Richard Lehman’s journal review – 23 December 2010

Richard LehmanJAMA 15 Dec 2010  Vol 304
2595   New England is a wonderful place: from its little towns a nation was born, full of the idiosyncracies of seventeenth century Britain. The cadences of the 1611 Bible can still be heard in the speeches of President Obama, and even on hoardings advertising health products; miles, pints, and pounds abound; shops sell apparel. Even an expedition to Mars came a cropper when someone confused metres with feet. Small wonder that in dosing directions on American children’s medicines, archaic confusion reigns – drams, ounces, ccs, teaspoons: they’re all there on over-the-counter bottles, helping them to poison or under-dose their feverish, itchy, or hurting children. But the real reason for my citing this study is the commentary piece by Darren DeWalt, “Perfecting the dismount.” The analogy is with a gymnast or horseman: you can do your act perfectly, but if you fumble the dismount, the judges will never give you a good mark. Similarly with drugs: no matter how good they are, they’re no good if you use the wrong size of spoon. A neat metaphor, pointed out to me by friends at Yale.

2628   For all the years I’ve written these reviews, I’ve praised The Clinical Rational Examination series, and was amazed when David Simel responded by sending me a copy of the book of the series a couple of years ago: I little thought that my comments had ever reached him. But I have to admit that many of the more recent contributions seem to me to address misdirected questions. Does this patient have malaria? How can you possibly know without doing a blood film? Does this older adult with lower extremity pain have the clinical syndrome of lumbar spinal Stenosis? “Absence of pain when seated and improvement of symptoms when bending forward are the most useful individual findings.” That’s excellent clinical advice, but the real question is whether any features of the history, examination of MRI scan can predict likely success from decompressive surgery. We know from the randomised trials that many patients with clearcut MRI findings fail to benefit from surgery: how can we identify those who will?

NEJM  16 Dec 2010  Vol 363
2385   Biventricular pacing is a good intervention for patients with left systolic heart failure and a widened QRS complex. We knew that already and it’s confirmed here in the RAFT study of mostly male patients, mean age 66, mean ejection fraction 22% (!). The odd thing is that this trial gave priority to the implantation of an implantable cardioverter-defibrillator. Those who got both BVP and ICD fared better than those who got ICD only. Personally, if I got heart failure I would run a mile from anyone trying to put an ICD in me, prevented only by the fact that if I had heart failure I would not be able to run a mile. I would want the better daily function which BVP can provide, while being perfectly happy to die suddenly, rather than by slow drowning accompanied by electric shocks as in some demonic torture chamber.

2406   “Say no to surrogate endpoints” could be the motto of the wonderful group of people I have fallen in with just recently. Judge every intervention by its real effects on a large representative group of people over the time it takes to find out. If we demand anything less, we risk harming our patients or even killing large numbers of them. Torcetrapib is a drug that inhibits cholesteryl ester transfer protein (CETP) and so lowers levels of nasty low density lipid cholesterol (LDL-C)and raises levels of good high density lipid protein (HDL-C). Unfortunately it also increases death and cardiovascular events. Anacetrapib is a similar drug. Here Merck test it out on 1623 subjects with known coronary heart disease or at high risk, over a 24 week period. Note that in practice you would be treating them for life. “Prespecified adjudicated cardiovascular events occurred in 16 patients treated with anacetrapib (2.0%) and 21 patients receiving placebo (2.6%) (P = 0.40). The prespecified Bayesian analysis indicated that this event distribution provided a predictive probability (confidence) of 94% that anacetrapib would not be associated with a 25% increase in cardiovascular events, as seen with torcetrapib.” Do you follow that? I’m pleased to say that Merck doesn’t intend to market the drug on the basis of this finding, but to conduct a large RCT. But until recently, they could have gone straight to the FDA for licensing.

2417   This study of H1N1 vaccine given to schoolchildren in Beijing sheds some benign light on Chinese society as well as telling us that this particular vaccine had an effectiveness of 87%. The vaccination strategy was to offer vaccine to all children attending celebrations of the 60th National Day. Hearteningly, the vast majority of Chinese children either didn’t turn up to celebrate the 60th anniversary of the Glorious People’s Republic, or didn’t want to be vaccinated. This sounds like the advance of democracy.

2434   I love reading New Scientist, and can’t understand why the BMJ hasn’t pitched in with a similar magazine to fill the obvious market gap for something to tell the interested public about advances in medicine. This article on Nanomedicine would fit in perfectly with the NS line in perfectly crafted futuristic bullshit. It’s got quantum dots and dendrimers and buckyballs and all the other balls that make these articles so irresistible. Ideal Christmas fireside reading. Can also be used for kindling.

Lancet  18 Dec 2010  Vol 376
2075   Last week, The Lancet allowed a group of British authors to over-hype a marginal advance in the treatment of newly diagnosed multiple myeloma: this week an Italian group shows a nice line in what used to be called British understatement. ” VTD induction therapy before double autologous stem-cell transplantation significantly improves rate of complete or near complete response.”

Too right it does! If you add bortemozib to standard initial treatment with thalidomide and dexamethasone, you treble the number of complete or near-complete responses. They are quite right to go on to say that this ” represents a new standard of care for patients with multiple myeloma who are eligible for transplant”.

