Pencil & paper. Boot time appears almost instantaneous. Very handy for jotting down an idea or two. Battery doesn't run out. I keep a pencil+paper on the door of my fridge, so it's always easy to find. For storage, I use "back pocket of jeans" until I can upload it somewhere permanent.
They didn't *translate* it; they *correlated* it. From the BBC news article:
"In the study, conducted in Nebraska, 46 volunteers were first asked about their political views on issues ranging from foreign aid and the Iraq war to capital punishment and patriotism."
I think your paraphrasing seems misleading. "More protective attitudes" is one thing. But "Do you support more troops in iraq" and "do you support capital punishment" are unambiguously classed as conservative/liberal political views by everyone.
(1) Their actual complaint itself said NOTHING about his blog. This looks like a bad slashdot summary of a bad article. The blog was mentioned only in background.
(2) They are criticising him and his client jointly for obstructing the discovery process and needlessly dragging out the court process.
(3) The reason they mention his blog is because (in their view) his blog posts substantiate their claim that he and his client have obstructed the discovery process and have dragged out the court process.
It's true that they point out that his motions were posted on his blog. But they're not criticizing these blog-posts at all.
They're already implementing one mechanism for crediting-back installs (i.e. if the install hasn't "phoned home" for 10 days).
If I were a developer, I certainly wouldn't waste developer-hours on a SECOND mechanism for crediting-back installs (i.e. if the user does an uninstall). Especially since it's useless, given the kink you point out.
And since the game hasn't yet been out for 10 days, then of course no one has yet encountered the "10 day credit-back" mechanism in their anecdotes.
So the people who suffer are the unusual lot who reinstall windows four times in ten days, and they re-install Spore each time. Or the ones who uninstall then reinstall Spore four times in ten days. These are NOT "regular users". And the longest they'll have to wait is a week or so.
As I understood it, the limit was "3 concurrent installs". If one of your installs hadn't called back to EA within the past 10 or so days, then that install is credited back.
Which seems fine to me.
I imagine your anecdotes were from people making the test immediately rather than waiting 10 days.
If you've been dreaming of a multi-process browser for ages, you could start using IE8 on Windows! It lets you configure how many processes you want, from one process for all tabs+plugins through to a separate process for each tab/plugin. (And the "frame" running in a separate frame). http://blogs.msdn.com/ie/archive/2008/07/28/ie8-and-reliability.aspx
Really, the things you worry about work a lot more smoothly in practice.
I read my corporate webmail via the URL "http://mail.mycompany.com" and it's always counted as INTERNET mode, regardless of whether I browse from within corpnet or from home or from public kiosks. How does it know? Because "http://mail.mycompany.com" is an internet address, not a corpnet address.
But when I read my payroll at "http://payroll" then it's always counted as INTRAnet mode, and obviously I can't connect to it from outside the corpnet. How does it know? Because "http://payroll" is a corpnet address, not an internet address.
If some IT department makes a website that's accessible from two different ADDRESSES, one internal and one external, then they must have positively gone out of their way to create trouble for themsleves.
Obviously the things work a lot more smoothly than you worry.
Don't be ridiculous. Of course it's configurable by group setting. The default is a good one so that existing corpnets can upgrade without worries. And any IT department that's ready to make their corpnet standards-compliant will CERTAINLY know how to either (1) incorporate the DOCTYPE tag to force standards mode on each page, or (2) set group policy so that all machines in the company use standards mode by default instead.
"there are more pressing issues". And yet you thought that immunity for Telcos was more important than social justice, patriot act abuses, guantanamo, iraq, afghanistan, healthcare, missile defence?
It's kind of dishonest to equate the current scientific near-consensus on global warming with the isolated and speculative thoughts on global cooling in the 70s.
20 years is just how long it's taken to go from the discovery of a chemical effect, on to gathering the brains of alzheimer's sufferers who have just died, developing reliable test-tube assays, developing models of the disease, developing transgenic animals, finding funding, seeking ethical and regulatory approval for clinical trials, running Phase1, and the same for Phase 2.
