
So, now I can start to use it, pay everything on-time, and build my credit history.
The question is - what is the best way to do that? For example, if I'm going to buy a TV on Black Friday with $200 paid in cash and $200 with credit card - is that a good way? Or better would be to start from small amount and then step by step increase it? That's really important for me. Thank you all in advance.
Here are some tips on getting a good credit.
samanthainglis, you are right first credit card can be exciting, tempting and intimidating. when I was getting the card from Alliance Bankcard, I was so happy and my girl friend can't controlled and hugged me.
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Reasons Why Property For Sale in Ubud Bali The Best Investment For Retirement?
Ubud is a natural tour, shopping, culinary, and artistic tourism. Not enough just a day to explore Ubud. Ubud is in the highlands so it feels cool. Ubud maintains the layout of the city by following the natural contours. Falling in love with Ubud is one of the reasons tourists return to Bali. Deciding to stay in another country needs a lot of consideration. But many foreign tourists decided to settle in Bali. They are willing to start a new life in Bali.
Property for sale in Ubud Bali, one of the most popular in the world. For investors, this is an advantage. As for tourists, property in the form of a house or villa is a savings budget, as a vacation accommodation. There are many ways to invest, either near or long term. Especially in Ubud, popular tourist destinations and offering tranquility for tourists.
There are many reasons why property for sale in Ubud is the best investment. This is the best investment for your old age. Ubud Property can be utilized to get a short-term profit. Some reasons and benefits why property for sale in Ubud is a perfect investment.
Do you know many activities and activities held in Ubud? Starting from jazz festivals, painting exhibitions, writers' meetings, to culinary festivals. Villa is an investment that is in great demand today. When people go to Bali, the question is what is your vacation destination?
If you want peace, surely Ubud is the answer. Enjoying the atmosphere of Ubud in the villa is a perfect vacation. For that reason, villa investment is appropriate for the short term. You can benefit from villa rent, both daily, weekly, monthly or yearly.
Other properties for sale in Ubud Bali are in the form of land. You can build and use it as desired. Property investment belongs to a very profitable business. Currently, people buy land and build into a working space. Recommendations, you can find land with view paddy field. With the only internet and furniture supplies, you have taken advantage of the property for multiple benefits.
You need to be aware that workers need the best and calmest place to work. The idea of building a working place on your land property can be a profitable business. There is no need to have the big capital to get a business and get a profit. Property for sale in Ubud Bali is best for your investment and business. Especially if you want to do business when your retirement arrives.


Feel the magic of Disney in Japan at Tokyo Disneyland. Right next door is DisneySea, which has more thrilling rides if you're feeling bold.
Climb to the top of this 333 m-tall tower for unbelievable views of sprawling Tokyo city. If you're brave enough, walk out on the seethrough glass floor!
Build, learn and play. The Legoland Discovery Center has several play areas, an incredible Miniland including iconic buildings of Tokyo city, a 4D cinema experience and the Kingdom Quest interactive laser ride. Plus learn Master Builder techniques with the three million bricks under one roof.
There's so much hands-on fun to be had at this museum, with kid-friendly exhibits on almost every floor. The huge dinosaur exhibit is a must-see.
See how the royals really lived. You'll find the beautiful grounds and gardens are a great place to get some fresh air, and the views of the palace are stunning.


Erica Chan is an Asian-American who grew up in Las Vegas, Nevada. After exploring many different artistic avenues throughout her life, such as drawing, piano, violin, and dance, she soon discovered editing and the ability to create and manipulate content to evoke emotion.
From then on, she knew that becoming a filmmaker was what she wanted pursue. She went to the FSU College of Motion Picture Arts to complete her MFA in Film Production. Here she grew a fascination with cinematography, writing, and producing.
Erica resides in Los Angeles where she continues to finesse her craft, share her unique voice and follow her dream in becoming a female director.


