Marking time on the Phantom Hourglass

Last night, as Hillary accepted the zero delegates she won from Florida, I finished the latest entry in the Legend of Zelda series, Phantom Hourglass. I found it to be a fun, lightweight romp.

Phantom Hourglass is a sequel to the Gamecube game Wind Waker. It inherits cel-shaded rendering, a general character aesthetic, and an oceanic setting from its predecessor, while the terraced look of the islands (once you are on them) is more closely related to Zelda games from the SNES days (see left). Motion and combat are touch-driven, as are all of the tools—boomerang and bombchu routes are drawn on the screen. So too is your steamship's route through the seas (below, right). You can annotate the map (shown in these shots on the upper screen), circling important points or noting safe routes through treacherous areas. The controls generally work well and make most of the tools and weapons very intuitive. There were a couple of hiccups, however.

The first was that the touch control is not quite as sensitive as I might like. I had difficulty executing roll attacks consistently, and to be honest I was never quite able to pin down the motion that would produce one regularly. Also, I found stopping time in the final battle to be a bit of a crapshoot—I typically needed to draw five of the required hourglass shapes before one took. The other problem is that there just isn't a very good way to make Link run left (or the right, if you're left-handed). Unless you use an odd grip on the stylus your hand tends to block one screen or the other.

These minor issues aside, the gameplay is not very challenging, especially if you quickly catch on to how the various tools can be used. The eponymous hourglass serves as a time limit on one of the dungeons, in which a modest kind of stealth is required. This, not a serious challenge, is the most difficult part of the game except for one of the boss battles.

The gameplay fits the classic Zelda mold with the same additions as Wind Waker: you travel around the sea, visiting various islands and breaking into their dungeons. The dungeons themselves are pathfinding environmental puzzles—each dungeon contains a tool that is needed to traverse it and a bafmodad you are supposed to retrieve. Though the islands seem a little closer together than they were in Wind Waker you still spend a lot of time in transit, and the occasional appearances by enemies and pursuers are more annoying than entertaining. On the other hand, the addition of a minigame has much improved the dullest task in Wind Waker, i.e. the retrieval of sunken treasure.

Mini-games and sidequests are abundant, as is typical for these games. Seeking out all the various power-ups and perfecting your scores in these accessory games can add plenty of time to the game. However, your actual rewards are somewhat paltry, and mostly come in the form of parts for your ship. You can customize your ship in various ways, but the result is almost entirely aesthetic. Your ship gains greater stamina if all its parts come from the same set, but with one exception there's no reason to choose one set over another. Even a few minor effects would have made this more interesting—if, for instance, the stone hull decreased your speed but added stamina, or the restful cabin healed Link at a slow rate while he was on the ship. Effects of this kind would have added interesting dimensions without taking up much space on the card.

The role of guide and assistant is once more played by a fairy. Fortunately Ciela is much more helpful (and much less annoying) than Navi. She has a story, and it's somewhat interesting, but in general the story of Phantom Hourglass is very lightweight and silly. This was true of Wind Waker as well, but that game did a better job of winking at its own silliness, and also gained a sense of gravitas from the helplessness and regret expressed by the various spirits you encountered. Phantom Hourglass lacks both sensibilities, and as a result no real theme ever emerges.

In the end, the light story and easy gameplay make Phantom Hourglass seem like a slight little breeze of a game. It's easy to pick up and easy to forget once you put it down. The adventure sandwiched in between is fun, and retains much of the charm of its predecessor. Despite a few interesting variations on the way some items are used, however, it just doesn't leave much of an impression.

And now, a definition:

bafmodad (baf mō dad) - In a video game, an object which is not of any intrinsic use but which must be obtained in order to advance the plot. The Medallions from Ocarina of Time are a classic example. The bafmodad is conceptually related to the cinematic MacGuffin. Term invented by Jerry Holkins and Mike Krahulik as a corruption of the name of an actual item from Starfox Adventures.

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The Console Scorecard

It's time to start with a decision-making process. I'm not definitely in the market yet for one of the three next-gen consoles, but I will be, perhaps within the next year. This is an open post that I'll probably keep updating for a while. Keep in mind that my must-have games may not be the same as yours, though I'll welcome your suggestions.

This table looks really screwed up and I don't know why. I have no idea why all these break tags appeared in this post. Sorry for the megascroll. All fixed now. See what effort I go through to bring you my bullshit?

Positives	Negatives	Must-Have Games
Wii
motion control = activity backwards compatible with my GC library awesome downloadable retro games selection system and games more affordable robust controller many WiiWare titles are totally awesome	motion control = activity limited RPG selection (?) shovelware limited original downloadable content DS is enough for casual gaming	Fire Emblem: Radiant Dawn Metroid Prime 3: Corruption No More Heroes Okami Super Mario Galaxy Super Smash Bros. Brawl
XBox 360
robust online service (friends) robust original downloadable games listing great HD graphics very durable controller	robust online service (John Gabriel's GIFT) red ring of doom I don't have an HDTV	Assassin's Creed Blue Dragon BioShock Eternal Sonata Mass Effect
Playstation 3
comes with blu-ray player greater HD graphics Fumito Ueda	expensive... ...or not backwards compatible with my huge PS2 library I don't have an HDTV will cheaper blu-ray cause buyer's remorse? may melt my apartment flimsy controller	Assassin's Creed Final Fantasy XIII LittleBigPlanet Metal Gear Solid 4 Ratchet & Clank Future Uncharted: Drake's Fortune Valkyria Chronicles

Issues to consider:

Where will the RPG market land? Right now the Xbox seems to be leading on the quirky RPG front. Unless the install base widens significantly, it doesn't seem terribly likely that the PS3 will be as successful in that regard as the PS2 was. However, the PS3 is a likely landing place for the main Final Fantasy titles and the Tales series. The low development costs of Wii games may end up turning the 2-D RPG and strategy RPG markets to that console, even though the Gamecube was notoriously weak in the genre. Thus, the Wii may end up catching the narrow-market RPGs I often adore.

Can the HD consoles attract classic adventure games? It can't be a secret that I really like adventure games in the Zelda mold. Assuming that the X360 and PS3 split the RPG market, the clincher for either of these consoles will be success in attracting this generally ignored genre. Games like Beyond Good & Evil suggest that this genre can grow beyond the Zelda clones to include experiences of great emotional depth. Will the HD market go this way, or will the genre languish once again, save for the loving devotion of Nintendo?

