JAMA  17 Jun 2009  Vol 301

2453    For several years there has been lively controversy over the respective merits ofvirtual colonoscopy (by computerised X-ray tomography) versus actual colonoscopy in various clinical settings. The basic presumption seems to be that we would rather be exposed to large doses of ionising radiation than be sodomised by a sort of plastic eel. Having submitted to the eel, I would agree with a correspondent to the NEJM that the actual sodomy is less awful than the bowel prep and starvation; in fact it’s rather intriguing to watch the inside of one’s bowel while under the influence of midazolam. However, let’s move on (as the colonoscopist said after taking the biopsy): this big Italian study compared the two kinds of bowel imaging in three high risk groups: those with a family history of bowel cancer, those with previous adenomas, and those with positive faecal occult blood. A thousand brave Italians (with a few satellite Belgians) underwent both procedures within the space of three hours. The negative predictive value for CT colonography was 96% overall, but only 85% for the positive FOB group, who are the ones most likely to be screened in the UK programme. It’s the eel for them, I fear.  http://jama.ama-assn.org/cgi/content/abstract/301/23/2453

2462    Every few months I pay a visit to the academic department of general practice in Oxford, where through the kindness of the Head I rejoice in the honorific title of senior research fellow. Each time I’m on site I get lost in a maze of tall bright new buildings which house genomic people unconnected with my humble avocation. A better location for these gene gnomes would be underground, in some vast clanking Niebelheim like the one overseen by Alberich in Wagner’s Das Rheingold. Down there the Regius Professor could whip them by the flickering light of a thousand VDUs as they ceaselessly search their databases and their multiple arrays and their SNP detectors. But to what end? To perform one gene association study is the labour of years: there have been 26 seeking to establish a link between theserotonin transporter gene (5-HTTLPR), stressful life events, and the risk of depression; fourteen were selected for this meta-analysis: and what they show is that there is no association. Come up into the light, ye doleful gnomes: breathe the free air and learn again to make poorly people better.  http://jama.ama-assn.org/cgi/content/abstract/301/23/2462

2472    The ancient Dutch university of Leiden is famous these days for its studies of the genetics of thrombosis risk  - we have all heard of Factor V Leiden, and locally we measure it once as part of a “thrombophilia screen” when people discontinue warfarin after their firstvenous thromboembolism. Others have measured it in family members of those with this common mutation: and yet others have taken an interest in a much rarer thrombophilic mutation, prothrombin G20210A. In fact the authors of this systematic review from Baltimore found 7777 papers on these topics. They selected 46 and tried to find out what this thousand-fold septiform activity might mean for patient care. Again, the answer is nothing. “There is no direct evidence that testing for these mutations, and the resultant management, reduces VTE related outcomes in individuals who have had VTE or in the probands’ family members who have been tested”. O come into the light, ye doleful gnomes of Leiden.  http://jama.ama-assn.org/cgi/content/abstract/301/23/2472

NEJM   18 Jun 2009  Vol 360

2605    Is everyone dead yet? Not you and I, dear Reader, not yet: but for that we cannot thank those responsible for influenza virus containment measures. These would have failed anyway, no doubt, but by golly they made sure of it in the UK, as any of you who have gone through the farce of enacting the HPA protocol will know. For our continued survival we must thank the novel swine-origin influenza A (H1N1) virus itself, the subject of several useful studies and other pieces in this week’s NEJM – something for which the journal can and does congratulate itself with good reason, while The Lancet just moans and waffles. Here is as clear and authoritative account as you are ever going get of the origin of this pandemic, within weeks of its confirmation. For a good summary of flu pandemics generally, see p.2595. 
http://content.nejm.org/cgi/content/full/360/25/2605
http://content.nejm.org/cgi/content/full/360/25/2595

