Showing papers by "Jeffrey K Aronson published in 2006"

Meyler's side effects of drugs : the international encyclopedia of adverse drug reactions and interactions

Abstract: Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions, Sixteenth Edition builds on the success of the 15 previous editions, providing an extensively reorganized and expanded resource that now comprises more than 1,500 individual drug articles with the most complete coverage of adverse reactions and interactions found anywhere. Each article contains detailed and authoritative information about the adverse effects of each drug, with comprehensive references to the primary literature, making this a must-have reference work for any academic or medical library, pharmacologist, regulatory organization, hospital dispensary, or pharmaceutical company. The online version of the book provides an unparalleled depth of coverage and functionality by offering convenient desktop access and enhanced features such as increased searchability, extensive internal cross-linking, and fully downloadable and printable full-text, HTML or PDF articles. * Enhanced encyclopedic format with drug monographs now organized alphabetically* Completely expanded coverage of each drug, with more than 1,500 drug articles and information on adverse reactions and interactions* Clearer, systematic organization of information for easier reading, including case histories to provide perspective on each listing* Extensive bibliography with over 40,000 references* A must-have reference work for any academic or medical library, pharmacologist, regulatory organization, hospital dispensary, or pharmaceutical company

Clarification of terminology in medication errors: definitions and classification.

Abstract: We have previously described and analysed some terms that are used in drug safety and have proposed definitions. Here we discuss and define terms that are used in the field of medication errors, particularly terms that are sometimes misunderstood or misused. We also discuss the classification of medication errors. A medication error is a failure in the treatment process that leads to, or has the potential to lead to, harm to the patient. Errors can be classified according to whether they are mistakes, slips, or lapses. Mistakes are errors in the planning of an action. They can be knowledge based or rule based. Slips and lapses are errors in carrying out an action - a slip through an erroneous performance and a lapse through an erroneous memory. Classification of medication errors is important because the probabilities of errors of different classes are different, as are the potential remedies.

Anecdotes that provide definitive evidence

Abstract: When a criminal is caught in the act, other evidence is unnecessary. Should the same be true for adverse drug reactions?

A prescription for better prescribing.

Abstract: No-one knows the origin of the well-known prescription sign (Figure 1), but an attractive hypothesis is that it is derived from the utchat, or Eye of Horus, the symbol of good fortune and healing used by the ancient Egyptians and others (Figure 1) [1]. The sign of the utchat was worn by Egyptians to give them the strength of the sun and to maintain their good health, and it was inscribed in documents to ensure their success. When we inscribe its modern equivalent on a prescription we symbolically give the prescription the seal of success. But are our prescriptions always successful? Figure 1 The prescription sign (left) and the Eye of Horus (right). Unsuccessful prescribing takes several forms: underprescribing, overprescribing, inappropriate prescribing, irrational prescribing, and prescribing errors. Underprescribing is perhaps the most common of these, and we are again reminded of it in this issue of the Journal. In one of a series of four thorough reviews of various drug treatments in elderly patients, Mangoni and Jackson remind us that only a proportion of elderly patients with stable heart failure receive ACE inhibitors, despite good evidence of efficacy, and that those who are treated often receive inappropriately low doses [2]. In another of their articles they suggest that elderly patients should be given a statin regardless of their serum LDL cholesterol concentrations [3]; but we have previously published evidence that although prescribing of statins is increasing they are still being underprescribed [4]. ‘Postcode prescribing’, as it is known in the UK, refers to variable prescribing in different parts of the country. Muller et al. in this issue of the Journal present evidence that suggests that there may be international variability of this kind [5]. They discovered marked discrepancies in a French hospital between the WHO-defined daily doses of antimicrobial drugs and the doses that were actually prescribed. This suggests that there are wide differences between prescribing habits in different countries. It would be interesting to know if such differences correlate with international differences in reporting adverse drug reactions [6]. Prescribing errors are also common. Headlines like ‘Hospital makes 135 drug errors a week’[7] (and of those 135 errors 34 were potentially serious [8]) have highlighted this, and we have previously published information about prescribing errors, including, for example, an epidemiological assessment of predictors of such errors in hospital [9]. Inappropriate prescribing and irrational prescribing also feature from time to time in the Journal[10]. The UK General Medical Council's document Tomorrow's Doctors[11] states that ‘graduate [doctor]s must know about and understand the principles of treatment, including … the effective and safe use of medicines as a basis for prescribing, harmful interactions … [and] be able to … write safe prescriptions for different types of drugs’. Of course they must. So must any prescriber. But both in the UK [12] and elsewhere [13] medical students have said that they feel that not enough time is devoted to therapeutics teaching. Our first prescription should be to expose them and other prescribers to more.