Which console will generate the most interesting artistic innovations? I think the knee-jerk response here is the Wii, but it seems to me that developers have so far done much less with motion control than they could have. Instead, the Wii seems to have become a grand repository of casual-gaming shovelware, with a few truly innovative titles here and there. Despite its potential, the Wii has yet to see a game that achieves the true gestalt of emotional communication and interactivity that marks games as an artform. Does No More Heroes fill that void? And Sony Computer Entertainment cannot be ignored in this regard—Ueda's Ico and Shadow of the Colossus were some of the best art made for the last generation of consoles. Also, as the PS3 and Wii have been getting up to speed, Bioware and Irrational have started to take interesting steps on the X360. This is currently an open question, but for me it's a significant one.

And, to track my position by date:
1/30/08 - leaning towards Wii first, HD console (much) later.
2/13/08 - If the PS3 lacks backwards compatibility that is a major minus in my book. Baroque will come out on PS2, so it's no longer in the Wii column. The more I hear about Lost Odyssey the more ambivalent I feel. On the one hand I like the idea that short stories are built into the game, on the other hand I hate games that string cutscenes together using lame gameplay, not to mention that I hate hate hate amnesia as a plot device.
2/15/08 - Okami hops into the Wii category. I was underwhelmed by the gameplay on the PS2, but this is a game that would really benefit from the motion controller.
2/24/08 - Added Insult Swordfighting's controller reviews.
2/25/08 - Valkyria Chronicle looks really interesting. Into the PS3 pro column it goes.

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Super Tuesday

Well, today is the day of the Florida semi-primary, yet another chapter of the ridiculous primary leapfrog game that occurred this year. A week from now, almost half the states in the nation will have their own, very early, primaries. The madness will not end there, of course, especially in the case of the Democrats. The long slog of the primary season will continue for some time, and it is entirely possible that the candidates will not be decided until the end of March, leaving only a paltry seven months for the parties to assassinate the character and distort the record of their candidates more than has already been accomplished in the extended primary season. I have decided not to vote in the primary for a couple of reasons that I'll explain. If I were to vote in the primary, however, I would vote for Barack Obama or John McCain, and I'll explain that, too.

Why won't I vote in the primary? Well, it's not because I can't. Massachusetts has a semi-closed primary, so, because I am not a member of either party, I can vote in either primary. I disagree with this policy, because I feel it discourages additional parties and also third-party candidacies. Independents tend to be more moderate than party faithful; open primaries allow these voters to select centrist candidates. Were the electorate confronted with the true extremes of both parties, the enormous repulsion they felt would make a third-party candidate viable and weaken the parties. I'm also unwilling to signal tacit assent to the parties and their corrupt selection system by joining the primary. Finally, both parties only have terrible, horrible, no good, very bad candidates.

If, however, you put a gun to my head and forced me to vote in the Democratic primary, I would vote for Barack Obama, out of negative selection. None of the candidates have any real, relevant experience—Hillary's claim to "35 years" is a bunch of crap, and at the same time, her politics-as-usual behavior in every state, in every primary, belies her claim to "change" as well. She's a rerun of her husband, and frankly, I've had enough of the Clintons and the cynical politics of "triangulation". We didn't need four more years of Bill back in 2000, and we certainly don't need four more years of him now. Moreover, while it may not be fair to Hillary, the fact is that for reasons entirely unrelated to her actual degree of competence she is incredibly divisive. The issues we face right now are simply too difficult for us to have our President and Congress engaged in a four-year partisan wrestling match. Hillary has neither the leadership nor the charisma that the job presently requires.

So that leaves us with Edwards and Obama. I understand that Mr. Edwards is very angry at rich people and corporations, and feels that elites are waging war on the middle class. This is probably true, but Edwards doesn't actually supply any kind of believable answers, except perhaps waving his magic wand to create 1 million jobs. The adversarial position he adopts is not presently advantageous, in my view. We need to partner with corporations to get things done while reining them in gently, not harangue on and on about how bad they are. They are bad, and the present distribution of wealth is dangerously polarized. Edwards, however, doesn't have any better answer for this, his touchstone issue, than the next guy.

Obama is charismatic, has the right priorities, and lacks the baggage. He doesn't have much experience, but that's true of all the candidates. The Republicans hate him less, which means that he has a better chance of getting Congress moving than Hillary does. Moreover, his message of change is legitimate and inspiring. The message itself is trite, of course, but it gives him a chance of getting a true mandate from the electorate, rather than the narrow, confusing results of the last two elections. That will be a much-needed tool to break the intransigence of Congress. So I would vote for him to be a candidate, if I did not hate the parties, the primary system, and the fact that I can't find any candidate with more positives than negatives.

If you put a gun to my head and forced me to vote in the Republican primary, I would probably ask you to pull the trigger. On the other hand, I might hold my nose and vote for McCain.

Giuliani is a joke, and not even a particularly funny one. Huckabee, with his creationism and "fair tax", is an inhabitant of some absurd fairy wonderland. And Ron Paul's only virtue is that he is the only candidate who seems to be aware that "they hate us" more for what we have done than for who we are. I feel sorry for my uncle Sam, who is a fiscal conservative and therefore has no candidate. The whole row of them parrots the line of tax cuts and reduced spending, but nothing in the background of any of them really suggests they'll hold that line. Hell, at the Florida debate Huckabee practically suggested starting the WPA up again.

And Romney... my God, Mitt Romney running on his record of job creation in Massachusetts is laughable. I am not intrinsically concerned by the fact that Romney's position on every issue has changed—a considered change of opinion is every man's right. What bothers me is that all of his new positions just happen to be more expedient for getting a Republican nomination. Changing your opinion so that you will be more popular makes you a jackass, not a philosopher. Moreover, his side-swapping has ruined all credibility with Democrats and Democratic constituencies. He'll be trusted by neither party in Washington—a bad situation to be in with a Democratic Congress.

I disagree with John McCain on almost everything. However, I think he's as strong on the environment as a Republican can get. He has what the Democrats lack, i.e. experience, and has a track record of working with both parties to get things done. If, as a Republican, you want anything that matches your values to emerge from a Democratic congress, then he is probably the best bet. Also, McCain has the best chance out of all the candidates to rebuild the U.S. reputation in the world. Alone of all the Republicans he could believably claim that the United States does not torture, and his word on that would be more credible than any of the Democrats either (trivia time: under which President did "extraordinary rendition" begin?). As an independent, I could tolerate him as a president. He's certainly not a conservative's dream candidate, but since none of these candidates have real conservative credentials, IMO he's the least of the available evils from a Republican standpoint too. At least he would be strong on defense and capable of restoring our standing with our allies.

So those are the least bad in two fields of terrible choices. I'd be least bothered by a race between Obama and McCain, and I wouldn't know what to do in a race between Clinton and Romney, not least because they'd have the same talking points. What the country needs now is an intelligent leader who can work with the other side of the aisle and mobilize public support for necessary changes, not a partisan hack or professional windvane.

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What do we learn from the Protein Ensemble Method?