2616    The SARS scare and this latest virus have made us all mug up on our virology in the last couple of years, but it’s still a swine to understand why some strains infect the whole world within weeks while others just pick off a few pig farmers in America. As a fascinating editorial on p.2667 points out, H1 viruses are triple assortants of viruses from pigs, humans and birds. They are normally highly infectious from pig to pig but only occasionally spread to humans in close contact with pigs. The paper I refer to here contains case reports, including fatalities, from such sporadic infections with other H1 triple assortant viruses. By contrast, the latest kind, which is best called S-OIV, came from a pig and spreads rapidly from human to human but hardly at all from pig to pig. And all these H1s are probably the result of a catastrophic melding of bird and pig and human flu early in the last century. “The current situation is not ‘1918 again’, it is ‘1918 continued’, in that we are still being infected with the remnants of the 1918 pandemic.” In other words, this pandemic is just a ripple, not a new catastrophe; this virus has already learnt that it is more profitable to make people sneeze at each other than to kill them.  http://content.nejm.org/cgi/content/full/360/25/2616  
http://content.nejm.org/cgi/content/full/360/25/2666

2626    Streptococci can behave in rum ways, too: it was only in the 1970s that group B infection in the first week after birth became widely recognised as a leading cause of illness and death. The prevention strategy adopted in the USA was to introduce universal antenatal screening for strep B in the birth canal between 35 and 37 weeks of gestation and prophylactic antibiotic administration for those who are culture positive. This was associated with a 65% decrease in incidence between 1993 and 1998. Here’s a progress report up to 2004. Screening rates have nearly doubled, but most babies with strep B disease are now born to mothers who screened negative, showing that although useful, current screening methods are not completely effective.  http://content.nejm.org/cgi/content/abstract/360/25/2626

Lancet  20 Jun 2009  Vol 373

2113    “Crown him, ye morning stars of light, who fixed this floating ball” might be a good line for a hymn to Bill Gates, would-be global fixer, sponsor of this paper on the financing ofglobal health, and naturally a hero (with Melinda) of the glorious tale. (The hymn in question was actually addressed to the Name of Jesus for the Children of Israel by the mad Bishop of Methodism, Edward Perronet, around 1780). And if global health is not fixed, it won’t be for lack of good intentions and massive philanthropism, as detailed here. The policy challenges are discussed at enormous length later on in the journal (p.2137). No talk here of population control or the role of the pharmaceutical industry, however. And yet, with no world revolution likely for a decade or two, we should celebrate the unprecedented outpouring of human goodness that this effort represents with a glass or two of chilled Gavi di GAVI (Global Alliance for Vaccines and Immunization; or else the best white wine growing area in northern Italy).  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60881-3/abstract

2125    I have spent a day in the last week listening to and talking about the latest diabetes trials; not my natural stamping ground, and one that fills me with consternation at the awful evidence base for our clinical decision-making in this immensely important area. Most of these trials are plain bad, this one included, though it does not set a new RECORD. What really bothers me is how difficult it is to get to the actual data in diabetic trials, beyond the spin that is put on them by the investigators – UKPDS being a notorious example, despite its 80+ manifestations in the literature. RECORD is actually quite well written up, but it still manages not to tell us much about the glycated Hbs actually achieved by any of the drug combinations, or how many people actually took rosiglitazone for how long. It was an open-label trial addressing the reasonable question of how people fare if you give them rosi in combination with metformin or a sulfonylurea as opposed to combining the two with the option of adding insulin if they got beyond 8.5% HbA_1c. Judging from disclosures subsequently made by the study’s sponsors, GlaxoSmithKline, the figure was about 60% for people staying with rosi to the end (as paid to do) versus about 50% for the controls staying with their specified drugs: statin use rose markedly during the study, more so in the rosi group. And so: we know that in this unblinded study, analysed by intention to treat, rosiglitazone did not increase cardiovascular mortality. But more people got heart failure and many more women got distal fractures. Argue on, and if that interests you, look at the excellent debate in CardioBrief: but as to treating patients, I’m none the wiser, and I’ll continue to avoid rosiglitazone.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60953-3/abstract

BMJ  20 June 2009  Vol 338

1491    It may be that you are more interested than I am in the control of dengue fever, how many people don’t turn up for breast and cervical screening, how “matched” patients fare under private or NHS midwives, the non-effect of statins on elderly pneumonia rates, or which way round to have child car seats fitted: if so, gorge away at this week’s British Medical Journal. I am interested in prognostic research, so the final Altman piece on p.1887 is a must, but I don’t expect you are, so I’ll content myself to comment only on a short but very useful run-through of acute leukaemia in children. I guess it’s the diagnosis we all most dread to make, and to have to break to unsuspecting parents. This piece is written by the doctors I’d actually send such children to, and they begin by pointing out that 85% of them will be cured. They get full marks for looking at the primary care literature and for pointing out the difficulty of making the diagnosis at first presentation. Now and again even the blood film may be misleadingly normal. The prognosis of acute lymphoblastic leukaemia remains better than for acute myeloid leukaemia but even in the latter, survival has risen since the 1980s from 15% to 66% at five years. Chemotherapy for leukaemic children can be pretty ghastly, but at least it gets results.   http://www.bmj.com/cgi/content/extract/338/jun11_1/b2285 

Ann Intern Med   16 Jun 2009  Vol 150

830    If you ferment rice with the red fungus Monascus purpureus, you get a mixture containing various statins, including lovastatin. Apparently there has been a study purporting to show that this red yeast rice does reduce cardiovascular events. This single-centre trial seeks to discover if it can be tolerated by statin-intolerant patients as a “natural” alternative to other lipid-lowering agents. The authors of the study claim success in a double-blinded trial with 31 patients in each arm. But the authors of the accompanying editorial (p.885), who run a large clinic specifically for statin-related muscle problems, say that this contradicts their experience. I don’t think I’ll rush to recommend red rice to any patients.  http://www.annals.org/cgi/content/abstract/150/12/830

840    Stents began their life in the dental surgery of Charles Stent, but their use has spread from the mouth to virtually every tube in the body, including the renal arteries. People withatherosclerotic renal arteries get renal impairment and hypertension, so they generally end up on an antihypertensive, aspirin and a statin. How about stenting the artery as well? This led directly to death in two of 64 patients and did not improve outcomes. Don’t do it.  http://www.annals.org/cgi/content/abstract/150/12/840

849    More and more of us will have to undergo colonoscopy at some stage, and that will cause bowel perforation in about one examination in 1,800 – a fact confirmed in this large study of Medicare recipients. Other adverse effects include GI bleeding and cardiovascular events, and tend to be commoner with increasing age and co-morbidity, as you’d expect.  http://www.annals.org/cgi/content/abstract/150/12/849

858    Statin-related myalgia is such a common problem that I never tire of reading reviews about it, and this one is the most useful I’ve encountered so far. It even suggests how to manage it without resorting to red yeast rice. It contains nice biochemical diagrams with lovely names like geranylgeranylation and ubiquinone. It explains some of the discordance between the randomised trials and our everyday clinical experience. But I think the point best worth remembering is that simvastatin is metabolised by the CYP3A4 isoenzyme and so interacts with all sorts of things like grapefruit juice, amiodarone, cyclosporine and antifungals, whereas rosuvastatin is metabolised by CYP2C9 and has far fewer interactions likely to cause myalgia. Also it allows you to get away with a lot more, including very low dosing or alternate day dosing regimes. About 40% of your statin myalgia sufferers will tolerate a return to the original statin at lower dose, and most of the rest may tolerate another statin if you keep trying.  http://www.annals.org/cgi/content/abstract/150/12/858

Plant of the Week: Kniphofia ‘Wol’s Red Seedling’

A gentleman called Wol Staines raised this really red hot poker, which flowers abundantly from now until late August. There are cool low pokers like “Timothy” for the more tasteful, restrained parts of your garden, but this mid-sized fellow will blaze with orange scarlet wherever your summer composition needs a bit of pep.

JAMA   24 Jun 2009   Vol 301

2563    Imagine a remote island populated by a monoculture of settlers from 1,100 years ago, still speaking their original language. Add glaciers, geysers, Northern Lights, failed banks, fish restaurants, etc. and you get Iceland, now classed by the UN as the most developed nation on earth. A far cry from the Icelandic sagas, in which characters like Gudmundsson and Sigurdsson would smash each others’ heads with axes and carry off women with names like Eiriksdottir. Nowadays, descendants bearing these exact names sit together and write learned papers together in geothermally heated university offices: this one is aboutmigraine in middle life and late-life brain infarcts. You can see how findings from a population of 320,000 people, most of them related to each other, may not necessarily apply to the whole of the world, but the weak association found here between migraine with aura in women and cerebellar infarction in later life is consistent with other studies in European populations. Why these infarcts should favour the female cerebellum is a mystery, and I’d like to know how many of these dottirs have a patent foramen ovale. Now that all Icelanders have been genotyped, perhaps we should insist that they all have autopsies. But not before death, as was once traditional.  http://jama.ama-assn.org/cgi/content/abstract/301/24/2563