2104   Omsk haemorrhagic fever. Golly – ever heard of that? Well, you have now: it is a tick-borne virus from which you are largely safe, provided you suppress your urge to handle muskrats in western Siberia. Should you unwisely molest these rodents, ticks of the species Dermacentor reticulatus may attack you and the virus will lay you low – perhaps for good – with blotches, fever, nephrosis, pneumonia and/or meningitis. (Christmas puzzle: construct a limerick beginning “There was a young lady from Omsk”, describing the aetiology and clinical features of Omsk haemorrhagic fever.)

Ann Intern Med  7 Dec 2010  Vol 693
693   Have you ever wondered what elderly Australians get up to in bed? I must say that this is not a field of intellectual speculation which has ever galvanized my attention. This study took sexual histories from male Ozzies ages 75 to 95 years. About half of them rated sex as important and one third had had some in the last year. This was more likely if they had few health problems. How their partners rated these leathery embraces, we are not told.

728   I have, on the other hand, spent a lot of time trying to think of the best way to use B-type natriuretic peptide in clinical practice. At first sight, it seems such a wonderful marker: the very voice of the distressed ventricle. But ventricles get distressed quite easily and their cry varies from minute to minute. If you are having a sufficiently bad exacerbation of COPD, for example, your right ventricle may be complaining quite loudly; on the other hand, if your heart failure has gone out of control, your left ventricle will be shouting. Biochemically, there will be little to tell these apart. Initial trials of using BNP to discriminate between causes of acute dyspnoea in the emergency department seemed to show a useful degree of discrimination, but later ones have been negative. Meta-analyse them for clinical benefit and it is hard to find any – perhaps a day less in hospital.

Arch Intern Med  13 Dec 2010  Vol 170
1968   The longer you spend in general practice, the more you spend your time adjusting the analgesics of ladies aged 80 and over. There were other elderly people in this study of Medicare recipients, but these predominated. And the message is not reassuring: non-selective nonsteroidal anti-inflammatory drugs may be hazardous, but overall it is the opioid analgesics that carry the highest risk for fracture and death.

1979   The same authors now go on to assess the relative hazards of the different opioids in the elderly. Again, the results are not what you might expect. Consider all the trouble we had weaning people from (dextro)propoxyphene in coproxamol: it turns out that codeine is much more hazardous in this age group for falls and death. The only drug more hazardous is hydrocodone, which we seldom use in the UK. Tramadol comes off quite lightly, to my surprise.

1996   We generally advise patients on levothyroxine to take it in the morning; we are wrong. Thyroxine taken in the evening has a greater effect on TSH and blood T3 and T4 levels, according to this cross-over study from Rotterdam.

2012   Patients unfortunate enough to have a stone stuck in the distal ureter are often given an α-blocker such as tamsulosin in the hope that it will relax the ureteric smooth muscle and help the stone to pass. But this French randomised trial shows that this drug makes no difference to the rate of stone passage.

2035  Last year, Joe Ross, Harlan Krumholz and the other authors of this research letter produced an excellent structured analysis of what harms of rofecoxib were known to its manufacturers from randomised trials at each stage before the withdrawal of Vioxx in 2004. Here they look at the harms which patients who had been taking Vioxx in one trial continue to experience. The increase in cardiovascular risk comes in at a cool 100%.

Blake’s Christmas Message

William Blake largely stopped writing poetry in 1811, and concentrated on painting and engraving the greatest of his prophecies, Jerusalem. Most people find Blake’s prophecies unreadable, so the Christmas passage from the book, which Blake added at a late stage, is far too little known. I have given it to you before and I will give it to you again. For Blake, the redemption which came with the birth of Jesus consisted in forgiveness; it was the result of love and fecundity, not virginity. By pure coincidence, Richard Dehmel wrote a poem on exactly the same theme at the end of the nineteenth century, wonderfully set to music by Schoenberg. I will give you this first:

Zwei Menschen gehn durch kahlen, kalten Hain;
der Mond läuft mit, sie schaun hinein.
Der Mond läuft über hohe Eichen;
kein Wölkchen trübt das Himmelslicht,
in das die schwarzen Zacken reichen.
Die Stimme eines Weibes spricht:
„Ich trag ein Kind, und nit von Dir,
ich geh in Sünde neben Dir.
Ich hab mich schwer an mir vergangen.
Ich glaubte nicht mehr an ein Glück
und hatte doch ein schwer Verlangen
nach Lebensinhalt, nach Mutterglück
und Pflicht; da hab ich mich erfrecht,
da ließ ich schaudernd mein Geschlecht
von einem fremden Mann umfangen,
und hab mich noch dafür gesegnet.
Nun hat das Leben sich gerächt:
nun bin ich Dir, o Dir, begegnet.“
Sie geht mit ungelenkem Schritt.
Sie schaut empor; der Mond läuft mit.
Ihr dunkler Blick ertrinkt in Licht.
Die Stimme eines Mannes spricht:
„Das Kind, das Du empfangen hast,
sei Deiner Seele keine Last,
o sieh, wie klar das Weltall schimmert!
Es ist ein Glanz um alles her;
Du treibst mit mir auf kaltem Meer,
doch eine eigne Wärme flimmert
von Dir in mich, von mir in Dich.
Die wird das fremde Kind verklären,
Du wirst es mir, von mir gebären;
Du hast den Glanz in mich gebracht,
Du hast mich selbst zum Kind gemacht.“
Er faßt sie um die starken Hüften.
Ihr Atem küßt sich in den Lüften.
Zwei Menschen gehn durch hohe, helle Nacht.