Anonymous left a comment on my post on Bruschweiller's work, referencing a couple of papers by Amarda Shehu, Cecilia Clementi, and Lydia Kavraki, the cites for which you can find at the bottom of this post. The most fascinating thing about these papers is the remarkable fidelity with which their Protein Ensemble Method (PEM) reproduces NMR-derived order parameters, 3-bond J couplings, and residual dipolar couplings. The authors demonstrate excellent correlations for ubiquitin, eglin c, Fyn SH3, Fnf10, and CI-2, and while all of these are relatively small proteins this is still a major accomplishment. Nonetheless, it is striking how little we learn from the exercise.

Keep in mind that one of the key goals of a structural biology research program is to get a veridical ensemble, i.e. an ensemble of structures that closely resembles those actually sampled by a protein under equilibrium conditions. We can learn important information from other kinds of ensembles, but the one that contains the information we are really after is the veridical ensemble.

The limitation here is intrinsic to the technique, so the technique bears some explanation. PEM utilizes an algorithm derived from robotics to move pieces of the protein. Initially, the approach was designed to map the ensemble of structures available to a loop, and I want to stress that with regards to that task I have no complaints. When given the task of mapping out the range of likely conformations of these regions this seems like an excellent approach, and the second figure of the 2006 paper seems to put this usage on fairly solid footing. The overall idea is that positioning the ends of a loop next to their anchor points is similar to solving a problem for getting a robotic arm with some number of degrees of freedom to adopt a particular pose. The authors' algorithm solves this inverse kinematic problem with a coarse-grained view of the backbone. At this point the backbone is frozen, the side chains are added back and their conformations are sampled randomly. The conformations thus generated are then subjected to energy refinement using a conventional force field. For a loop with no surroundings, this is all well and good.

The problem arises when the whole protein is subjected to the technique. This is done by using a rolling window of residues: the fragment is chosen, an ensemble defined for it while the rest of the protein is held rigid, and then the window moves to the next overlapping fragment. The various structures determined in this phase are all stored; the dynamic properties of a given residue are derived from a weighted average of all snapshots of all fragments that include that residue, with the exception that the first and last few residues of any fragment are out of bounds due to artificial restraints.

The ensemble of structures derived is therefore not veridical. Because of the fragment-replacement approach, only a single part of the protein is ever actually departing from the equilibrium or minimum-energy structure—it is unlikely that motions are actually distributed this way. Moreover, because the endpoints of all snapshots cannot be simultaneously resolved, it is not possible to assemble whole-protein conformational ensembles from the individual fragment ensembles. So, no individual snapshot is likely to reflect a significantly populated member of the ensemble, and also there is no way to collate the snapshots in such a way that the energetics of the real ensemble are accurately sampled. We thus end up with an ensemble of structures that does not reflect the set of structures actually sampled by the protein at equilibrium.

As a result, the structure that is produced can give us only limited information about the protein. For instance, this might be a reasonably reliable way to predict what sorts of deformations are possible or likely in a binding interaction. Also, PEM probably does a good job of reporting at least the lower limit of the range of the structural ensemble. However, because it does not allow for significant compensating deformations outside of the modeled region the conformations obtained probably do not cover the entire solution ensemble even for a particular fragment.

A clear implication of this work is the idea that the data are dominated by local fluctuations. That is, dynamics information derived from NMR relaxation experiments, quantitative J-coupling analysis, and RDCs primarily reflects short-range motions that do not involve major excursions from the overall structure. If this were not the case, it is unlikely that an intrinsically short-range method such as PEM could reproduce the data so well. This is not exactly a surprise, however, and the nature of PEM for the most part prevents us from learning how local motions in one region of the protein affect local motions in a distal region.

In a larger sense, however, this work reinforces the idea that the ideal approach to constructing a veridical ensemble will involve some combination of coarse-grained and all-atom approaches. The key problem here is not the computational method but the windowing. If the inverse kinematics approach used here can be extended to treat the whole protein—or at least multiple regions of the protein—simultaneously, then I think the situation improves. The question is whether this kind of algorithm will be any more efficient than MD if the whole system is in motion; I suspect at least some part of the computational savings (after what comes automatically with the coarse-graining during step one) arises from having rigid context for the fragment motions. However, this approach is also likely to be more amenable to parallelism than standard MD simulations, and because of the coarse-graining it has the ability to sample structures accessible on a timescale longer than MD can treat.

The authors of these studies imply that their future focus will be on extending this approach to larger structures; I would urge them instead to prioritize developing a way to employ PEM or a similar method without relying on fragment replacement.

Shehu, A., Kavraki, L.E., Clementi, C. (2006). On the Characterization of Protein Native State Ensembles. Biophysical Journal, 92(5), 1503-1511. DOI: 10.1529/biophysj.106.094409

Shehu, A., Clementi, C., Kavraki, L.E. (2006). Modeling protein conformational ensembles: From missing loops to equilibrium fluctuations. Proteins: Structure, Function, and Bioinformatics, 65(1), 164-179. DOI: 10.1002/prot.21060

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What will cure your child's cough?

Continuing with the recent mini-theme of pharmaceutical agents going awry, it seems appropriate to revisit last week's FDA advisory that children under the age of 2 should not be given over-the-counter cough medicines. This advisory had been expected for several months, of course, and the companies involved had already pulled most of these products from the shelves voluntarily. The FDA has not yet resolved the question of what to do about cough medicines for children aged 2-11, but because of the risks of accidental medication and the existence of serious questions about the actual effectiveness of these medications, there is a substantial probability that the agency will decide to ban these as well. Of course, this would seem to leave parents in a bit of a bind: what will they turn to now that nasty-tasting cold medicines are gone?

Of course, the situation isn't that dire: after all, cold medicines do not cure colds: they merely treat symptoms. No cold medicine can actually diminish the length of time a child is sick. The main upshot of this decision will be to put more of a burden on parents, who will have to deal with illnesses using more traditional means. At the same time, I am reminded of a recent study indicating that traditional means might work just fine, at least in limited cases. In December, a report in Archives of Pediatrics and Adolescent Medicine stated that honey was more effective in easing cough symptoms in children aged 2-18 than the popular cough suppressant dextromethorphan (DM).

The study did not rely on objective measures of coughing frequency or intensity, but instead depended on the subjective reports of parents to determine the effects of the medicine. Children were treated with either honey-mimic DM (formulated to approximate the taste and consistency of honey), actual buckwheat honey, or nothing at all. While families receiving no treatment were not blind to this fact, the honey and DM treatment groups were blinded. Surveys filled in before and after treatment dictated who entered the trial and assessed the treatment results. The study involved a few more than 100 children from the Hershey PA area; the sample size was limited by the requirement that no cough medicine have been given to the child in the previous 24 hours.