2571   The town of Framingham may not be separated from the rest of the world by hundreds of miles of stormy ocean but it still manages to capture lots of useful longitudinal population data. Here the indefatigable team including familiar names such as Daniel Levy and Ramachandran Vasan look at the association between a prolonged PR interval on the ECG and later events. An atrioventricular conduction time of more than 200 milliseconds (first degree block) increases your risk of atrial fibrillation twofold and your risk of having a pacemaker threefold. Your mortality risk increases by over 40% (HR 95% CI,1.09-1.91).  http://jama.ama-assn.org/cgi/content/abstract/301/24/2571

NEJM   25 Jun 2009  Vol 360

2705    If you shut off a coronary artery acutely, it’s best to get someone to go in there and unblock it acutely: that much has been clear for about ten years. Moreover, the faster they do it, the better, as that excellent Yale study showed us a couple of weeks ago. But what if you happen to be somewhere where there isn’t a handy interventional cardiologist standing by? Go for fibrinolysis, obviously, but still try and find the handy cardiologist as fast as you can. That’s the simple message of this study from Canada, a country where access to cardiac catheter labs is frequently compromised by distance, snow, moose, bears and so forth. Get there in six hours following fibrinolysis and outcomes will be better than if you’re delayed longer. The fact that you’ve had a thrombolytic will not increase your chance of major bleeding during the procedure.  http://content.nejm.org/cgi/content/abstract/360/26/2705

2730    Cast your mind back to that good little update on childhood leukaemia in the BMJ last week: acute lymphoblastic leukaemia is the commonest kind and the one with the best prognosis. But traditionally a lot of these poor kids are subjected to cranial irradiation to prevent CNS relapse, making them feel awful in the short term and carrying a risk of secondary tumours, endocrine disorders and cognitive impairment in the long term. This study of newly diagnosed children with ALL from Tennessee brings the welcome news that this is no longer necessary: at any rate, this is what the authors say, though I find it almost impossible to follow their protocol and randomisation procedures, and no flow chart is provided. The main thing is that five-year survival topped 90% with chemo alone.  http://content.nejm.org/cgi/content/abstract/360/26/2730

2749    A few months ago, I was worried I had alpha₁-antitrypsin deficiency, but then I looked up the normal range and found that I was only 1% below. This is good, because try as I might, I could not get interested in this condition for which there is little useful therapy and a number of unwelcome outcomes. The major ones are chronic obstructive pulmonary disease and progressive liver disease. This review article takes you through what is known about the genetics (an awful lot) and its management (nothing much): we probably miss most of it because of limitations in standard testing, including genotyping, but I’m not sure this makes much difference to the affected individuals.  http://content.nejm.org/cgi/content/extract/360/26/2749

2758    “In the troughs made with bur grass, there is sweet beer. I will have the cupbearers, the boys and the brewers stand by. As I spin around the lake of beer, while feeling wonderful, feeling wonderful, while drinking beer, in a blissful mood, while drinking alcohol and feeling exhilarated, with joy in the heart and a contented liver -- my heart is a heart filled with joy! I clothe my contented liver in a garment fit for a queen! The heart of Inana is happy once again; the heart of Inana is happy once again!” This Sumerian drinking song from about 4,000 years ago is the first recorded joint mention of alcohol and the liver. But maybe we should not take its praise of beer too literally: young Inana, the Goddess of Love, was a notorious girl-about-town and is later (in the Epic of Gilgamesh) portrayed as a raddled old whore. Perhaps this is also the first reference to teenage binge drinking. Anyway, most Sumerians drank a litre or two of beer a day because it was the only safe cool liquid available in ancient Mesopotamia. By filtering the soiled water of the Tigris and Euphrates through sprouting grain and leaving it to stand, they may have begun humanity’s love affair with alcohol. This review article on alcoholic hepatitis opens on an altogether less lyrical note: “Excessive alcohol consumption is the third leading preventable cause of death in the United States.” The Sumerians would have regarded a fatty liver as a good omen, but these grim hepatologists allow no such comfort: as far as they are concerned, this portends cirrhosis – though it doesn’t in 95% of people - and they won’t even stoop to define “hepatitis” or contemplate any strategy short of total abstinence. The same Temperance Hall rhetoric pervades this week’s Lancet too. The harms of alcohol may perhaps outweigh its benefits, but it is uncommonly hard to find anyone who is willing even to admit the latter, let alone place the two objectively side by side.  http://content.nejm.org/cgi/content/extract/360/26/2758

Lancet  27 Jun 2009  Vol 373

2201    Placing the harms and benefits of alcohol in Russia side by side, even I have to admit there is no contest. Tolstoy’s answer was to ban it in the expectation that this would result in the peasants asserting their native dignity and trust in God; Chekhov as ever was wiser and subtler (“the only Russian author with any common sense”, as Auden called him). Though he wrote harrowing stories of alcohol-induced brutality and murder, he died with the words, ”It’s a long time since I drank champagne.” Blessed is the Russian who can take it or leave it. When the Soviet Union collapsed in 1990, there was a terrible plunge in life expectancy, which this paper attributes almost solely to alcohol. It kills Russian men preferentially in their most productive years. Some would advocate prohibition – like a character called Joatmon in Rakesh Biswas’ newly published post-modern medical tale The Conscious Notebook – a must-get, especially if you teach medical students. But although Joatmon (standing for Jack-of-all-trades) is an honoured figure in the Tolstoy-Gandhi tradition, he may also be read ironically as a self-satisfied generalist dispensing easy wisdom in his protective cave. See what you think. Alcohol is too much part of civilization, and too ready a palliative for the awfulness of the Russian climate, ever to be suppressed. As with all comforting addictions, we need better harm management and better alternatives. For a global view, see the three later papers, pp.2223, 2234, 2247.  
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61034-5/abstract
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60746-7/abstract
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60744-3/abstract
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60745-5/abstract

2215    Type 2 diabetes, like heart failure, hypertension, renal impairment, thyroid disorder and many of the “diseases” we treat every day is not actually a disease in itself but a range of processes defined by an arbitrary measurement. This simple fact seems to me one of the most important perceptions for every doctor to keep in mind - whether you are a jobber like me or an academic like those who wrote this valuable paper about trajectories of glycaemia, insulin sensitivity, and insulin secretion before the onset of type 2 diabetes in the Whitehall II cohort. People who are going to “get diabetes” – i.e. cross the fasting glycaemic threshold of 7 mmol/L – show characteristic changes in their glucose homeostasis in the years leading up to the condition. The abstract is tough to follow so here is an extract from the text which sums up this intriguing advance in knowledge: “Our findings support a multistage model of diabetes aetiology: a long compensatory period, when insulin secretion increases to compensate insulin resistance without any major changes in glucose values; a stable adaptation, when β-cell mass is decreasing in spite of β-cell adaptation; and a transient unstable period with a rapid rise of glucose to overt diabetes.” Look at the plots in this paper and ponder how you might identify these people and help them.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60619-X/abstract

BMJ  27 Jun 2009  Vol 338

Although I don’t usually stray beyond the research and education pages of the BMJ, the non-academic articles this week are of such interest that they cry out for mention. Three pieces – about methylphenidate on p.1532, about breast screening on p.1534, and about the mode of action of psychiatric drugs on p. 1535, deal with widely differing subjects but they are linked by a common theme of mental states. William Blake saw the whole of life as a play of states within the soul, and reality as a construct we create from these. Most of our waking time is spent in the consolidation of a state called Generation by which we concern ourselves with the safety and prosperity of our material lives and our families. But beneath this lies the state of Ulro, in which we are alone and paranoid and there is no such thing as a beloved or society. It is here that we do the greatest harm to ourselves and others. Above both of these lies the dangerous, happy land of Beulah, a place of sexual love and music, where contrarieties are equally true. Called by its happiness, we forget the tasks of Generation, and from this Beulah we either ascend to the City of Eden, where all activity is a mutual divine construct, or fall straight back through the pie-crust of Generation and into the nightmare single vision of Ulro.  