If you go to http://www.wischik.com/claude/pubs.html you'll see some 40 peer-reviewed publications spanning 20 years that document how slow and painstaking the research is.
There's no indication that MTC in particular causes cancer, and it's been prescribed for other conditions for many decades.
The reasons for the 100mg ineffecacy seemed to be related to how much of the chemical was reduced or absorbed in the intestines.
Analysing the data is hard in general. What's clear is that there was no statistically significant difference between the start state and end state of patients on the drug.
The trademark word "rember" is written with a lower-case initial letter.
But I agree with your concern about advertisments on slashdot.
What happened is that they went to present their results at the ICAD 2008 alzheimer conference in Chicago. The ICAD committee selected Rember as one of the "top presentations" at the conference, and organized all the PR and news briefings.
Yes it is patentable, and TauRx holds several patents around the drug. It's not just the chemical itself. You can also patent the formulation, the test-tube tests, the "use of chemical for a specific purpose", the transgenic animal tests...
Thanks for the bug report. I don't suppose you happen to remember how you answered the questions, do you? We don't keep any logs (because the data seems personal and confidential!) But I think I'll update the error-handling mechanism to show what answers the person gave, so I can reproduce bugs...
Toxicity is minimal, and methylene blue has been used for many many years. In fact it was used even before the FDA came in and standardized toxicity testing. That means that there's no "officially approved" toxicity data for the drug. The company's hope is to do Phase 3 trials concurrently with toxicity.
On the serious side, we had a battery of several hundred questions that were administered to patients. Lots of the old ones just couldn't cope with sitting through an hour of questions. So we had to figure out statistical ways to make a diagnosis even when some of the questions aren't answered.
For the online version, I didn't display confidence intervals because I thought they'd be too confusing. But the statistical engine under the hood (if you answered 1 incorrect and 2 correct) says "the patient has somewhere between 0 dementia and FULL dementia, with a confidence level of 95%"...
I'm very sorry about your wife. That sounds really awful. This idea, that it's the carers who suffer most, is something my father repeats all the time.
It was administered in pills. The world's supply of methylene blue largely comes from a factory in china, but TauRx wanted much higher purity for their drug, so they invented a new process for manufacturing it and oversaw production in a new factory. The methylene blue is put into pills and taken orally.
There were difficulties with formulation. It had to do with the problem of getting the right dose to the brain, and not having it get digested. Also there was a problem (I can't remember which way round) about acid/base conditions. Maybe it was that the stomach acid wanted to oxidise the drug, so it had to be mixed with a reducing agent so it lasted long enough to reach the brain? I'm afraid I worked on the questionnaire side, not on the chemistry....
You're right that the questions have leading phrasing. But for a standardised clinical trial, the questions have to be phrased exactly identically and administered in an identical way. The questions we use come from standardized vetted tests for alzheimers (MMSE, ADAS-COG, ADLS, ADFACS, CAMCOG, CAMDEX,...). Half the questionnaires are done by interview with the carer, the other half by interview with the patient.
What we do is look at the questions and statistics as a black box. Ignore the semantic content of the questions. Look solely for statistical correlates between results on the questionnaires, and disease pathology (in terms of tangles in the brain, in people who died prematurely and we got their brains under a microscope.)
The statistical analysis lead to some interesting results! "Principal Component Analysis" is a technique for, more or less, "letting the data speak for itself". In this case the data told us that there are two completely separate areas of decline in the disease, one the loss of "personhood", one the loss of "cognition". They don't go hand in hand.
Actually, the loss of "personhood" starts FIRST in alzheimers disease.
And amongst all the questionnaires, the single question that was best correlated with the onset of the disease was, "and for how long have you been depressed?" !!
But you're right, the questions are leading and cosed. It was needed for a standardized clinical trial. But a true diagnosis is best made also with a doctor and light chat. Actually, this is standardized in a test called "CIBIC" -- Clinician Interview-Based Impression of Change -- and this CIBIC test was routinely administered in the Rember clinnical trial.
TauRx does freeze progression of the disease, though, even before it's begun to manifest as a reduced MMSE score. You can catch people at this stage (Braak 1 or 2, equivalent to MMSE 28/29/30) before they've deteriorated much at all, and start administering the drug.
I should say that Claude Wischik thinks he *does* know what causes Alzheimer's disease. He's sure that tau tangles cause it. He's spent the past twenty years accumulating evidence and trying to convince people of the fact, but it's been hard because of the entrenched scientific dogma that amyloid causes it. The success of this drug finally is a vindication.
You're absolutely right, though, it was a case of trying lots of chemicals. At least, the larger pharmeceutical companies have been trying hundreds of thousands of chemicals from their libraries. A smaller company like TauRx can only manage far fewer.
But what's needed is a test-tube test to judge whether your chemical works. Previous attempts have judged whether their test chemicals work to prevent Amyloid buildup, and so they skip right over the useful ones. Claude Wischik realised that the test-tube test should be judging whether a drug works on tau tangles. This test-tube assay was the first key invention.
After that, you need an animal test to judge whether the drug works in animals. The second key invention by TauRx is a transgenic mouse where you can make it selectively express tau aggregates. They created mice with alzheimers, watched them make their demented way around water-tanks looking for firm ground, and then showed that Rember improved their condition.
You're right to ask about the temporary remissions. The clinical trial lasted 19 months and had 321 patients -- not a short trial! The test results had a p-value of 0.2%, i.e. there's a 0.2% chance that the improvement was due to the common random fluctuation rather than the drug's effect.
I'm sorry to hear about your grandmother. It sounds heartbreaking. With our statistical analysis of the questionnaire results, what became clear was that alzheimers was a disease where (1) the sufferer lost their "personhood", and (2) the sufferer lots their cognitive faculties. You clearly experienced the first part. It's a shame that current FDA regulatory approval only take into account effectiveness for point (2).
Slashdot Mirror
Pencil & paper.
Boot time appears almost instantaneous.
Very handy for jotting down an idea or two.
Battery doesn't run out.
I keep a pencil+paper on the door of my fridge, so it's always easy to find.
For storage, I use "back pocket of jeans" until I can upload it somewhere permanent.
They didn't *translate* it; they *correlated* it. From the BBC news article:
"In the study, conducted in Nebraska, 46 volunteers were first asked about their political views on issues ranging from foreign aid and the Iraq war to capital punishment and patriotism."
http://news.bbc.co.uk/2/hi/science/nature/7623256.stm
I think your paraphrasing seems misleading. "More protective attitudes" is one thing. But "Do you support more troops in iraq" and "do you support capital punishment" are unambiguously classed as conservative/liberal political views by everyone.
From my reading of the RIAA's memorandum http://blog.wired.com/27bstroke6/files/vexatious.pdf
(1) Their actual complaint itself said NOTHING about his blog. This looks like a bad slashdot summary of a bad article. The blog was mentioned only in background.
(2) They are criticising him and his client jointly for obstructing the discovery process and needlessly dragging out the court process.
(3) The reason they mention his blog is because (in their view) his blog posts substantiate their claim that he and his client have obstructed the discovery process and have dragged out the court process.
It's true that they point out that his motions were posted on his blog. But they're not criticizing these blog-posts at all.
They're already implementing one mechanism for crediting-back installs (i.e. if the install hasn't "phoned home" for 10 days).
If I were a developer, I certainly wouldn't waste developer-hours on a SECOND mechanism for crediting-back installs (i.e. if the user does an uninstall). Especially since it's useless, given the kink you point out.
And since the game hasn't yet been out for 10 days, then of course no one has yet encountered the "10 day credit-back" mechanism in their anecdotes.
So the people who suffer are the unusual lot who reinstall windows four times in ten days, and they re-install Spore each time. Or the ones who uninstall then reinstall Spore four times in ten days. These are NOT "regular users". And the longest they'll have to wait is a week or so.
As I understood it, the limit was "3 concurrent installs". If one of your installs hadn't called back to EA within the past 10 or so days, then that install is credited back.
Which seems fine to me.
I imagine your anecdotes were from people making the test immediately rather than waiting 10 days.
If you've been dreaming of a multi-process browser for ages, you could start using IE8 on Windows! It lets you configure how many processes you want, from one process for all tabs+plugins through to a separate process for each tab/plugin. (And the "frame" running in a separate frame). http://blogs.msdn.com/ie/archive/2008/07/28/ie8-and-reliability.aspx
Really, the things you worry about work a lot more smoothly in practice.
I read my corporate webmail via the URL "http://mail.mycompany.com" and it's always counted as INTERNET mode, regardless of whether I browse from within corpnet or from home or from public kiosks. How does it know? Because "http://mail.mycompany.com" is an internet address, not a corpnet address.
But when I read my payroll at "http://payroll" then it's always counted as INTRAnet mode, and obviously I can't connect to it from outside the corpnet. How does it know? Because "http://payroll" is a corpnet address, not an internet address.
If some IT department makes a website that's accessible from two different ADDRESSES, one internal and one external, then they must have positively gone out of their way to create trouble for themsleves.
Obviously the things work a lot more smoothly than you worry.
Don't be ridiculous. Of course it's configurable by group setting. The default is a good one so that existing corpnets can upgrade without worries. And any IT department that's ready to make their corpnet standards-compliant will CERTAINLY know how to either (1) incorporate the DOCTYPE tag to force standards mode on each page, or (2) set group policy so that all machines in the company use standards mode by default instead.
"there are more pressing issues". And yet you thought that immunity for Telcos was more important than social justice, patriot act abuses, guantanamo, iraq, afghanistan, healthcare, missile defence?
It's kind of dishonest to equate the current scientific near-consensus on global warming with the isolated and speculative thoughts on global cooling in the 70s.
95%? That's extraordinary! Inner-loops comprise 95% of your source code? I've never seen a program like that in my 25 years of programming.
20 years is just how long it's taken to go from the discovery of a chemical effect, on to gathering the brains of alzheimer's sufferers who have just died, developing reliable test-tube assays, developing models of the disease, developing transgenic animals, finding funding, seeking ethical and regulatory approval for clinical trials, running Phase1, and the same for Phase 2.
If you go to http://www.wischik.com/claude/pubs.html you'll see some 40 peer-reviewed publications spanning 20 years that document how slow and painstaking the research is.
There's no indication that MTC in particular causes cancer, and it's been prescribed for other conditions for many decades.
The reasons for the 100mg ineffecacy seemed to be related to how much of the chemical was reduced or absorbed in the intestines.
Analysing the data is hard in general. What's clear is that there was no statistically significant difference between the start state and end state of patients on the drug.
The trademark word "rember" is written with a lower-case initial letter.
But I agree with your concern about advertisments on slashdot.
The work was announced at the ICAD 2008 conference in Chicago.
Here's the ICAD press release that mentions Rember:
http://www.alz.org/icad/_release_icad_072908_130pm_trials.asp
What happened is that they went to present their results at the ICAD 2008 alzheimer conference in Chicago. The ICAD committee selected Rember as one of the "top presentations" at the conference, and organized all the PR and news briefings.
Yes it is patentable, and TauRx holds several patents around the drug. It's not just the chemical itself. You can also patent the formulation, the test-tube tests, the "use of chemical for a specific purpose", the transgenic animal tests...
Thanks for the bug report.
I don't suppose you happen to remember how you answered the questions, do you? We don't keep any logs (because the data seems personal and confidential!) But I think I'll update the error-handling mechanism to show what answers the person gave, so I can reproduce bugs...
Not your eyes, but the drug does stain your urine blue...
Toxicity is minimal, and methylene blue has been used for many many years. In fact it was used even before the FDA came in and standardized toxicity testing. That means that there's no "officially approved" toxicity data for the drug. The company's hope is to do Phase 3 trials concurrently with toxicity.
That's funny :)
On the serious side, we had a battery of several hundred questions that were administered to patients. Lots of the old ones just couldn't cope with sitting through an hour of questions. So we had to figure out statistical ways to make a diagnosis even when some of the questions aren't answered.
For the online version, I didn't display confidence intervals because I thought they'd be too confusing. But the statistical engine under the hood (if you answered 1 incorrect and 2 correct) says "the patient has somewhere between 0 dementia and FULL dementia, with a confidence level of 95%" ...
I'm very sorry about your wife. That sounds really awful. This idea, that it's the carers who suffer most, is something my father repeats all the time.
It was administered in pills. The world's supply of methylene blue largely comes from a factory in china, but TauRx wanted much higher purity for their drug, so they invented a new process for manufacturing it and oversaw production in a new factory. The methylene blue is put into pills and taken orally.
There were difficulties with formulation. It had to do with the problem of getting the right dose to the brain, and not having it get digested. Also there was a problem (I can't remember which way round) about acid/base conditions. Maybe it was that the stomach acid wanted to oxidise the drug, so it had to be mixed with a reducing agent so it lasted long enough to reach the brain? I'm afraid I worked on the questionnaire side, not on the chemistry....
You're right that the questions have leading phrasing. But for a standardised clinical trial, the questions have to be phrased exactly identically and administered in an identical way. The questions we use come from standardized vetted tests for alzheimers (MMSE, ADAS-COG, ADLS, ADFACS, CAMCOG, CAMDEX, ...). Half the questionnaires are done by interview with the carer, the other half by interview with the patient.
What we do is look at the questions and statistics as a black box. Ignore the semantic content of the questions. Look solely for statistical correlates between results on the questionnaires, and disease pathology (in terms of tangles in the brain, in people who died prematurely and we got their brains under a microscope.)
The statistical analysis lead to some interesting results! "Principal Component Analysis" is a technique for, more or less, "letting the data speak for itself". In this case the data told us that there are two completely separate areas of decline in the disease, one the loss of "personhood", one the loss of "cognition". They don't go hand in hand.
Actually, the loss of "personhood" starts FIRST in alzheimers disease.
And amongst all the questionnaires, the single question that was best correlated with the onset of the disease was, "and for how long have you been depressed?" !!
But you're right, the questions are leading and cosed. It was needed for a standardized clinical trial. But a true diagnosis is best made also with a doctor and light chat. Actually, this is standardized in a test called "CIBIC" -- Clinician Interview-Based Impression of Change -- and this CIBIC test was routinely administered in the Rember clinnical trial.
It's an awful calculation to make, isn't it?
TauRx does freeze progression of the disease, though, even before it's begun to manifest as a reduced MMSE score. You can catch people at this stage (Braak 1 or 2, equivalent to MMSE 28/29/30) before they've deteriorated much at all, and start administering the drug.
I should say that Claude Wischik thinks he *does* know what causes Alzheimer's disease. He's sure that tau tangles cause it. He's spent the past twenty years accumulating evidence and trying to convince people of the fact, but it's been hard because of the entrenched scientific dogma that amyloid causes it. The success of this drug finally is a vindication.
You're absolutely right, though, it was a case of trying lots of chemicals. At least, the larger pharmeceutical companies have been trying hundreds of thousands of chemicals from their libraries. A smaller company like TauRx can only manage far fewer.
But what's needed is a test-tube test to judge whether your chemical works. Previous attempts have judged whether their test chemicals work to prevent Amyloid buildup, and so they skip right over the useful ones. Claude Wischik realised that the test-tube test should be judging whether a drug works on tau tangles. This test-tube assay was the first key invention.
After that, you need an animal test to judge whether the drug works in animals. The second key invention by TauRx is a transgenic mouse where you can make it selectively express tau aggregates. They created mice with alzheimers, watched them make their demented way around water-tanks looking for firm ground, and then showed that Rember improved their condition.
You're right to ask about the temporary remissions. The clinical trial lasted 19 months and had 321 patients -- not a short trial! The test results had a p-value of 0.2%, i.e. there's a 0.2% chance that the improvement was due to the common random fluctuation rather than the drug's effect.
I'm sorry to hear about your grandmother. It sounds heartbreaking. With our statistical analysis of the questionnaire results, what became clear was that alzheimers was a disease where (1) the sufferer lost their "personhood", and (2) the sufferer lots their cognitive faculties. You clearly experienced the first part. It's a shame that current FDA regulatory approval only take into account effectiveness for point (2).