The outcome is shown in the figure at right—higher scores on the survey reflect a worse condition (i.e. 6 = extremely frequent cough). "First night" reflects the pre-treatment condition, while "Second night" comes from the results of a telephone survey carried out after treatment. You'll notice right away that the claim honey is "better" than DM reflects a pretty narrow difference. For the most part, scores are not that different no matter what treatment was used. This is especially surprising in light of the fact that the "no treatment" option was not blind. One might reasonably expect that awareness of null treatment would produce a negative effect on the subjectively reported outcomes; however, this seems not to have happened. Still, there is a clear, if slight, advantage for the honey treatment in this study. At the same time, it does not appear that parents will be much worse off if they do nothing at all. Keeping in mind that cough suppressants only alleviate symptoms, and have no effect on the underlying infection, these results sharply call the benefits of DM treatments for children into question.

This is not actually as crazy as it sounds. As the authors explain, honey has well-known antioxidant and anti-microbial properties. The dark honey used in this study is likely to be even stronger in this regard. Also, the authors note that sweet placebos have often shown a comparable effect to DM, so physiological effects of the sugar may also play a role. Shelley Batts of Retrospectacle, who covered this study when it came out, suggests that the viscosity of honey may also have a role, as it "coats the throat".

There are some complaints to be made about the study: geographically and temporally it is rather limited, and factors such as income and nutrition seem to lack controls. DM might have benefits in children with poor nutrition or additional conditions that would not be picked up by this study. Moreover, the nature of the sample—cases of cough that were severe enough to cause a parent to visit the doctor but not severe enough to induce the parent to use an OTC medication—may be selecting for parents who overreact to a single bad night of an otherwise mild cough. Clearly a larger study with additional data-gathering and controls is desirable. The best situation would be to enroll families at the beginning of cold and flu season in a truly blind trial and track the coughs longitudinally. Also, "no treatment" should be replaced by something, perhaps a colored simple syrup, to preserve blindness, and a fourth group in which DM is mixed directly into honey should be added to assess the possibility that characteristics of the honey-mimic DM broke the blind. Cynically, one would also prefer that such a study not be funded by the honey board.

Despite these limitations, the results are quite striking. In light of this study and its own evolving but clear preference to err on the side of caution it is likely that the FDA will either ban children's cold medications or recommend significantly stricter labeling. This shift in attitude on the part of FDA may mark the beginning of a generalized swing away from medication and back towards traditional treatments for children with mild illnesses. However, the advent of the preference for medication did not arise from medication itself; rather it evolved in concert with social considerations such as the rise in families where both parents work. In the social context of the 21st century a prescription for "plenty of bed rest, lots of fluids, chicken soup, and honey for the cough", may not be as workable as it was 50 or even 20 years ago.

Paul IM, Beiler J, McMonagle A, Shaffer ML, Duda L, Berlin CM. "Effect of Honey, Dextromethorphan, and No Treatment on Nocturnal Cough and Sleep Quality for Coughing Children and Their Parents." Arch. Pediatr. Adolesc. Med. 161 (12) 2007 p. 1140-1146.

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Uptake blockers do not improve on statins

It has not been a very good couple of weeks for big pharma in the public eye. They've been taking a pounding in the political arena since the primary season finally got into full swing. Last week, we learned that today's medicines, rather than funding tomorrow's miracles, mostly finance power lunches with your cardiologist. And this week, Merck and Schering-Plough, after much delay, finally announced the results of a major study, called ENHANCE, that did not demonstrate any benefit to using the highly-touted drugs Vytorin and Zetia rather than a generic statin.

Because almost everyone who owns a TV knows that Vytorin blocks both sources of cholesterol, and that "Zetia works differently", the results seem particularly damning. The companies involved did not help this appearance by holding back the results so long, and indeed doing so may have exposed them to lawsuits from shareholders and customers. The study was primarily performed by imaging the carotid artery, and in this regard no statistically significant difference was observed between patients treated with Vytorin (statin + Zetia) and statin alone. Also, there was no statistically significant difference in the number of patients who died from cardiac events or strokes, or suffered non-fatal infarctions in the study. While vytorin lowered cholesterol levels by 56% after 24 months vs. the 41% lowering seen in the statin group, this did not translate into improved outcomes by any measure.

So, is this a case of evil pharmaceutical companies trying to gouge consumers over worthless medications? Not exactly. Like every campaign promoting prescription drugs, commercials for Zetia and Vytorin oversold the benefits and did not sufficiently emphasize the risks of these medications. Their failure to improve outcomes in this study is troubling, but because adverse outcomes were so rare overall, it would be difficult to establish an effect one way or another. Also, this study was not geared towards measuring plaques and clots directly; rather it (indirectly) measured the effect of these drugs on atherosclerosis. The effect of uptake blockers on infarction rates was an incidental measurement.

One important consideration when interpreting these results is that the study group was not constructed to resemble the general population. Rather, the study was performed on individuals who had familial hypercholesteremia, a genetic condition that causes greatly elevated levels of LDL in the bloodstream. Without the data in hand I of course cannot make a solid judgment, but one possibility that immediately suggests itself is that in this population even a significant diminution of LDL levels is not sufficient to improve outcomes. There's just too much cholesterol for these uptake blockers to affect the outcome. In a normal individual with significantly lower levels of LDL Zetia and Vytorin might have a much greater effect.

Moreover, all the individuals in this study were already taking statins—which contributed to the low rate of adverse outcomes. It may be that the marginal improvement from adding an LDL blocker on top of a statin simply isn't that great. However, for individuals who cannot take a statin due to side effects, taking an uptake blocker might be a significant improvement over doing nothing. The study does not, as far as I can tell, speak to this possibility.

There is always the possibility that this study points to completely unsuspected aspects of arterial disease. For instance, these results might indicate that once lesions form they attract cholesterol very strongly, and therefore only extreme reductions in circulating LDL can affect their growth. Alternately, this outcome may indicate that mechanisms unrelated to circulating lipids play a more significant role in determining plaque thickness than previously suspected. In light of the highly unusual population used as study subjects, any grand pronouncements in this regard are premature. If these findings are replicated in upcoming studies of greater duration on more representative samples, however, a substantial re-examination may be in order.

The findings of the ENHANCE study don't really indicate that you should burn your Vytorin prescription and go back to just a generic statin, but it does create doubt as to whether this approach will prove efficacious in the general population. Further study, promptly published, is called for, and it would be wise for Merck and Schering-Plough to pull their advertising campaigns for the time being. Doctors should also be less eager to prescribe Vytorin for patients who are responding well to statins alone, but for patients who are not improving greatly with statins (or cannot take them at all), then a prescription for Vytorin (or Zetia) would still seem to be justified. As always, the best approach is to exercise and eat healthy foods, though that's much easier said than done.

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A Chilling Dilemma

Back when I was at Chapel Hill, a fellow student asked my help in figuring out a strange phenomenon he observed with one of his proteins. It seemed that the protein was perfectly soluble at room temperature, but precipitated when it was cooled. Because proteins typically denature at higher, rather than lower, temperatures, he was mystified. Mostly out of luck, the first question I asked him proved to be the right one: "What buffer are you using?" As it happened, he was using Tris buffer, a very common buffer in the biosciences, but also one that changes pH significantly upon cooling. It was not temperature that was denaturing his protein, but rather a change in the alkalinity of the solution it was dissolved in. The change of buffer pH with temperature is one of the most subtle and least-discussed issues in biochemistry, but as in my friend's case, can often produce confusing effects that significantly complicate research. An article by scientists from the University of Illinois online now at Chemical Communications (click link for open access), however, aims to resolve this problem by producing a temperature-independent pH (TIP) buffer for biological applications.

The approach they employed was actually very simple: rather than search the ends of the earth for a buffering agent that would maintain its pH across a huge temperature spread, they just found two that had opposite reactions to chilling and mixed them together. The buffer system they ended up with contained 60% HEPES and 40% potassium phosphate and experienced a pH change of less than 0.07 ± 0.1 over a temperature range from 25 °C to -180 °C. Readers who have encountered this subject before will recognize that HEPES and K₂HPO₄ are already fairly pH-stable over most of the laboratory temperature range, but as the paper's first figure shows, the TIP maintains these benefits down to very low temperature. A colorimetric assay was used to track the pH to very low temperatures.

So, problem solved, right? Well, not exactly. This finding is very nice as far as it goes, and has some promise for labs that do a lot of work that involves freezing proteins—structural biology labs come to mind. But while it would be nice to be able to select buffers on the basis of pH characteristics alone, that's rarely feasible. Not all buffers work with all proteins. In some cases, this can be rationalized: proteins that bind ATP or nucleic acids often bind or interact with phosphate buffers, resulting in poor solubility or aberrant structural dynamics. In other cases the observations are harder to understand—it seems that some proteins just "don't like" some buffers. So long as you're dealing with very dilute proteins, this is not usually an issue, though the biochemistry is sometimes deranged as a result. However, when high protein concentrations are employed—again, this is characteristic of structural biology—incompatible buffer-protein combinations tend to result in crashed protein.

The good news is that, with the exception of proteins that normally interact with phosphate moieties, both of these buffers are fairly well tolerated by a wide spectrum of systems. So long as a nearly-neutral pH is desired, this buffer combination should be useful. Researchers wishing to safely put pH-sensitive small molecules into long-term cold storage are also likely to find this buffer a boon. Moreover, because the buffer components are common and inexpensive almost any lab will be able to use this approach.

Sieracki, N. A., Hwang, H-J., Lee, M.K., Garner, D.K. and Lu, Y. "A temperature independent pH (TIP) buffer for biomedical biophysical applications at low temperatures." Chem. Commun. 2008 DOI 10.1039/b714446f

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Ethanol from switchgrass: the answer?

With the Iowa caucuses over, the corn ethanol mania that seized the campaigns of candidates from both major parties appears to have passed. This can only be a good thing, because producing ethanol from corn starch is an ecological and agricultural dead end. But the siren song of biofuels continues to beckon, with cellulosic ethanol from switchgrass now being the alcohol du jour. Cellulosic ethanol has tremendous advantages, not least that if cellulosic facilities are the basis of our alcohol infrastructure then practically any vegetation can be used to supply them. Switchgrass, because it is high in cellulose, simple to cultivate, and can be grown on reserve plots, is a tremendously attractive plant to serve as the backbone for such a system. However, research on the full-scale feasibility and energy output from switchgrass cultivation has been lacking. Last week, that deficiency was addressed when PNAS released a study from the U.S. Department of Agriculture and University of Nebraska claiming that the energy output from switchgrass ethanol was more than 500% of the energy put into making it. The article is open access, so you can go on over to PNAS and read it yourself if you like. The findings of this article are encouraging and promising, but it is the start, not the end, of the necessary research.

Assuming that the production and distribution of a biofuel are feasible—this is not a minor assumption—the ultimate decision of whether we should wholeheartedly pursue biofuel production and if so what approach to use should be decided by the answers to the following questions, based on our strategic and environmental needs:

1. Does the biofuel produce substantially more energy than is needed to generate it?
   
2. Can the biofuel significantly reduce or eliminate our dependence on petroleum?
3. Do production and use of the biofuel add less greenhouse gases to the environment than they remove?
4. Does the biofuel produce fewer non-greenhouse pollutants than petroleum products?
5. Can the biofuel be produced without significant disruptions to agriculture or the food supply?
6. Are the other negative environmental effects of biofuel monoculture manageable?
   

Obviously, we want every answer to be "yes", and a little quick thinking will show that switchgrass scores higher than corn ethanol on questions 5 & 6, with a tie on question 4, and less clarity on questions 1-3. Question 2 doesn't really get a good answer in this paper (so far the answer is "no"), but questions 1 & 3 are treated, albeit incompletely.

The authors of this study answer question 1 with a resounding yes, claiming that the switchgrass fields produced an astonishing 540% more energy than was used in seeding and maintaining them. Given that it is still not clear whether corn ethanol is capable of breaking even on this kind of energy balance, that seems like an end to the question. It's important to realize, however, that no energy was actually produced in this study, because no large scale cellulosic ethanol plants actually exist. This would appear to be a significant advantage for corn—although its production is less energy efficient, such production is at least not fictional. The energy numbers and ethanol yields in this study emerge from a computer model based on pilot studies; the efficiency of cellulosic ethanol plants on a large scale, though promising, has yet to be demonstrated. As such, this number should be taken with a grain of salt.

The energy numbers for this comparison also do not appear to include the diesel used in agriculture or any estimates of energy costs involved in transporting the substantial quantities of biomass to ethanol plants. The latter is either totally outrageous or completely fair; one of the uncertainties in treating this question is the infrastructure that would be developed. If most ethanol production ends up in large centralized plants the transport costs will be high and the energy efficiency per year will be less. On the other hand, if ethanol production is distributed to many small local plants the energy costs of transport will be diminished while the costs of start-up in terms of materials, money, and energy will be high. This question is significant and one that needs an answer quickly; fortunately, given ballpark figures for energy consumption and output it should be relatively easy to model computationally. That said, I doubt any two models will agree.

So, this study has many nice things to say about the energy yield of switchgrass ethanol, but no experimental proof. But what about question 3? Here again the authors have nice things to say. Most of the plots were carbon-neutral, with slight deviations up or down in different years. Of course, this is again the result of a model; the final answer will depend to a large degree on how effectively carbon can be sequestered in the soil and how much energy the burning of the lignaceous or woody portion of the biomass can contribute to the production process and energy grid.

However, our joy at finding a carbon-neutral fuel should be tempered by remembering that the problem with greenhouse gases is that they are too concentrated in our atmosphere. This is important, so I will repeat it in larger text with a color accent:

The problem with greenhouse gases is that they are too concentrated in our atmosphere.

That is to say, the problem is not that we are adding more greenhouse gases, the problem is that the atmosphere has too much greenhouse gas already. While adding more certainly makes that problem worse, adding nothing does not make it better. Those poor plants and animals got buried underground and hid their carbon away from the world for millions of years; until we put it back where we got it, our climate will be altered. Thus, what we require is permanent sequestration, something that cannot be achieved to any meaningful degree by biofuels.

I'm being mean to switchgrass, of course. Every biofuel fails this test, but so far switchgrass comes closest to success, and the most optimistic estimates certainly seem to indicate that a substantial quantity of carbon would be sequestered in the soil. As the transit system switched over to renewable fuels that advantage would be increased. Biofuels can stop or slow global warming, but they cannot turn back the carbon clock.

So, is this study worthless? Not by a long shot. However, the real contribution of this study is not in its publicized conclusions: they are largely based on modeling and possibly overstated. No, the great contribution here is the substantially more detailed assessment of the required inputs for producing switchgrass biomass on a large scale. The ratio of inputs to outputs was far smaller than expected; from this work it appears that switchgrass cultivation will be more energy-efficient than previously suspected. However, even in this regard the study is limited: the geographic area studied was small and not particularly diverse in climate. It remains to be seen whether switchgrass cultivation will be as effective in warmer or drier climates.

Nonetheless, this study, and others like it, are precisely what we need: detailed research dedicated to finding the best answer. Yet this sort of critical assessment will be all too infrequent in the coming year, as bloviating presidential candidates lurch from hot topic to hot topic, and our useless, brainless Congress lards the budget with pork based on speculation rather than research to find facts.

M. R. Schmer, K. P. Vogel, R. B. Mitchell, and R. K. Perrin, "Net energy of cellulosic ethanol from switchgrass." Proceedings of the National Academy of Sciences 15 January 2008 pp. 464-469 DOI: 10.1073/pnas.0704767105

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"You may have left me before / but you can't leave me behind."

The two or three of you that have perused my link section have probably come across the oddly-named Ray Bradbury's Love-Camel, Eric's teamblog about pop culture. In a moment of insanity, he invited me to cross-post my own economy-priced cultural musings, and I've decided to do so until the comments get too mean or he returns to his senses.

As it turns out, my first post for rblc is actually inspired by Eric's post yesterday about Blankets, which reminded me of one of my favorite graphic novels, and so even though it was a little early for me to hit it on the decadal rotation I went home last night and re-read Stuck Rubber Baby by Howard Cruse. Although it's a work of fiction, Cruse admits that it is heavily influenced by his time in Birmingham in the sixties, and this shows through in much of the plot and also in some of the characters. The inspiration for Sutton Chopper, for instance, will be immediately obvious to anyone who remembers any part of their Black History Month lessons. But Stuck Rubber Baby is not about the Civil Rights Movement, except to the degree that the characters' reactions to it help define their relationships with each other. This story is about a young man coming to terms with his homosexuality in an extraordinary and difficult time, and the mistakes he and others make in the course of that effort.

This isn't a subject that everyone wants to read about, and I'll forgive you if it turns you off, while warning you that you are missing out on a wonderful story. On the other hand, both civil rights and gay coming-of-age are hardly topics lightly served by literature; it's tempting to dismiss this book (if you haven't read it) as a retread of overdone themes. Yet Cruse manages to avoid the all-too-easy trap of populating this kind of story with saints and sinners. Despite the enormous cast, almost every character who appears on more than one page comes across as realistically mixed. You will find something to criticize in every protagonist (especially the main character), and also something to like, or at least a basis for forgiveness, in the villains. The saintly black preacher unleashes a sarcastic, acid tongue, and the obese bigot who commits one of the book's worst acts comes across as genuinely remorseful and ashamed at the end.

The black-and-white art reflects this sensibility. The characters are highly detailed, and the lines used to draw them are very curvy. This style allows Cruse to create very expressive faces, and yet at the same time it seems to highlight physical imperfections. These characters are not supermen, nor are they ostentatiously ugly. They simply seem real—not in the trivial way one associates with photorealistic artwork, but rather the deeper reality of memory and emotion. Even the sexual content works, a rare example of art avoiding pitfalls I have mentioned before.

Who knows how much of this tale is drawn from Cruse's experience and how much is entirely made up? The strength of Stuck Rubber Baby is that you simply can't tell. This story, though it is fiction, feels real, almost frighteningly so. It has no perfect heroes, no perfect villains, and the last page holds no happy ending... only the impression that someone else's memories, with all their joy and sorrow, have been made your own.

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Pharma's Funding Lie

With medical coverage emerging as a major domestic issue for this election cycle, the cost of drugs is likely to become a hot topic, especially given the array of pills many aging baby boomers must take. The industry line is best articulated by a GlaxoSmithKline campaign implying that high drug prices really fund R&D for future drugs ("Today's medicines finance tomorrow's miracles"). Activists counter that the pharmaceutical companies are actually marketing-focused, a view popularly reinforced by incrementalism and the highly-visible promotional campaigns for conditions that are primarily cosmetic, such as hair loss and erectile dysfunction. A new study in PLoS Medicine by Marc-André Gagnon, and Joel Lexchin (click the link, PLoS is free) suggests that the latter view is closer to reality: they find that companies spend in excess of $57 billion annually on marketing to doctors and consumers. This amounts to nearly twice as much being spent on promotion as on R&D (which receives ~$30 billion). While by no means the final say in the dispute, this paper and distortions of its findings (on both sides) may figure significantly in future debates.

The easiest criticism of this paper, and one that may often be repeated, is that the authors did no primary research. The paper is essentially a synthesis of research performed by two independent firms: IMS (its data is widely cited by industry groups such as PhRMA), and CAM. The article contains a single table, and a quick glance at it will inform the reader that whenever two numbers were available, the authors always took the larger. The authors explain this well in the case of detailing, and I agree with their decision there. I also agree with the principle, though I am not convinced of the magnitude, of the "other" category. When it comes to the cost of free samples, however, I disagree with the choice to use the retail price in the assessment.

The authors' justification on this point is rather feeble, and comes across as almost petulant in tone:

Using the wholesale value for samples, the CAM figure would be appropriate if we were arguing that the money spent on samples should go to another activity such as R&D. However, we have used the retail value of samples because this is consistent with companies' reporting of drugs they donate [19]. As these are both categories of products that are being distributed without a charge to the user, it is inconsistent for donations to be reported in terms of retail value and samples in terms of wholesale value.