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text:
Q: Quickly filter by timestamp falling within a number of ranges I'm trying to quickly filter a pandas dataframe containing a series of timestamps, such that the times fall with a set of ranges (in a different dataframe).
Currently I use a filter function and use apply, which works but is quite slow. Am I missing an obvious solution?
import pandas as pd

# Dataframe of timestamps
df = pd.DataFrame(pd.date_range('20180117', end='20180118', freq='60s'),
                  columns=['time'])

# Dataframe of intervals
df2= pd.DataFrame([[pd.Timestamp('201801170005'), pd.Timestamp('201801170020')],
                   [pd.Timestamp('201801171415'), pd.Timestamp('201801171430')],
                   [pd.Timestamp('201801171800'), pd.Timestamp('201801171900')]],
                  columns=['start','end'])

def flag_during(timestamp, df):
    """Test if a timestamp falls between any [start, end] pairs"""
    return any((df['start']<timestamp) & (timestamp<df['end']))

# Add a column indicating if the time falls within any interval
%timeit df['During'] = df['time'].apply(lambda l: flag_during(l, df2))

Timeit  returns
682 ms ± 2.71 ms per loop (mean ± std. dev. of 7 runs, 1 loop each)

Result
I implemented the solution from How to join two dataframes for which column values are within a certain range? (or the accompanying answer) and came up with the following:
%%timeit
idx = pd.IntervalIndex.from_arrays(df2['start'], df2['end'], closed='both')
event =  ~pd.isna(df2['start'].reindex(idx.get_indexer(df['time'])))
df['During2'] = event.values

Returns
826 µs ± 7.4 µs per loop (mean ± std. dev. of 7 runs, 1000 loops each)

About 1000 times faster.

redpajama_set_name: RedPajamaStackExchange


Wickersham was a seventeen year old girl who was born and raised in Bend and had just finished her junior year at Bend High School. She is described by her friends as a likeable young lady with a bubbly outgoing personality. On the evening of July 11, 1973 Wickersham and a friend had been cruising town in her mother's car. After taking her friend home, Wickersham delivered the car to the Sage Room Restaurant (in downtown Bend near the Tower Theater) where her mother worked. Wickersham told her mother that friends were going to pick her up in front of the restaurant and take her home. Wickersham left the restaurant at about 11:30 PM and was last seen walking toward the Owl Rexall Drug Store on Wall Street. On January 20, 1976 skeletal remains and some personal items were found by a wood cutter approximately five miles south of Bend in a wooded area behind a weigh station on Hwy 97. The remains were identified as Wickersham through dental records and the recovered personal items. Examination of the skull by the state medical examiner's office determined Wickersham had suffered a gunshot wound to the head.
On November 27, 2004 an unidentified white male was found deceased in a green sleeping bag along the Deschutes River in Bend, Oregon, near Meadow Camp. The victim was dressed for the elements; wearing a gray stocking cap, black coat, brown extra large sweater, gray sweatshirt, black Levi jeans, gray wool socks and brown Danner boots. He also had an orange backpack with him. The victim appeared to be homeless. The victim's estimated age is between 40-50 years old. He is approximately 6'0" and 180-190 lbs. The victim has brown hair with a beard and mustache. It does not appear this death was the result of foul play.
On March 27, 1989 Chan disappeared and has not been seen or heard from since. Her vehicle was found on the north shoulder of Hwy 126 just west of the Cline Falls Bridge. The car was in good running condition, however the passenger side window had been broken out and a large rock was lying between the front seats. Chan was described as an attractive white female with blond hair, blue eyes who was five feet two inches tall and weighed about one hundred twenty pounds. At the time of her disappearance she was married to Bruce Chan, an American of Chinese decent, who was a lieutenant in the U. S Marines stationed at Camp Pendelton in California. The couple was estranged but continued an amiable relationship. Angela was living with her parents in Redmond and her husband, Bruce, was visiting during the weekend. On the morning of Monday March 27 Angela and her husband went trap shooting. According to Bruce Chan, after shooting, he dropped Angela off in front of her parents house at about 2 PM and he left to return to Camp Pendelton. Several witnesses claim they saw Angela's car and a female matching her description around the Cline Fall Bridge later that afternoon. After Bruce Chan's departure, Angela's parents believed she had gone to Sisters to stay with a friend. On Wednesday March 29 they discovered she had never shown up at the friends house and was reported missing.


The Desired state of conservation was sent to the World Heritage Centre in February 2010 and is currently under review.
June 1996: UNESCO / IUCN mission (including World Heritage Committee Chairperson); June 2003: UNESCO mission; April 2005: UNESCO informal visit; February-March 2006: Joint WHC/ / IUCN mission; April 2007: Joint WHC / IUCN mission (including World Heritage Committee Chairperson); April 2009: UNESCO informal visit; April/May 2010: Joint WHC/IUCN reactive monitoring mission.
On 12 February 2010 the State Party submitted a report on the state of conservation of the property. The report included a draft Statement of Outstanding Universal Value, and a proposal for the Desired state of conservation for the removal of the property from the List of World Heritage in Danger. Both are currently under review.
The joint World Heritage Centre/ IUCN reactive monitoring mission requested by the World Heritage Committee at its 33rd session (Seville, 2009) took place from 28 April to 6 May 2010. The principal factor leading to the inscription of the property on the List of World Heritage in Danger arises from the breakdown of its ecological isolation due to the increasing movement, mainly driven by growth in visitation, of people and goods between the islands and the continent, facilitating the introduction of alien species, which threaten native and endemic Galapagos species. Additional issues include illegal fishing pressures in the Galapagos Marine Reserve (GMR), and institutional instability. A full discussion on the 15 corrective measures is included in the mission report. The corrective measures addressed below are those for which further action is particularly required. Those corrective measures not appearing below are considered by the mission to be either being fully or largely implemented.
The number of continental air and maritime ports serving Galapagos has been reduced to three. At least basic biosecurity inspections services are available in all of these ports. In Galapagos, two commercial airports and four maritime ports receive commercial traffic directly from the continent. However, the mission noted that the multiple entry points disperse the limited biosecurity inspection capacity in the islands. Baltra, a small, dry island, is an ideal setting for the establishment of a single maritime entry point where biosecurity inspection and control infrastructure should be concentrated. In 2007, a large airport terminal was constructed at Villamil. The mission noted that it was clearly built to accommodate hundreds of passengers. Though the terminal is unused, the mission noted a strong sense of expectation among various stakeholders on the eventual approval of commercial air service, presenting a risk for the opening of a new access point in the future and increasing the level of threat to the property. The mission concludes that there are still too many access point and that this unnecessarily increases the risk of introduction and dispersal of invasive species.
The mission notes that the new constitution for Ecuador, adopted on 20 October 2008, resulted in the amalgamation of the National Institute for Galapagos (INGALA) and the Provincial Government, now directed by a governing council comprised of three ministers and the elected mayors of Galapagos. Though formally in existence, the council has not yet hired its director of operations – a post with significant responsibilities towards the property. The mission was assured that the position would be filled based on technical specifications, and by transparent means. The World Heritage Centre and IUCN consider that the recruitment process for the director of operations should be as fully transparent and competence-based as that of other key positions including the Director of GNPS and Agrocalidad, and that a clear line of communication between the Governing Council and the Director of GNPS should be assured.
An international sport fishing tournament (focusing exclusively on bill-fish such as marlin and swordfish) was organized for December 2009 independent of the Galapagos National Park Service, which is responsible for all activities within the marine reserve. The activity was deemed illegal by the Park and was not allowed to proceed. The organizers re-packaged the tournament as "artisanal subsistence fishing", an allowable fishing modality in the marine reserve. Under this modality, the same activity was subsequently authorized by the Park. The tournament focused on catching and releasing as many bill-fish as possible within the time frame of the tournament. Mortality of bill-fish is understood to be significant despite this practice The World Heritage Centre and IUCN are concerned by the Park's de facto authorization of sport fishing within the Galapagos Marine Reserve, without a clear understanding of its likely impacts on the Outstanding Universal Value of the property. They note that there is a lack of information on the targeted bill-fish populations, which are under very high pressure from commercial and sports fishing activities throughout the eastern Pacific. They also consider authorization of this activity can be taken as one indicator of reduced effectiveness of the management of the Galapagos National Park Service.
Ship based capacity is strictly limited by government authorities and reached a steady state approximately 10 years ago. Land based capacity is limited only by the capacity of commercial aircraft delivering visitors. Land based visitation in Villamil is reported as having increased from 5,000 in 2003, to 25,000 in 2009. The mission noted that hotel construction and the opening of informal guest houses continue at a rapid pace often without the requisite municipal or Tourism Ministry approvals. One hotel, the Iguana Crossing in Villamil, is currently undergoing a judicial process for having built on GalapagosNational Park land. The National Park Service is struggling to implement its concession based model of new tourism services in the park and marine areas (scuba diving, inter-island transport, artisanal fishing, day tours by boat). It faces a growing number of non-licensed operators, judicial challenges to its decisions made and active and increasing pursuit of non-authorized activities within the property. The World Heritage Centre and IUCN consider that there is a need to develop and implement a clear tourism vision and strategy for Galapagos, with a focus on establishing mechanisms to discourage rapid and uncontrolled growth visitation.
The mission found that the weakest link in the biosecurity control chain continues to be the shipping of goods from the continent to the islands. Seven small ships ranging in age from 28 to 56 years are involved, using three different loading facilities in Guayaquil. Though minimum biosecurity standards have been imposed, experts indicate that the very design of these ships render effective controls very difficult. Efforts are underway, with the support of WildAid, to equip one private dockyard (of the three currently being used by Galapagos bound cargo ships) with the necessary biosecurity inspection infrastructure. Only ships using such facilities should be licensed to serve Galapagos – and these should be audited regularly by certified third parties. The World Heritage Centre and IUCN strongly recommend policies leading to the replacement of the existing ships with fewer, larger modern vessels designed to facilitate biosecurity control. In Galapagos, goods are offloaded in a time consuming and disorganised fashion at each of the three main settlements. The main towns have no deep water docks, notwithstanding the fact that establishing cargo handling facilities there would also seriously conflict with these towns' vocation as ecotourism centres. The best option remains the use of BaltraIsland, with its pre-existing deep water facility, as the only receiving terminal in the islands.
Agrocalidad, the biosecurity agency, informed the mission that it was in the process of hiring 25 new technicians. Sniffer dogs (for drugs and shark fins) are now working in the three main ports of the islands. However, the mission noted that these dogs are not trained to detect plant and other animal matter, which are the primary imports of concern in terms of invasive species. The National Park is also reported to be installing x-ray equipment at the Baltra airport to improve the detection of banned products. It remains critical to concentrate all resources in fewer access points, such as BaltraIsland.
The World Heritage Centre and IUCN take note of significant progress in the consolidation of Agrocalidad. However, its effectiveness is compromised due to the dispersal of its efforts amongst several entry points. Similarly, in the absence of a modern approach to handling cargo loading in Guayaquil, and as long as the ships transporting the cargo to the islands do not meet adequate standards, investment by Agrocalidad will be significantly undermined. Until this chain is effectively completed, this property will continue to remain vulnerable to the arrival of new invasive species.
Though the Galapagos National Park Service appears to be implementing its day to day activities efficiently, the World Heritage Centre and IUCN are concerned about its ability to deal with long term strategic issues. The recent forced ceding of 70 hectares of park lands to the town of Puerto Ayora is also an indicator of reduced effectiveness of the Park's management. This was also the case in the Park's reversal regarding sport fishing tournament brought on by pressure from a small group of foreign and local stakeholders. These incidents point to a renewed weakening of institutional governance in the islands, whereby outside agents, and not the national authorities, take the initiative in determining how park lands and the marine reserve are to be used.
· Establishing a single cargo loading port in Guayaquil, with the necessary infrastructure in place.
· Commit to replacing the current aging and mal-adapted cargo ships with new ships designed to facilitate the application of biosecurity measures.
· Application of established bio-security practices, with regular compliance audits, at cargo loading and off-loading points, and on cargo ships.
· Carrying out the feasibility of selecting Baltra as the only Galapagos port authorized to receive cargo directly from the continent.
· Ensure that the Villamil air terminal is not put in service and consider its dismantling to discourage speculation.
· The State Party develop and implement a clear tourism strategy for Galapagos, with a focus on establishing mechanisms to discourage rapid and uncontrolled growth in visitation. A moratorium on sport fishing until a) a government run risk assessment on the potential impact of sports fishing on the Galapagos nature tourism brand be done, and if a decision to proceed is taken, b) sufficient scientific evidence is obtained allowing for the development of clear regulations set by the Galapagos National Park Service (e.g. intensity, seasonality, zonation, licensing).
· The State Party consider implementing a mechanism, such as imposing an upper limit to the number of Park entrance permits awarded annually, which would give it the time to develop and implement effective tourism management mechanisms.
3. Ensure that that the decisions taken by the new Governing Council of the Galapagos prioritise consideration of the Outstanding Universal Value of the property (corrective measure c).
· Ensure that the recruitment process for the director of operations of the Governing Council is as fully transparent and competence-based as that of other key positions including the Director of GNPS and Agrocalidad.
· Ensure a clear line of communication between the Governing Council and the Director of GNPS with regard to the management of the National Park and Marine Reserve, as well as on all policies affecting the Park.
The World Heritage Centre and IUCN note that until these remaining corrective measures are achieved, the property should remain on the List of World Heritage in Danger.
8. Decides to remove the Galapagos Islands (Ecuador) from the List of World Heritage in Danger and further requests the World Heritage Centre to continue to cooperate with the State Party to follow up and assess the progress on the implementation of the recommendations contained in Paragraph 6 above, in line with the draft Statement of Outstanding Universal Value proposed by the State Party.
8. Decides to retain the Galápagos Islands (Ecuador) on the List of World Heritage in Danger.


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There's no better time than Christmas to create your own gifts, decorations and giveaways for kids! With over 200 different items included in our collection of Christmas craft supplies for adults, we guarantee you'll find all they DIY supplies you need at prices that can't be beat. Browse and save on everything from mini Christmas stockings and Christmas jingle bells, to red canvas tote bags, poinsettia garland, favor jars and so much more!
If you're looking to create your own Christmas decorations, our natural pine cones are a good place to start. Ignite your creative spark when using these pine cones in handmade wreaths and garland. Give your Christmas tree a rustic touch by stringing pine cones together for garland or hanging separately as Christmas ornaments. Simple yet beautiful, the possibilities are unlimited when it comes to decorating with one of nature's greatest winter gifts!
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No matter how you plan on using our craft supplies, we guarantee you'll find everything you need to satisfy your creative hunger! Whether you're looking to create Christmas ornaments in bulk, or trying to create your own DIY gifts for friends, family and coworkers, our prices on unique craft supplies make stocking up easy and fun!


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Q: Load Lat/Long data into QGIS layer from MSSQL Query I'm very new to QGIS.
I have a table with lat long data stored as text, which I can save as a .csv and load in as a Delimited Text Layer and it shows up just fine.
I'm now trying to load the data directly from my MSSQL database, and am struggling to find how to create a layer based on a query. Is this even possible or am I going about it the wrong way.

A: *

*Open Layer > Data Source Manager in QGIS.

*Go to the tab MS SQL Server: there you can create a connection to your database.

Once established and loaded as a layer, in the layer properties (right click layer > Properties), there is a tab called Source where you can set a Provider Feature Filter: fill in your SQL query in the Query builder.
There is also the DB manager plugin, but not for MSSQL databases.


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Tuition fees for Home students
The University is committed to providing a world class education and access to the very best teachers, resources and support. Therefore, we invest significantly more than the amount of the maximum government regulated (Home) fee on each student every year.
At Cambridge, the government regulated tuition fee for Home fee status1 students starting their first undergraduate degree2 in 2020 will be £9,250 for the year and, currently, may be different in future years.
You should check this website for the most up-to-date information on tuition fees before applying and prior to accepting an offer from the University should your application be successful.
Currently, Home students can take out a government loan for their tuition fees. At the moment, students can defer payment of the loan until after they've left university and are earning a certain minimum salary, at which point the loan is paid in instalments. Please see the information on government financial support and refer to the appropriate student finance award agency for full advice and details.
Year abroad tuition fees
If your course includes a year abroad, the tuition fee for that year is different. Currently, the fee for a Home student on a full year abroad is set at 15 per cent of the tuition fee for that year in Cambridge (please see the undergraduate tuition fees documents, right, for the most recent figures). Year abroad tuition fees for later years haven't been set yet but are likely to increase annually in line with inflation.
1 Islands students (from the Channel Islands and Isle of Man) are usually classified as international students and so charged tuition fees at the international rate. As overseas students, Islands students have to pay College fees in addition to tuition fees. See below for further information.
2 Students studying for a second undergraduate degree should refer to the information regarding fees on the second undergraduate degrees page of this website.
Tuition fees for EU students
The UK has voted to leave the European Union. It's not currently known how long that process will take or the impact that it will have on UK policy on higher education tuition fees, loans and bursaries. However, the University of Cambridge can confirm that the fee for undergraduate EU students who are already studying at Cambridge, or who'll start their studies in 2019 or 2020, will be at the applicable Home rate (which for undergraduate students may be up to the maximum level allowed under UK law for each year) and they'll not be subject to the overseas fee rate at any point during the course of their study. Please note that all fees may be subject to increases, which may be annual.
EU students should regularly check for updates at: www.cam.ac.uk/eu.
Tuition fees for international and Islands students
Tuition fees for overseas students (from outside the EU, and including students from the Channel Islands and the Isle of Man) vary depending on the course you're studying. Most overseas students also have to pay College fees in addition to tuition fees. See international fees and costs for details.
Cambridge Bursary Scheme website
University Composition Fees
Undergraduate Tuition Fees
Undergraduate tuition fees 2020-21

redpajama_set_name: RedPajamaCommonCrawl


Why won't my username/password work?
There are two points at which Analyzer checks your subscription username and password. The first is when you run Analyzer for the first time after installing. You will be asked for your credentials and once you input them and they are verified, you will not be asked again. You will need an active internet connection for the verification to happen.
The second time that verification occurs is during parameterization once a shot is done. During parameterization, the software briefly communicates with our servers to verify your subscription. Again, an active internet connection is needed during this time.
Occasionally there are issues that can lead to the credentials being rejected. Likely causes and solutions are discussed below.
1.) Make sure you are copying and pasting your credentials exactly as they were given to you. Including extraneous spaces or omitting characters will cause verification to fail.
2.) Check to see if your firewall is allowing Analyzer to access the internet. Additionally, if in an office environment, check with your information technology professional to make sure that Analyzer can access the internet through the office's firewall.
3.) Please ensure that the date and time are correct in Windows on your machine. Only the minutes need to be adjusted, the hours can remain appropriate for your specific time zone. If your machine is more than a couple minutes off of our server's time, you will not be able to validate Analyzer. The easiest way to ensure that the time is correct is to sync to internet time in Windows.
4.) Your internet connection may be timing out during the authentication process.
5.) If these are tried and repeated attempts fail, contact support@facewaretech.com and we'll assist you.
Analyzer stores your old credentials in a .config file and sometimes it is necessary to delete the config file to add new credentials. If you are switching from a trial to a paid subscription, we highly recommend doing this to eliminate any variables when entering your new subscription credentials.
2.) Find the folder labeled Image_Metrics,_Inc. and open it.
3.) Select everything inside that folder and delete it.
After this, run Analyzer again. You should be asked for your subscription credentials. Enter them as normal and proceed on your merry way.


If you are still on the hunt for that perfect wedding gown why not pop into Forever Bridal as Sanyukta Shrestha will be hosting a designer weekend on the 29th & 30th of June.
Head along on Saturday between 10am-6pm or 12pm-6pm on Sunday.
Forever Bridal are offering 10% off oll orders taken that day. Sanyukta will also be there to give all brides help and advice.
For more details email [email protected] or call 028 90 600 400.


If you're thinking about buying a new car in 2019, one of the biggest decisions to make before you go out car shopping is whether you want a manual or automatic gearbox. Here are just a few of the reasons why an automatic may be beneficial in 2019.
The government plans to ban the sale of diesel by 2040. This is creating a surge in popularity for electric vehicles. Electric vehicles do not need to have a gearbox (as all of their power is available at 0 rpm, so there is no need to change up gears), so there is no need for drivers to know how to use manual vehicles. In fact, experts predict that manual cars will disappear from UK roads altogether in the next ten years.
Tip: While EVs do not need a gearbox, some manufacturers add a gearbox to help control the power.
If you drive in the USA or Canada, you will struggle to find a manual car to hire. Furthermore, in Australia, New Zealand, the US and Canada, it is much cheaper to hire an automatic vehicle from a rental agency. However, in Europe, manual cars are still a popular choice. If you travel to the States regularly, then an automatic car while making the transitions between driving in the UK and the USA easier.
In an automatic vehicle, you are far less likely to stall which makes it much easier, less stressful and less embarrassing to tackle tricky hill starts. If your automatic vehicle does stall, then this will usually indicate a mechanic issue rather than a driver error.
Of course, without the pressure of stall, automatic vehicles are much easier to drive. Instead of worrying about gears you can focus on speed and road position. It can also make driving much safer as you can keep both hands on the wheel for the majority of the time.
A common urban myth is that manual cars are more efficient than fuel-guzzlingautomatic vehicles. While automatics used to have less fuel efficiency, modern technology means that most automatic vehicles are incredibly fuel efficient and will often outperform manual vehicles. This means you can receive more miles for your money with an automatic.


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text:
#ifndef HASH_H
#define HASH_H
#if !defined(INTERNAL) || !defined(EXTERNAL)
# error Missing amalgamation macros
#endif

#include "string.h"

struct hash_table {
    int capacity;
    int count;
    struct hash_entry *entries;
};

/* Reset table, clearing all values. Does not deallocate memory. */
INTERNAL void hash_clear(struct hash_table *tab, void (*del)(void *));

/* Free resources owned by table. */
INTERNAL void hash_destroy(struct hash_table *tab);

/*
 * Insert element, or return existing with the same key.
 *
 * Initializer, if provided, is invoked when data is added.
 */
INTERNAL void *hash_insert(
    struct hash_table *tab,
    String key,
    void *value,
    void *(*add)(void *, String *));

/* Retrieve element matching key, or NULL if not found. */
INTERNAL void *hash_lookup(struct hash_table *tab, String key);

/*
 * Remove element matching key.
 *
 * Finalizer, if provider, is invoked when data is removed.
 */
INTERNAL void hash_remove(
    struct hash_table *tab,
    String key,
    void (*del)(void *));

#endif

redpajama_set_name: RedPajamaGithub


text:
Judge orders Iran to pay Flint ex-Marine Amir Hekmati, jailed for 4 years
Judge Ellen Huvelle of the U.S. District Court in Washington, D.C., granted Amir Hekmati's motion for a default judgment.
Judge orders Iran to pay Flint ex-Marine Amir Hekmati, jailed for 4 years Judge Ellen Huvelle of the U.S. District Court in Washington, D.C., granted Amir Hekmati's motion for a default judgment. Check out this story on Freep.com: http://on.freep.com/2yEBzxG
By Jeff Karoub, Associated Press Published 9:16 p.m. ET Oct. 2, 2017
Former U.S. Marine Amir Hekmati says he feels humbled and lucky to be free again, after being one of four Americans released by Iran as part of a prisoner swap. (Jan. 19) AP
Former U.S. Marine Amir Hekmati, 32, arrives at Bishop International Airport on Thursday, Jan. 21, 2016, in Flint.(Photo: Salwan Georges Special to DFP)
A judge has ordered Iran to pay $63.5 million to a former U.S. Marine who was jailed in that country for more than four years.
Judge Ellen Huvelle of the U.S. District Court in Washington, D.C., granted Amir Hekmati's motion for a default judgment after Iran failed to respond to the complaint. Hekmati, who was released in January 2016, alleged he was falsely imprisoned and tortured.
It's unclear if Hekmati will get any money.
An e-mail sent by The Associated Press seeking comment from Hekmati's family wasn't returned.
Hekmati was detained in August 2011 on espionage charges. He says he went to Iran to visit family and spend time with his ailing grandmother.
Hekmati was born in Arizona and raised in Michigan. His family has lived in the Flint area.
More on Freep.com:
Flint's Amir Hekmati files lawsuit detailing torture in Iran
Read or Share this story: http://on.freep.com/2yEBzxG
Weather radar captures billions of mayflies over Lake Erie
Novi family angry over request to remove Virgin Mary statue
Cops: Suspect beat Warren man to death, returned for shoes
Police: Mich. woman drunk, speeding on I-75 while towing horses
Woman arrested after stealing, crashing Ferndale police car
It's dangerously hot outside, but relief ahead