A prescription for better prescribing

Abstract: Many medical students are unprepared to properly prescribe drugs after they qualify, argue Jeffrey K Aronson and colleagues. Will your training equip you with the skills you need?

Rare diseases and orphan drugs

Abstract: The word orphan comes from the Greek word orphanos, a child who has lost one parent or both, or an adult who has lost a child. It goes back to the putative Indo-European root ORBH, bereft, as in the Latin word orbus. The obsolete English words orbation and orbity meant orphanhood or childlessness. One who is bereft of freedom is a slave, made to work hard – consider the words for work in some modern European languages, such as the German Arbeit and the Czech robota. In his 1920 play R.U.R. (Rossum's Universal Robots) Karel Capek introduced the word robot (female robotka) for an imagined race of mechanical men and women. And the etymology reminds us of the link between orphans and the workhouse. In modern English the word orphan is most commonly used in its original Greek sense, but metaphorical meanings have also emerged. An orphan vehicle, for example, is a discontinued model, and an orphan is a line of type that begins a new paragraph at the bottom of a column or page.

Case reports of suspected adverse drug reactions--systematic literature survey of follow-up.

Abstract: Objective To determine whether anecdotal reports of suspected adverse drug reactions are valuable early warning signals. Design Systematic literature survey Data sources We evaluated all case reports of adverse drug reactions published in 1997 in five medical journals. Reports were excluded if the adverse reaction had previously been described in earlier publications and was already listed in the product information of the drug reference source (the British National Formulary (BNF) or the Medicines Compendium). We used the Web of Knowledge Citation Index and Medline for 2003 to identify follow-up studies. Main outcome measures Primary: the number of suspected adverse reactions subjected to formal validation studies and the findings of these studies. Secondary: the number of instances in which the warning from the case report was incorporated into the product information. Results We evaluated 63 suspected adverse reactions and found that most (52/63, 83%) had not yet been subjected to further detailed evaluation. Data from controlled studies that supported the postulated link between the drug and the adverse event were available in only three cases. Of the 48 agents listed in the drug reference sources, details of the suspected reaction were subsequently added to the Medicines Compendium in 15 instances, and to the BNF in seven instances. In each case, only one reaction had been confirmed. Conclusions Published case reports of suspected adverse reactions are of limited value as suspicions are seldom subjected to confirmatory investigation. Furthermore, these alerts are not incorporated into drug reference sources in a systematic manner.

Communicating information about drug safety

Abstract: It can be hard to interpret information about potential harms from drugs, whether through adverse effects or drug interactions. A simple visual coding system could help

Gold standards in pharmacovigilance: the use of definitive anecdotal reports of adverse drug reactions as pure gold and high-grade ore.

Abstract: Anecdotal reports of adverse drug reactions are generally regarded as being of poor evidential quality. This is especially relevant for postmarketing drug safety surveillance, which relies heavily on spontaneous anecdotal reports. The numerous limitations of spontaneous reports cannot be overemphasised, but there is another side to the story: these datasets also contain anecdotal reports that can be considered to describe definitive adverse reactions, without the need for further formal verification. We have previously defined four categories of such adverse reactions: (i) extracellular or intracellular tissue deposition of the drug or a metabolite; (ii) a specific anatomical location or pattern of injury; (iii) physiological dysfunction or direct tissue damage demonstrable by physicochemical testing; and (iv) infection, as a result of the administration of an infective agent as the therapeutic substance or because of demonstrable contamination. In this article, we discuss the implications of these definitive ('between-the-eyes') adverse effects for pharmacovigilance.

Polypharmacy, appropriate and inappropriate.

Abstract: I have seen it asserted that ‘polydactyly’ is an inappropriate word, because it means many digits (fingers or toes), and we all have many digits. This analysis is superficial. The Greek word ![Formula][1] (polus) had several meanings, such as many, mighty, long, and wide. The English prefix poly-usually takes the first of these meanings; polymyalgia means pain in many muscles, polyneuropathy disease of many nerves. However, ![Formula][2] could also mean too much or too many. We all have many red blood cells, so polycythaemia means having too many; someone who drinks too much has polydipsia; and polydactyly means too many fingers or toes. But there is one word in which both meanings are possible — polypharmacy, the prescribing of either many drugs or too many drugs. The term is usually used in the second of these senses, and pejoratively. But polypharmacy can be beneficial, and by itself is not the real problem—the problem is whether each drug has been prescribed appropriately or inappropriately, both individually and in the … [1]: /embed/mml-math-1.gif [2]: /embed/mml-math-2.gif

Poor prescribing is continual

Abstract: EDITOR—An editorial should bring an important topic to readers' attention and engage their interest, provoke a reaction, and trigger debate. We are delighted that the recent editorial on poor prescribing in the United Kingdom seems to have done all of these things.1 We did not give a thorough account of all the evidence, but we are surprised that Rubin thinks that we provided no evidence at all.2 We cited …

The diagnosis of art: arthrogryposis and Ribera's The Clubfoot.

Abstract: The Clubfoot by Jusepe de Ribera (1591-1652) in the Musee du Louvre in Paris (oil on canvas, 164×92 cm) has historically been thought to represent a hemiplegic disabled child begging for a living.1 It was painted in 1642 in Naples and was known as The Dwarf before it entered the collection of the Louvre in 1870. The work displays a young boy with apparent right-sided spastic hemiparesis, with a flexed wrist, an extended elbow, and an equinovarus deformity of the right foot and ankle. There is evidence of right-sided hemi-hypoplasia, with a shorter arm length and smaller girth of the right leg. With his left hand, he carries a crutch over his shoulder and holds a small piece of paper with the words Da mihi elimo / sinam propter / amorem dei (Give me alms, for the love of God), which some have suggested indicates mutism. However, there is no clear evidence for this.2 After all, modern beggars often display begging placards, and the artist has to show graphically what he cannot indicate by sound. Ribera used this technique in other paintings, for example his Blind Old Beggar, who holds a paper proclaiming Dies illa, dies illa. The boy has normal facial features with no evidence of dysmorphism or microcephaly. His smile and proud, upright posture are in keeping with Ribera's remarkable ability to capture the dignity of the individual, inviting respect rather than pity from the viewer. Diagnoses that have been entertained in the past have included hemiplegic cerebral palsy, infarcts in the area of the middle cerebral artery, and the sequelae of congenital infection, such as rubella and cytomegalovirus.3 However, in the left upper limb, seen holding a crutch, ignored by previous commentators, there appears to be a flexion deformity of the wrist with an adducted thumb and extended elbow (although the latter could be as a result of shouldering the crutch). With involvement of three limbs and normal facies, the diagnosis of hemiplegic cerebral palsy seems unlikely. But these changes would be consistent with a diagnosis of arthrogryposis. Arthrogryposis is from Greek words for a joint (arthron) and hooked (grupon), the latter referring to the hooked nails of the mythical griffin (grups). It is a condition defined by non-progressive contractures of two or more joints, often resulting from fetal akinesia.4 Its most common clinical features include symmetric contractures of all four limbs, tending to affect distal joints more than proximal, and fusiform atrophic limbs with absent skin creases. Intelligence is often normal and facial involvement is variable, the most common feature being micrognathia. Arthrogryposis is, in fact, an umbrella term for a wide range of distinct syndromes with specific phenotypes and characteristic gene defects. A more accurate diagnosis here would be distal arthrogryposis, in particular type 1A, where the clinical features include flexion contractures at birth with predominant involvement of the hands (with adducted thumbs a prominent feature) and feet (rigid equinovarus deformity), and variable expressivity with asymmetric limb involvement. The face is not normally affected and intelligence is normal. The features seen in Ribera's painting are consistent with this diagnosis. The gene defect in distal arthrogryposis type 1A has recently been characterized as an autosomal dominant mis-sense mutation (Arg91Gly) on chromosome 9p21-q21 which affects tropomyosin 2, a protein present in fast skeletal muscle fibres.5​5 Figure 1 The Clubfoot (1642) by Jusepe de Ribera (oil on canvas, 164 × 92 cm) [courtesy of Musee du Louvre, Paris, France] Arthrogryposis in its many forms has been documented in earlier societies in both prose and painting. A case of arthrogryposis multiplex congenita, most probably amyoplasia, which is the most common type of arthrogryposis, was described in an 8-year-old girl with hand and foot deformities by Thomas of Monmouth in a mid twelfth-century English hagiographic narrative, The Life and Miracles of St William of Norwich.6 A 16th century illustrated document, The Forme and Shape of a Monstrous Child, Born at Maydstone in Kent (1568), housed in the Huth Collection in the British Library, contains an anterior and posterior illustration of a newborn child with congenital deformities compatible with arthrogryposis, along with a poem and prose describing the anomalies.7 For example, the bilateral clubfoot anomaly is described as `the left leg growing upward toward the head, and the right leg bending toward the left leg, the foote thereof growing into the buttocke of the sayd left leg'. This particular case was seen in association with other congenital anomalies, such as genu recurvatum congenitum, cleft lip, and microcephaly, and is thought to be the earliest representation of Larsen's syndrome, one of the types of arthrogryposis. It is therefore likely that arthrogryposis occurred in Spanish society in the 17th century, at the time of Ribera, and although the final diagnosis for The Clubfoot is speculative, arthrogryposis is certainly one worth considering.

Rare diseases, orphan drugs, and orphan diseases

Abstract: Rare comes from the Latin rarus (loosely spaced or sparse) and eventually from the putative Indo-European root ERE, denoting separation, as in hermits and eremites and the net-like structures rete, retinaculum, and retina. Orphan comes from the Greek orphanos (a child deprived of one parent or both, or an adult deprived of a child). Metaphorically it denoted poverty and unspiced food. Its Indo-European root was ORBH (bereft) giving the Latin orbus and the obsolete English words orbation and orbity (orphanhood or childlessness). One bereft of freedom is a slave, forced into hard work, as in the German Arbeit and the Czech robota. Karel Eapek coined the word robot (female robotka) in his play R.U.R. ( Rossum's Universal Robots , 1920) to denote an imagined race of mechanical people. And the etymology reflects the link between orphans and the workhouse. Modern …

The diagnosis of art: melancholy and the portrait of Dr. Gachet.

Abstract: Dr Paul Gachet (1828-1909), born in Lille, studied medicine in Paris and Montpellier, and wrote a thesis entitled Etude sur la melancolie.1 In 1858, he returned to Paris to practise as a doctor and moved to Auvers-sur-Oise in 1872. There he befriended many painters, including Cezanne (who painted The House of Dr Gachet), Daubigny, Guillaumin, and Pissarro. Gachet himself became an artist, signing his works ‘P van Ryssel’. Vincent van Gogh (1853-1890) moved to Auvers on 20 May 1890, after leaving the asylum at St-Remy. He made three portraits of Gachet, an etching (May 1890) and two paintings (June 1890)—the second, for Gachet himself to keep, a near copy of the first.2 The best known of these, Portrait of Dr Gachet (oil on canvas, 67× 56 cm, location unknown), shows the doctor with his head propped on his right hand; his elbow rests on a table next to a purple foxglove and two books, Germinie Lacerteux (1865) and Manette Salomon (1867), both by the Goncourt brothers, Edmond and Jules. The portrait is profoundly melancholic: the colours are mostly heavy and oppressive; the two novels are depressing in content—Germinie Lacerteux is about a young servant who lives a debauched life and dies miserably in the workhouse and Manette Salomon describes the lives of four more or less unsuccessful painters. Gachet is palpably depressed—his head-in-hand pose is classical,2 as is his facial expression. Van Gogh wrote that Gachet's face was ‘grief-hardened’; ‘... he certainly seems to be suffering [nervous trouble] as seriously as I’, and ‘he is sicker than I am’. But van Gogh saw himself going beyond the doctor's individual melancholy to a more general state. As he wrote to Gauguin, ‘I have a portrait of Dr Gachet with the heart-broken expression of our time’. And to his brother Theo: ‘I had to paint [him] like that to convey how much expression and passion there is in modern heads.. .that is how one ought to paint many portraits’. And what is the foxglove doing in the painting? Some have suggested that it is the badge of the physician2—a role that it plays nowhere else in art. Others have suggested that Gachet treated van Gogh's seizures with digitalis. It has even been suggested that digitalis toxicity may have accounted for van Gogh's love of yellow,3 which does not bear scrutiny.4 But in the 19th century, digitalis was used to treat some psychiatric problems, including delirium tremens and mania, and it was also sometimes used to raise the spirits. According to William Withering's son: ‘... women of the poorer class in Derbyshire... drink large draughts of Foxglove tea, as a cheap means of obtaining the pleasures or the forgetfulness of intoxication’.5 Van Gogh described Gachet's foxglove as being ‘of sombre purple hue’. Perhaps he included it as another symbol of melancholy. But why was Gachet melancholic? Was it endogenous depression? Or was it the symptom of some physical illness? In the painting, his hands are slightly pigmented, albeit paler than his sunburnt face, and his nails are completely pale. Could he have had Addison's disease? Alas for this hypothesis, van Gogh's painting is impressionistic, not realistic; a contemporary photograph of Gachet shows that he had a fuller face than van Gogh portrayed; his hands are not seen. In fact, the portrait of Gachet is more like van Gogh himself or his brother, Theo, than Gachet. And indeed Gachet had asked van Gogh to paint it in the style of one of his self portraits. Perhaps Gachet was, like van Gogh, addicted to absinthe.6 We encourage further speculation.

When I use a word: Sometimes, never

Abstract: If something always happened, what percentage frequency would you assign to that event? Presumably 100%. And if something never happened? Presumably 0%. Well, not everyone shares that opinion. By “always” some mean as infrequently as 91% of the time, and “never” can mean as often as 2% of the time. The combined results of seven studies of what people mean when they use words such as always, commonly, often, frequently, occasionally, sometimes, seldom, rarely, and never are summarised in the table (for references see Drug Safety 2005;28: 851-70 [PubMed]). For comparison, I have also included definitions from the Oxford English Dictionary. Table 1 Interpretations of words used to indicate frequencies Look, for example, at “occasionally,” “infrequently,” and “seldom”; according to the dictionary they all mean roughly the same thing, but the frequencies that people think these words represent do not overlap at all. Perhaps the lexicographers should reconsider some of their definitions—although surely not “never”—nohow. And perhaps when we use words like this we should remember what the German conductor Hans Richter supposedly once said: “Up with your damned nonsense will I put twice, or perhaps once, but sometimes always, by God, never.”

Monitoring for harms of therapy.

Abstract: The word monitor comes from the supine form, monitum, of the Latin verb monere, which has several meanings – to remind, bring to the notice of, suggest a course of action to, advise, serve as a warning to, presage. Monere was the causative form of the verb meminisse, to remember, which itself came from the putative Indo-European root MEN, to have one’s mind aroused, with all that that implies, both religious and secular. Mnemosyne, the Greek goddess of memory and mother of the Muses, reminds us of mnemonic and amnesia. Minerva, the Roman goddess of wisdom, brings to mind mens, the Latin mind, which gives us mental, sentimental, dementia, and memento mori. The Norse god Odin had a raven on each shoulder, one called Hugin, mind, the other Munin, memory. A mantra was a Sanskrit instrument of the mind, a prayer or counsel; a mandarin was a counsellor to the Chinese Emperor; a maenad was an orgiastic worshipper; a mantis appears to be praying. The many words that end in – mancy are not unconnected, for they are methods whereby one can learn something by divination (Greek manteia). Another Greek word, menthenein, to learn, gives us mathematics and various learned words – polymath, philomath, opsimath (a late learner), chrestomathy (an educative selection of literary extracts) – and the learning problem of acatamathesia. And for want of a better theory, MEN may have given us the word man, the only creature that knows his own mind, or thinks he does.