It seems to me that anything that helps people out of the single vision of Ulro is a good thing. Love, mutuality, forgiveness and creative work were Blake’s answer: but if chemicals help too, why deny these, when the rest is so difficult to provide? This seems to me to be the message of the piece on methylphenidate, though at a rather generational sort of level: “Perhaps doctors older than 50 would be required to pharmacologically stave off their fraying cognitive edges.” Hmph. Where can I get some 
http://www.bmj.com/cgi/content/extract/338/jun18_2/b1955

The piece on psychiatric drugs points out, rather repetitively, that we don’t know how psychiatric drugs work but argues that people should be able to choose how to use them according to what benefits they perceive. I agree, broadly. Never deny anybody a way out of Ulro.  http://www.bmj.com/cgi/content/extract/338/may29_1/b1963

And Iona Heath’s piece on mammography? The Ulronic elements of cancer screening are well summed up in her quotation from Sackett about the threefold arrogance of preventive medicine, as carried out without an honest dialogue with its beneficiaries/victims. This is like Blake’s painting of the Condemned, the Judge and the Executioner: all three are walking to the block with fixed downward expressions of equal guilt and misery. Read Iona’s essay and see if anyone comes up with a convincing answer in the Rapid Responses. Bin your copies of Breast Screening: The Facts. ¡Viva La Presidenta!  http://www.bmj.com/cgi/content/extract/338/jun23_1/b2529

1538    And so to a new screening topic: once-only abdominal ultrasound for abdominal aortic aneurysm in men. At least the test is harmless and accurate, and there is evidence of a 46% reduction in AAA mortality in this UK study - MASS, followed up at 10 years. But the absolute numbers are small and the main debate is whether it is cost-effective. British calculations suggest it is, whereas Danish (p.1542) suggest it isn’t. 
http://www.bmj.com/cgi/content/abstract/338/jun24_2/b2307
http://www.bmj.com/cgi/content/abstract/338/jun24_2/b2243

1545    Now children, should we prescribe antibiotics for acute cough in primary care? Was there a naughty child at the back who said yes? Come to the front of the class, you bad bad boy, and look at this chart from 13 European countries. Now what does it show, Richard? Not much, Miss.  http://www.bmj.com/cgi/content/abstract/338/jun23_2/b2242

1548   Methadone is a useful drug, but a dangerous one, as this survey of mortality in Scottish methadone recipients shows. More methadone is being prescribed while the death rate has leveled off, but it makes one wonder if perhaps in high-risk patients like those on large doses of benzodiazepines, we wouldn’t be better off using safer alternatives such as buprenorphine, or heroin.  http://www.bmj.com/cgi/content/abstract/338/jun16_4/b2225

1552   Our most harmful drug of addiction is also one of the hardest to discontinue. Pregnant women, however, should try to stop smoking as soon as possible: if we can help them do it before 15 weeks’ gestation, the baby will avoid nearly all the harm in terms of premature delivery and low birth weight.  http://www.bmj.com/cgi/content/abstract/338/mar26_2/b1081

Arch Intern Med  22 Jun 2009  Vol 169

1104    Over the last few years, we’ve been discovering that erythropoietin-stimulating agents work very well at increasing haemoglobin and killing people. But does a haemoglobin over 12 at least make people with chronic kidney disease feel better? According to this systematic review and meta-analysis, the answer is no. Keep the Hb between 9 and 12, and they’ll live longer and feel just as well.  http://archinte.ama-assn.org/cgi/content/abstract/169/12/1104

1113    Is knee replacement cost-effective? It’s just done to elderly people, and we’d be better off shooting them, as one of them tells me at least every day. In these times of economic stringency, abolish TKR unless you value mobility and pain relief in the elderly. If you have to do it, then use large centres for the best cost/benefit ratio. This also applies to shooting.  http://archinte.ama-assn.org/cgi/content/abstract/169/12/1113

Blake for the Week:
(for a brief explanation, see BMJ section)

Now I a fourfold vision see,
And a fourfold vision is given to me;
‘Tis fourfold in my supreme delight
And threefold in soft Beulah’s night
And twofold Always. May God us keep
From Single vision & Newton’s sleep!
(end of a letter to Thomas Butts, 22 Nov 1802)