It seems to me that there is no point to this assessment unless our ultimate intention is to compare money spent on promotions that could be spent on R&D to the actual money spent on research. Certainly that is the only comparison that actually speaks to the issues the authors raise in the introduction. Including money that could not be spent on research or anything else, because it is fictional money, is nonsense. If the aim is to define the actual costs of the promotion to the drug company then the wholesale price is more appropriate. If the authors have an objection to using the wholesale cost for one kind of handout and retail costs for another, then the correct response would have been to use the proper, intellectually honest number (wholesale cost) in their own analysis and argue that pharmaceutical companies ought to do likewise when reporting charitable contributions. Just because Eli Lilly misrepresents its costs doesn't mean you can, too.

However, there are other factors that make the CAM estimate questionable on this point, especially that any number of samples was reported as one. Most likely the actual cost of samples to the company lies somewhere between the CAM and IMS estimates; promotional costs therefore lie somewhere between $48 and $57 billion, or 160% to 190% of research expenditures.

Another key feature to note from the table is that direct-to-consumer advertising makes up a relatively small fraction of the total expenditure. This reflects a truth that anyone even tangentially related to the healthcare system has known for a long time: most of the actual marketing that pharmaceutical companies do is lobbying your doctor. Although they are pervasive, fundamentally uninformative, and frankly annoying, television and print advertisements for drugs constitute such a small percentage of the actual promotional costs that banning them again would not lead to a noticeable reduction in drug prices.

The findings of this paper should also be put in the context of a transformation underway in the pharmaceutical industry. The so-called "blockbuster" drugs that provided substantial profits over the past decade or so will soon lose (if they have not already lost) their patent protection, and some needed to be withdrawn due to failures of the clinical trial system. In order to adapt, many companies are shedding most or all of their R&D operations. The emerging model in the industry is to allow "small pharma"—tiny companies started by academics or entrepreneurs using venture capital—to do most of the legwork and then buy up or enter marketing partnerships with those companies once they have promising products that have passed phase I or II clinical trials. This model was promising and robust up to about two years ago, because plenty of capital was available. In the present economic climate the availability of capital is far less certain, however. In addition, the same issue that induced big pharma to shed R&D—poor ROI—will eventually act to inhibit the venture capital investments that small pharma requires.

Despite this increasing aura of uncertainty, the fact remains that many pharmaceutical companies appear to be undergoing a transition from being primarily research entities to being primarily production and marketing entities. In that light, the new estimate of the research-to-marketing ratio is hardly surprising, though it will doubtless be embarrassing to PhRMA and feed the rhetoric of populists such as John Edwards. Yet despite the vitriol that will surely be spewed, in reality there is little that can be done. As mentioned, the most visible marketing efforts of pharmaceutical companies constitute only a minor portion of actual promotional costs. While it would be wise and probably beneficial to public health to restrict these advertisements once again, it is unlikely that any reduction in medical costs or increases in R&D budgets would be achieved by such regulations.

Congress, if it desired, could take steps to reverse the current trend and strengthen FDA power to restrict off-label marketing of existing drugs, and of course a new President could make this an enforcement priority at FDA. However, enforcement of any such provision would be extremely difficult and subject to legal challenge on First Amendment grounds. Moreover, the FDA (and not coincidentally the USDA) are in need of a major overhaul and possible restructuring in order to achieve their existing missions; stapling on another major enforcement problem will not serve anyone. Regardless, off-label marketing does not constitute a majority of the promotional budget.

The First Amendment clearly protects on-label marketing, and at any rate promotions of proven drugs actually serve the public interest, up to a point, by making doctors aware of improved approaches for dealing with illness. The truth of this statement, however, is inversely related to the degree of incrementalism in drug discovery. "It's a bigger pill" is generally not a compelling rationale for new prescriptions or enormous marketing outlays. Nonetheless, the presence of a definite public interest in allowing marketing to doctors makes unclear what steps Congress should (or even can) take to regulate or diminish promotional spending.

The only tool readily available for public use against on-label marketing is shame. Either the companies themselves can be pressured to reduce their promotional budgets (unlikely), or activists can put pressure on professional societies and medical boards to implement ethical restrictions on what kinds of promotions their members can engage in (possible). Regulations against accepting expensive lunches and dinners or attending marketing "seminars" in exotic locales may be able to push back some spending. In this regard, the Gagnon and Lexchin study may prove a useful tool; the grandstanding of politicians most likely will not.

Fundamentally, however, this trend cannot be stopped, because marketing will always be a better—or at least more predictable—investment than research. Although this attitude is ultimately self-defeating, the safer course to higher profits in the near term is to aggressively market existing drugs and secure longer periods of exclusivity by lobbying for longer patent protection or incrementally improving medicines and delivery systems. The release of combination drugs such as Caduet reflects this sensibility. Most money spent on research never produces so much as a Phase I trial, and the discovery of a revolutionary medicine, though extremely profitable, is also extremely rare. For that reason, a conservative mind will always prefer promotion and production to research and development. This is the attitude that underlies the ongoing strategic shift in big Pharma's approach, as well as the findings, debatable though they may be, of Gagnon and Lexchin.

Gagnon MA, Lexchin J (2008) The Cost of Pushing Pills: A New Estimate of Pharmaceutical Promotion Expenditures in the United States. PLoS Med 5(1): e1 doi:10.1371/journal.pmed.0050001

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America and the Meiji Restoration

While I was home, incidentally reading an enormous book on the history of Japan, Dad asked me why I was so interested in Japan and Japanese history. Despite the typical interest in understanding the samurai ethos, however, my interest is not in Japanese history generally, except in terms of contextualizing the Meiji era of its history. Japan transformed from a medieval, decentralized, semi-feudal congeries of partially autonomous states into a highly centralized modern empire ranking among the most important world powers with amazing speed. America had its part in this: Perry's gunboat diplomacy played a significant role not only in demonstrating the powerlessness of the Shogunate but also in convincing the elites that they must adopt Western technology. It is an interesting case of a social and technological transformation of a whole society. This of course begs the question: why am I interested in that?

Part of my interest arises from the fact that this transformation was actually a subversion of the intentions of many of its supporters. As the name implies, the Meiji Restoration was intended by many to be a return to an older version of Japan. The intention was to promote loyalty to the Emperor and expulsion of the foreigners. Since neither of these goals was truly compatible with the aims and abilities of the Shogunate, it was a powerful rallying cry against it. At the same time, the latter aim was totally unrealistic even for a reconstituted imperium. Thus the message changed to one of Imperial loyalty combined with national strength, to be achieved by adopting the technologies and institutions of Western powers. Some Meiji-era heroes reconciled themselves to this shift in emphasis, while others did not, or were not pleased with the way in which modernization was achieved. Samurai insurrections, recently romanticized in The Last Samurai, were one of the results. I find it interesting that this Restoration, with its roots in primitivism and xenophobia, actually resulted in modernization and international engagement.

More than that, however, I feel that we are in a similar time of transition and challenge. Scientific illiteracy and disrespect for science, especially in regard of religious meddling, seems to be rising. American industry, once a wellspring of innovation, is now tentative and fearful — the failures of the automobile giants are just one example of how conservative thinking is working against us. The budget for basic sciences has again suffered at the hands of an incompetent Congress. The rest of the world will soon embark on a significant transformation. By the end of the century petroleum will be dead, perhaps replaced by biodiesel, but it is also quite likely that hydrocarbon fuel itself will be a thing of the past. This single change alone will require enormous adjustments in infrastructure and the development of new technologies. The challenges of feeding the world's population and dealing with antibiotic- and drug- resistant infectious agents will also require scientific advances. The retirement of the baby boomers will place an enormous strain on our benefits system, reminiscent of the unsustainable samurai retainers which had to be done away with to revitalize Meiji Japan.

In short, the world is changing and we are not doing anything to keep up with it. The Japanese of the 1860s had Perry's black ships to tell them that they were too far behind the world order and had to catch up, but I doubt any such thing will happen to us. American corporations, bloated and clumsy, will not be able to catch up to the new world that is developing; American science, hamstrung by politicization, poor planning, and antiquated methods of delivering funding and education, to say nothing of the ongoing assaults of Christians, will also lag. We will simply wake up one day and realize that the rest of the world has undergone a green revolution and left us behind technologically and economically.

In order to avoid this fate I feel we must have our own restoration. And unlike the Meiji Restoration, I don't feel that we must start with fundamentalism and work our way around to progress. We have the advantage that a dedication to reason is part of our national heritage. Despite the distortions and outright lies of fundamentalists, we were founded as a secular nation by Enlightenment Deists who believed in the power of reason to resolve the problems of mankind. They were not superstitious men who believed that the answers to their problems lay within religious doctrine or the rulers those doctrines had imbued with absolute authority. The finest expression of this is in the First Amendment, which firmly places religion in a subordinate position. In the nation they devised, man would rule religion; religion would not rule man. That is our past, and I believe that principle can be used to build our future.

It's not a simple analogy — the differences between modern America and Meiji Japan are enormous. The transformation I am suggesting, being primarily cultural and economic, is also quite dissimilar to that undergone by Japan. Yet I feel it is equally necessary, especially in light of the rising tide of conservatism and superstition that seems poised to stifle innovation and scientific advancement at just the moment — with practically all of our industries foundering — that we need it most. Inventiveness, independence, rationality... these qualities are our heritage from our Founding Fathers. They are the true American values, and we ought to restore them to their rightful place at the center of our national identity.

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Holiday Trip Rundown

Well, I'll probably get around to a couple of thoughtful, intelligent posts later this week, but while I'm still getting back into the swing of things work is taking up all my brain, so you get a list post instead. Science, philosophy, and history will have to wait a day or two.

Holiday Notes

Best Food: Mom's pumpkin soup. Runners-up: Cranberry meatloaf, peppernuts, oysters.

Most Food: The oyster roast at Aunt Peggy and Uncle Frank's place in Charleston. Oysters (of course), along with beer, shrimp, barbecue pork, beer, barbecue chicken, grilled sausage, beer, dirty rice, pies, cakes, sangria, pecans, and cordials. Hope you brought some spare coronary arteries.

Cutest Child: Jackson Partch, as long as he has a cookie available. Here you can see him making critical adjustments to his tricycle. Milo, resigned to his fate, naps in the background, resting up for inevitable time when he will be chased around the apartment by a mad triker. Runner-up: Daniel Fuentes.

Best Gift to Anyone: My Dad got a Crosley vinyl-to-CD direct recorder from Mom, which translated into instant joy for him. I got to hear a Dylan bootleg LP, and also the famous Dave Van Ronk mono LP that led Dad to learn the...

Best Music: "One Meatball" Seriously, click the link. Van Ronk's version is a little angrier and more up-tempo than this mournful Josh White recording.

Funniest Gift: From Kevin Gardner at his lab's Yankee swap, I received a George W. Bush out-of-office wall calendar containing some of our noble leader's least intelligent quotes.

Most Depressing Gift: See above.

Best Science: Kevin's graduate thesis, with some crazy metal-ion R₁ dispersions.

Worst Science: Pretty much anything Fred Thompson says.

Best Game: Sudoku, of which Brain Age has probably 100+. Sudoku is pretty ideal for a touch-driven computer game, because you don't really remember these puzzles, and they contain relatively few symbols. Notation on the touch screen is also much cleaner than on paper. So there are advantages to this approach for the producer as well as the consumer. Needless to say, I really like my DS. Runner-up: Final Fantasy III, which lacks the cohesive story of later installments but is a very pleasant old-school RPG. Touch screen elements were obviously stapled on, however, and in most ways the game plays better using the buttons.

Travel Notes

Best Airline: JetBlue, who gave me a $25 voucher because of a minor delay. That's a consumer bill of rights that works. I wish they flew everywhere.

Best Airport Television: Charleston International (sic) Airport didn't have TV, or at least had it turned down so low I couldn't notice it. That makes it the winner.

Worst Airport Television: Chicago Midway, broadcasting WGN, which during my layover was airing what appeared to be the "Who Wants to be a Millionaire?" loudest idiot retrospective, followed by the Maury Povich paternity test special. (Dis)Honorable Mention: CNN's Tony Harris, who just may be the worst interviewer and anchor on any news channel anywhere.

Best Seat: JetBlue. I couldn't care less about the in-seat television — curiously, mine had its image reversed right-to-left, which I found very distracting, so I turned it off. But that legroom... wonderful, especially compared to the...

Worst Seat: On my AirTran flight from Atlanta back to Boston I was in the "fuselage" seat in the very back of a 737. I say "fuselage" because without a window it cannot really be a "window" seat.

Best Airport: There are no good airports.

Worst Airport: Dallas - Ft. Worth. I know you want me to say Atlanta, but it turned out that my connection there was just a few gates down, and the weather at that point was reasonably good up and down the coast, so I went through none of the hassle that can make Atlanta truly awful. DFW has a positively ridiculous layout, however, and a slower security line than even Logan. (Dis)Honorable Mention: Birmingham International (sic) Airport, for the longest baggage wait in history.

Strangest Airline Habit: Not leaving the whole can. Are you really saving that much money? I mean, with your purchasing volume, a can of Coke costs what, $0.30? If I'm paying $100 for an hour-long flight, does that $0.15 really make that much of a difference to your margin?

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