Two people are walking through a bare, cold wood;
the moon keeps pace with them and draws their gaze.
The moon moves along above tall oak trees,
there is no wisp of cloud to obscure the radiance
to which the black, jagged tips reach up.
A woman’s voice speaks:
“I am carrying a child, and not by you.
I am walking here with you in a state of sin.
I have offended grievously against myself.
I despaired of happiness,
and yet I still felt a grievous longing
for life’s fullness, for a mother’s joys
and duties; and so I sinned,
and so I yielded, shuddering, my sex
to the embrace of a stranger,
and even thought myself blessed.
Now life has taken its revenge,
and I have met you, met you.”
She walks on, stumbling.
She looks up; the moon keeps pace.
Her dark gaze drowns in light.
A man’s voice speaks:
“Do not let the child you have conceived
be a burden on your soul.
Look, how brightly the universe shines!
Splendour falls on everything around,
you are voyaging with me on a cold sea,
but there is the glow of an inner warmth
from you in me, from me in you.
That warmth will transfigure the stranger’s child,
and you bear it me, begot by me.
You have transfused me with splendour,
you have made a child of me.”
He puts an arm about her strong hips.
Their breath embraces in the air.
Two people walk on through the high, bright night.

(English translation by Mary Whittall)
1 BEHOLD: in the Visions of Elohim Jehovah, behold Joseph & Mary,
And be comforted, O Jerusalem, in the Visions of Jehovah Elohim.

She looked & saw Joseph the Carpenter in Nazareth, & Mary
His espoused Wife. And Mary said, If thou put me away from thee
5 Dost thou not murder me? Joseph spoke in anger & fury, Should I
Marry a Harlot & an Adulteress? Mary answer’d, Art thou more pure
Than thy Maker, who forgiveth Sins & calls again Her that is Lost?
Tho’ She hates, he calls her again in love. I love my dear Joseph,
But he driveth me away from his presence, yet I hear the voice of God
10 In the voice of my Husband: tho’ he is angry for a moment, he will not
Utterly cast me away : if I were pure, never could I taste the sweets
Of the Forgive[ne]ss of Sins; if I were holy, I never could behold the tears
Of love! of him who loves me in the midst of his anger in furnace of fire.

Ah my Mary! said Joseph, weeping over & embracing her closely in
15 His arms: Doth he forgive Jerusalem & not exact Purity from her who is
Polluted. I heard his voice in my sleep & his Angel in my dream:
Saying, Doth Jehovah Forgive a Debt only on condition that it shall
Be Payed ? Doth he Forgive Pollution only on conditions of Purity ?
That Debt is not Forgiven! That Pollution is not Forgiven!
20 Such is the Forgiveness of the Gods, the Moral Virtues of the

Heathen, whose tender Mercies are Cruelty. But Jehovah’s Salvation
Is without Money & without Price, in the Continual Forgiveness of Sins,

In the Perpetual Mutual Sacrifice in Great Eternity! for behold,
There is none that liveth & Sinneth not! And this is the Covenant
25 Of Jehovah: If you Forgive one-another, so shall Jehovah Forgive You:
That He Himself may Dwell among You. Fear not then to take
To thee Mary thy Wife, for she is with Child by the Holy Ghost.

Then Mary burst forth into a Song: she flowed like a River of
Many Streams in the arms of Joseph, & gave forth her tears of joy

30 Like many waters, and Emanating into gardens & palaces upon
Euphrates, & to forests & floods & animals wild & tame from
Gihon to Hiddekel, & to corn fields & villages & inhabitants
Upon Pison & Arnon & Jordan. And I heard the voice among
The Reapers, Saying, Am I Jerusalem the lost Adulteress? or am I

35 Babylon come up to Jerusalem? And another voice answer ‘d, Saying:

Does the voice of my Lord call me again? am I pure thro’ his Mercy
And Pity? Am I become lovely as a Virgin in his sight, Who am
Indeed a Harlot drunken with the Sacrifice of Idols, does he
Call her pure as he did in the days of her Infancy, when She
40 Was cast out to the loathing of her person? The Chaldean took

Me from my Cradle. The Amalekite stole me away upon his Camels,
Before I had ever beheld with love the Face of Jehovah : or known
That there was a God of Mercy: O Mercy, O Divine Humanity!

Forgiveness & Pity & Compassion! If I were Pure I should never
45 Have known Thee: If I were Unpolluted I should never have

Glorified thy Holiness, or rejoiced in thy great Salvation.

Mary leaned her side against Jerusalem, Jerusalem recieved

The Infant into her hands in the Visions of Jehovah. Times passed on: