.

.

Wednesday, December 31, 2014

Bah. Humbug.

So, I was going to say:

Here we are in the season of Merry Christmas and Happy New Year and etc etc posts where everybody looks back and goes over all the cool stuff, and wishes everybody else all the best and etc and etc. Good cheer and suchlike all around.

pfff.

It's been a rotten past several months. Sure, things happened before that, stuff that at the time was full of joy and wonder and I could hardly wait to write a year-end post like the others.
Now here we are at the year's end, and I just want it to be over. Please go back to normal, everybody.

And then I thought, if you don't have anything nice to say, don't say anything.
Well, alright. I'll just stop blogging. Get off Facebook.
But what's the point in only sharing nice things? It would be great if there were only nice things. But there are other things too. Isn't life poorer for pretending there aren't? And, if you don't have anything sweet and light to post, and you step out of the social circle, don't you isolate yourself even more? Isn't keeping a hand in part of what's going to bring you back to a place where good things happen regularly?

Do have a good day tomorrow. And better ones after that.

Monday, December 22, 2014

GET OUT



Ces plantes n'ont pas encore été composté, si tu veux les chercher.

Friday, December 19, 2014

Snarkiness -Or-

100 words on Why I love this Manuscript

Unsupported suppositions
Incomprehensible hypotheses
To our mind
Over-interpreted p-values:
If it’s statistically significant, it must be important
105 words when 10 will do.
The related statistics do not mean much.
Throw it all into a sack without controlling whether it belongs there.
Long meandering sentences with conjunctions that make no sense and verbs so far from their subjects you have no idea what is connected to what : always interrupted with a colon and frequently also with parentheses for self-referring references.*
Oppositely
We have the biggest database we know about.
Erroneous conclusions.


* I can’t even write that kind of sentence when I’m trying!

Monday, December 15, 2014

Friday, December 12, 2014

Nijmegen 2

The 16th A-T Workshop will be held in Beijing next fall. I went to my first ATW, the 5th in the series, in 1993 as a graduate student. 22 years later they're still having them, they're still announcing progress, and they're still looking for a cure. Family-run funding organisations have come and gone. Parents and patients are continually hopeful and disappointed.. One said I gave you millions - where's my cure? Forever elusive.
A couple of treatment options are tentatively on the table, though neither is a cure. Both carry risks. Neither can be tested in a randomized study. People don't agree about going forward with either one. Nor do they agree it is better to be careful.
As often happens, people start leaving before the last session. Trains and planes to catch now or wait a whole day. I'm waiting a whole day, mostly on purpose. This way I have the afternoon to see the town. Not to mention I hate meetings where the last speaker talks to an empty room.
I also hate travelling to a place for a meeting, going straight to the hotel, getting to know the venue really well, and then flying straight out again. Last night's little excursion notwithstanding.

Nijmegen? Oh, I've been there. Really nifty hotel out in the Berg en Dal region.

After a quick lunch I get my camera and check out the 90 minute trail around the park and agricultural area near the hotel. There are several viewpoints marked, but you can't see much from them. The hills aren't very steep and the trees still have most of their leaves. Makes for a nice view of the trees, but they get in the way of any view over the plain.
Now for a bus into town. The oldest part is off-limits to cars, making several blocks of pedestrian-district filled with shops and restaurants and today a long series of outdoor stalls along the main road means the central road is elbow to elbow with people. Throngs. Most of the architecture has been updated, and as I mentioned the large majority of shops are international chains. I'd like to pick up some unique souvenir, something that to me will say Here, without being a chunk of airport schlock made in China. I come across a place selling teas and coffess, with a gorgeous but limited and extremely expensive selection of hand-made pottery. Beautiful stuff but it will be difficult to get home intact. Perhaps I'll stop back for a trinket if I don't see anything else.

Ah, here's Hema. Load up on munchies for home and dutch cookies to share at work. By the time I come out of Hema it's getting dark and the open-air stalls are beginning to pack up. Hey, guys, it's not even 5. Ever thought of outdoor lights?
It starts to rain so I duck into one of the brasseries on the main street for a glass of wine and a cup of spicy tomato soup. Lots of people stop in for an afternoon beer or even dinner.
When I go out again the rain has stopped, the stands are in the last stages of packing, and the streets are deserted. The larger stores are still open, but nobody much is in there but the employees tidying up.
Saturday evening (not even - it's just late afternoon still, according to most of us) and Nijmegen is dead. Maybe they've all gone home for a rest and a shower before coming out for a wild night. Maybe.
I just don't really see that, though.
Several blocks later I catch a bus back to the hotel.
5:48

After a scalding hot shower I spend a quiet evening with a book.
At the desk they told we there were trains to Schiphol at 8:42 and at 9:12 that should get me there in time for my flight. To catch the train there are busses at 8:19 and 8:49.
Earlier is better, you know, just in case.
As usual I'm quick to get ready in the morning. I hang around the lobby interminably, then go out into the drizzle to the bus stop. The two blocks don't take nearly as long as they should, so I have plenty of time to hang out at the bus shelter in the dark, pacing against the cold. The rain is weak but makes a lot of nouse in the trees. Leaves come down as drops hit them just right. A day or two of this and they might be naked. The sky lightens gradually, and by the time the bus arrives it might be daytime. Hard to tell. Certainly it is by the time we pull up at the train station.
I have just four minutes to buy a ticket, find my train and get on it. For natives this might be child's play, but my dutch is rudementary. Good thing I have enough margin to take the later train.
Aha. Train to Amsterdam at 8:42, just like the desk clerk said; there's only one leaving at that time, and I find it & hop on just before it starts rolling.
Looking at the display of stops, though, this train does not seem to stop at Schiphol. Um. I suppose trains back to Schiphol from Amsterdam Central must be frequent and quick. Though I know that is a 20 minute trip - good thing I got the early train.
I ask the conductor, and he's all irritated I didn't stamp my ticket in the machine at the station. Tells me I need to change trains at Utrecht. And stamp my ticket there. Be sure to stamp.
OK, ok.
Off the train at Utrecht, there's the Schiphol one marked for quay 7. This is 5. To the right, quays 1-4. To the left, 8-12. Seven, please. Neither right not left leaves the middle, and the train at the opposite quay, not quay 6 but indeed 7 (what do they have against 6? there are other even-numbered quays), is just leaving... Ah, there is another train farther down quay 7, and it is the right one. Leaving immediately.
Ooh. Good thing I decided not to try and get a coffee.
I haven't completely figured out Dutch trains yet. Very helpfully, a screen on the train from Nijmegen told us what the stops where and when we would make them. Close to a stop they display what connections are leaving soon. I was relieved to see my destination, and doubly so on seeing a time 40 minutes later. If I'm going to spend 40 minutes in Utrecht waiting for my connection, thank goodness I took the early train. On the later one I'd miss my plane, or be so stressed about it I might as well. That's why I thought I had plenty of time to get a coffee. But when I saw the train, and the imminent departure time I was lucky to hop aboard in time. Was 40 minutes for the next one? Or did 10:30 refer to our arrival time at the airport (and we do arrive at 10:30) Bit of a difference.

Everything was fine. Nobody looked at my unstamped ticket. The airline was not on strike. There are multiple Starbucks at the airport, on both sides of the security check.

Wednesday, December 10, 2014

J+117

Un jour, c’est comme si un couteau a été retiré de la plaie. On se sent tellement bien. On peut commencer à cicatriser, finalement.
Puis le lendemain,
non.
Toujours là.

Ne me dit pas que tu me tiendras courant de quelque chose que tu n’as pas la moindre intention de faire.

Tuesday, December 9, 2014

False economies

So how’s the stagiaire, you might ask, that girl with the unfortunate timing and worse training ?

We were going to look at the clinical data for her samples before deciding which of them to choose to analyse, but ran into the problem that she doesn’t have with her, and cannot get access to, the clinical data (the f*? can’t someone email her a list? – is there no list?) So we have to be satisfied with the labels already assigned.

The problem of how to pick which ones to analyse has been very simply resolved. It turns out that most of the 300+ samples she brought with her are completely degraded and cannot ever be analysed. Only about 60 actually contain DNA in fragments long enough to do anything with. So we’ll go with the 60, whatever they are.

300 blood draws, and 240 of them are good for the trash? What happens when you don’t make the necessary investments up front, but try to get by as cheaply as possible. Instead of using some modern but relatively expensive kit for extracting the DNA, they used the tried and true phenol-chloroform method.

When I was in grad school, a wise post-doc always said “The fast way is the slow way, and the slow way is the fast way.” Very good advice, that. Same can be true of expensive and cheap, when cheap puts success at risk.

Now, you can get acceptable DNA with this method, but you have to really know what you’re doing. This is the method I used way back when I was a tech, and it was not always a success. The first thing to do was to get your reagents right, and that meant spending all the necessary time under the fume hood buffering the phenol to a neutral pH. No neutral pH, no good DNA. Just forget it. Whatever comes out might look good at first glance, then fall to pieces over the next week or month, leaving nothing.
Once you’ve got your phenol neutralized, and you extract the washed white cells from your blood, recover the aqueous phase, re-extract that twice with chloroform to get the phenol gone – and a third time if needed. Yes, just do it again. Phenol is the kiss of death for any further manipulation. Chloroform just evaporates no problem. Now you can precipitate your clean(ish) DNA with ethanol and just a bit of salt if there isn’t enough already. But don’t spin it down. Nice DNA will form a beautiful, fluffy white cloud, like magic, as soon as the ethanol hits it. Seal the end of a glass pipet (ooo yes, get to play with fire in the lab!), and fish the blob of DNA out (do let the pipet cool before dipping it in – otherwise the ethanol at 60% will ignite). Squeeze the DNA blob like a sponge against the edge of the tube and once the ethanol has evaporated, swish it around in a tube of aqueous buffer and let it resuspend for a couple of days before attempting to measure its concentration.


So our student is working on the samples that can be worked on, and we’ll see on Monday what sort of results can be had. Cross our fingers that once she passes the preliminary amplification step, all the rest is ok. After all, the rest all works off of the product of the first step, not the primary material. Because if there are no results, um, well there really is no plan B.

Monday, December 8, 2014

Nijmegen

Off to Holland on the early flight, then a proper train through such places as Utrecht and Arnhem. Last stop: Nijmegen.
I bring the camera, hoping to have some time to poke around Nijmegen, one of the oldest cities in this country, between sessions at the A-T meeting I've been sent here for. Alas, our hotel is several km outside of the city, in a modern university suburb. Neat & tidy, but boring. The area is nicely wooded and surprisingly hilly for the Netherlands. The hotel brochure mentions a 60 minute walk and a 90 minute one, and even a 16km connection to some sort of national trail network with no proposed timing. Hah, guess you can get out for a walk if you want to.
Ah, here's the meeting schedule. Everything's over with lunch on Saturday, and as long as it doesn't rain I'll have that afternoon to stroll around the autumn hills of Holland. Fingers crossed that the weather holds, because it isn't looking good.
I haven't been to an A-T workshop in ages. The APRAT, the local family association, holds a meeting every two years or so, and I do see one or two of my old colleagues at those events, but they're mostly for the families, not for scientists. They talk about daily issues - how to get the help they need, how to deal with school and physical therapy, tricks to keep their kids involved and active and as healthy as possible. They want to know about treatment, and what to expect of the future, but not too much.
This is a clinical meeting set up to talk about all the nitty-gritty and what can be done and what isn't working and what might eventually be a good idea. I'm here to distill all that into a progress report for the families in France. I hope there's good news. Something to say that they haven't been saying for years already.
There's a slide put up showing the increase in life expectancy for the general population over the past century, showing also the life expectancy curve for people with cystic fibrosis. CF is another recessive genetic disease for which the gene was cloned some several years ago but like A-T that did not particularly help in developing a cure for the illness. The CF curve is going up, though, faster than that of the general population. All the increase is linked to better everyday symptomatic care, and to being pro-active and staying ahead of problems before they're intractable.
At lunch, the father of two A-T patients said to me that he didn't think the curve for A-T patients had changed at all, in spite of all our meetings and networks and expertise.
I thought this just couldn't be true. Like CF, A-T patients are treated as their problems come up, with a recent accent on keeping ahead any bug to settle in the lungs and on exercises to keep the functions that one has, or at least lose them more slowly. So we must be doing better even if there's no cure for the fundamental problem. So I asked around, because these are just the people who would know. But the ones I asked didn't really know. Though they did suspect the father was right, and the survival curve, if it had improved at all, had done so very modestly. Not like the CF curve.
It's actually complicated to figure. In the past decade, lots of patients with variant phenotypes, all mild, have been found to have A-T, genetically. They have real deleterious mutations, just not the severe disease course. So the overall survival figures are inflated by the inclusion of these milder cases (or, conversely, the disease is being redefined). If you stick to 'classical' A-T, and people are increasingly careful to preface their talks with that word, then nobody has the numbers.
Any improvement is not very big.
Which is odd, because if we have better antibiotics, or at least a wider variety of them, and we know better how to do physical therapy (and when), and we're better at chemotherapy, then there should reasonably be some improvement. There are more anecdotes today about A-T patients in their 30s and 40s than there ever were - do they not shift anything?
We talk about health risks in heterozygotes. The cancer risk pretty much boils down to breast cancer in women, which is well-studied. The small residual increased risk for A-T parents to die of cancer is spread out over all types and ages, and there's nothing to follow up on there. The question today is how to catch the breast cancers early, and if the standard mammography might be provoking years later the very thing it's meant to detect. Scientifically, that would make sense. But because of the delay between starting screening and detecting a cancer, nobody can say for sure if the radiological screening itself increased the risk. So women are still being referred for mammograms as early as age 40, and we will see in 10 years if we've made a very big mistake. Or not.
There are other health problems in the carriers. Heart disease, diabetes, things that don't appear to have much to do with the gene defective in A-T.
Why heart disease?
Well, most of the known and studied carriers are the parents of patients. These people have a lot of stress, from caring from their chronically ill children, even more so when their kids become adults with less and less autonomy. And they tend to neglect their own health. It isn't because they have just one working copy of ATM. They have Caregiver Syndrome.
I don't know if it's an official syndrome, but it could be.
If you could get the non-parent carriers in a study (the brothers and sisters and aunts and uncles...) and follow them up long enough, you'd probably confirm this. And then all the carriers identified through the breast cancer risk cohorts - they have no A-T patients in their families at all. Do they have these same problems?
Anyway, it's an interesting meeting, which goes past far faster than I can write about it.
Friday evening there's a bus to take us into town, for a quick private tour of the museum and dinner in one of the historical buildings.
At the museum we skip the extensive temporary exhibit of fashionable hats. Ditto the installations of multimedia modern "art" (thank goodness). We tour instead the history of the city with its Roman camps and strategic positioning on a low bluff along one of the major arms of the Rhine delta. This was the northwestern edge of the Roman Empire.
Yeah, who'd'a thunk?
(Well, ok, anybody with a decent idea of European history)

There used to be interesting castles and forts around, but they've mostly disappeared. Often used as sources of ready-quarried stone or free bricks, and prominent buildings remaining from the middle ages were flattened in a mistaken but very efficient bombing run by the Americans in 1944.
The museum closes at 5 sharp, and we're told by our hosts before being ushered outside into the early night that we're welcome to gather even now at the restaurant for drinks, but at any rate please be there by 6:30 for the meal. It's right down the street here, then on the right. Can't miss it: it's the only "old" building on the square. Shops close at 6 if you're going to wander around town.
Shops close at 6? Dinner at 6:30? Thank goodness they pushed the schedule back half an hour - the program says dinner at 6, and I don't think anyone but the Dutch in our group is interested in eating so early.
I head off with my friend Janet, whom I haven't seen in years, since another of these A-T workshops. The buildings are typical brick rowhouses, three stories tall.. The old street surface is brick. The shops on the ground floors are just the same ones now that you find all over France and the UK, just about. Seems you could be anywhere. The eateries are mostly local, though there are a lot of chain restaurants and fast foods coming in. More homogenization.
Janet exclaims There's a Hema! Just the place to get decent(ish) stuff really cheap. Hema hasn't made it to Clermont, or apparently to Lyon where Janet is based, but Paris has them. The deli section has all sorts of cookies and crackers and sweets and jarred condiments and prepackaged meals, just the stuff an English person needs when in France for too long.
Indeed. I must come back here tomorrow.
Dinner is served at long, long tables in an old merchant storehouse and trading center. Very quaint, lots of wood with iron fittings and brick floors and magnificently high ceilings. Wine from Chile and Argentina, not from any of those little countries right next door.
I used to hate these dinners because I didn't know anyone, and you're stuck there until the bus comes to fetch you. Now I know some people at least a little bit, and I know some of the other people they mention so frequently when talking shop. Which is most of the time of course.  Janet I've known since moving to France, Luciana and our hostess Corry here at my sector of table since grad school, so I'm not so ill at ease. I don't work directly on A-T any more, but it's a good bunch, and the evening goes well.
After two and a half hours at table, though, I really would rather go out for a walk around for the last half hour. It's raining lightly, but what the hell.
The streets are deserted. Many of the shops use metal roll-down curtains, so you can't even look in the windows (not to mention the sad grey air that gives the whole street). The fabulous church is all shrouded in scaffolding. I get as far as the museum, where the bus will pick us up, and it isn't there yet. Curious. You'd think it would be there by now.
Perhaps there's a change in plans and the bus will after all be allowed to pick us up in front of the restaurant, and I'm at this very moment missing that announcement...
So I wander back the other way. Some of my colleagues have gotten their coats and gone for a stroll by now too, and here's Janet and Luciana and a young post-doc. Luciana appears to fear waiting in the drizzle, and looking back toward the museum I see our bus has arrived. If we get on now we can get the very very best seats - the front row on the upper deck. We do that, and save the Italian professor's hair from a soaking.
The thing with getting on the bus too early, however, is that you might end up missing it.
I'm not ready to sit still yet, so while the others settle in I go out again. It's just a few hundred feet through the park to the view over the river with its bridges and houses all lit up. And the ruins of the castle are lit up. Nice. I wander back, all the time in the world,, and see the bus close its doors. Somehow that fails to indicate to my sluggish brain that this means it's about to leave. Time has stopped. They're just closing the doors because it's cold out. What I would do - I'm getting cold.
Yeah, and then it starts to move.

Hey! Wait!

Thursday, December 4, 2014

par for the course

For years my lab has been noting/announcing/complaining that we definitely need a proper laboratory management computing system to handle the thousands of samples and tests we do. Things get lost. Mixed up. Set aside. It's hard to handle everything manually when you have some 500 tests pending at any given moment.

Several years ago we did win a grant to develop such a system with a local start-up company, but after a long time of throwing good money after bad, the project was given up as being far beyond the capacity of the startup.
Um, you might ask, might there be any appropriate commercial software available for your problem?
Yes, there is. But for a genetics lab, where we deal not just with individuals with families, and not just the analysis of one little item but a whole chain of items to make a whole, Appropriate Software costs hundreds of thousands of bucks.
Bucks we don't have, and that our computing department doesn't believe we need. They sent us off to develop what we needed on our own!

Then one fine day there was a problem with the identification of a patient (which was in fact not our problem at all, but a problem at the hospital level of the labels they print being limited to a certain number of characters, and a patient with a name longer than that), and the head of computing suddenly decided we needed a proper system for handling all our samples.
A-hah.
And then she decided that we should have this one particular program to do it. Without consulting us, of course. Just happens that this is one of the better systems we've looked into. We were happy enough to have this imposed upon us. Now we're getting into setting it up, and it comes to light that there's a new version coming out in the spring. And that the new version is far better adapted to our needs. So naturally they will start training now & all, but when it comes to the installation we'll get the new version, not the old.
Only, the new version doesn't work with Windows XP.
Why should it? Nobody uses XP any more.
Do they?
Well, um, we do.
And do you think they're just going to install a better operating system on all our machines?
HAHAHAHAHAHAHAHAHAHAHAHAHAHAHAHAHAHAHAHAHAHAHAHAHAHAHA