Today's science, tomorrow's medicines

Abstract: Today's pharmacological science leads to tomorrow's medicines and informs the use of the medicines we already have. And the wide spectrum of pharmacological science [1] is mirrored in a wide range of outputs, as reflected by the papers that we published in the Journal in 2005. In April, for example, Motola et al. reported on whether technological innovation in drug discovery results in therapeutic innovation in the market place, by reporting on 10 years of drug approval by the European Medicines Evaluation Agency [2]. Using an arbitrary therapeutic effect scoring system of major, partial, or minor benefit, they showed that the overall degree of important or moderate therapeutic innovation was 47% for all agents and that 80% of approved drugs were for serious conditions. These observations led us to ruminate on the need for more and better pharmacological science in the field of drug development [3]. Here we highlight some other reflections in the pharmacological mirror that caught our attention during last year.

The diagnosis of art: exophthalmos--Gustave Doré's ogre.

Abstract: Gustave Dore (1832-1883) was France's greatest illustrator. He first came to prominence through his illustrations for Rabelais's Gargantua et Pantagruel (1854) and Balzac's Contes Drolatiques (1856). Other works that he illustrated included Dante's La Divina Commedia, starting with the Inferno in 1861 and adding the Purgatorio and Paradiso in 1886-1888, Don Quixote de la Mancha (1862), the Bible (1865), Paradise Lost (1866), Raspe's Adventures of Baron Munchausen (1866), La Fontaine's Fables (1867), and Coleridge's Rime of the Ancient Mariner (1870). Although primarily a humorous illustrator, Dore was attracted by the darker side of Dickens's works and illustrated them in sombre engravings. Those who have seen Roman Polanski's recent version of Oliver Twist will have appreciated the use that he made of Dore's work as backdrops to the opening titles. Dore's interest in London was stimulated by Blanchard Jerrold, the son of the writer Douglas Jerrold, who in 1869 commissioned him to produce a portrait of the city, resulting in the 180 engravings that were published in London: A Pilgrimage in 1872.

"Open-access" publishing: first the evidence--then the verdict.

Abstract: `Nec audiendi sunt ii qui volent dicere, vox populi vox Dei, cum tumultuositas vulgi semper insaniae proxima est' [ignore those who say that the people's voice is God's voice—mob-led panic is ever akin to madness; Alcuin, in a letter to Charlemagne (804)] `No!' said the Queen, `first the sentence, and then the evidence!' [Lewis Carroll, Alice's Adventures Underground (1864)] We respect the medieval proverb vox populi vox dei in many walks of life, perhaps increasingly today, with vox pop so readily accessible. Vox populi (or at least suffragia populi) elects governments, although in return governments generally prefer to ignore it: in the UK it takes major dissent to deflect a government from its plans, and referenda are rare. The jury system also enshrines the principle, and when important matters are undecided we say that the jury, a sort of focus group, is still out. Focus groups as vox pop are a legitimate method of research in the social sciences, if used correctly and for proper ends.1 They can generate hypotheses or help in constructing questionnaires for larger studies, and they can uncover factors that affect people's behaviour, suggesting potential methods of altering that behaviour. However, using focus groups to inform political policy (popular in recent years) is risky, because they do not necessarily reflect the opinions of the majority; even if they do, the majority opinion does not necessarily dictate the best policy (buy The Sun—six million readers can't be wrong). In this issue of the JRSM, Schroter and Tite report the results of a questionnaire study on knowledge of open-access publishing and attitudes to it.2 Questionnaire studies in large populations can yield useful insights into what people know or believe. However, they are not suitable for some types of study.3 For example, don't ask doctors about their professional behaviour—they consistently overestimate their performance.4 Schroter and Tite found that their respondents, authors of research papers, knew and understood little about open-access publication and its implications. Are their other findings valid or useful? I don't know, but I have doubts. For example, bias in answering questions could have been reduced by sending half the sample a similar questionnaire with questions couched in opposite terms (e.g. negative for positive), but that was not done. Do their findings reflect the true opinions of a group of individuals whose views should be influential? Perhaps not: some were inexperienced in research and publishing; others confessed that they knew nothing about open access. And, however well-informed the opinions, the results tell us nothing about the important issue: whether open-access publishing will on balance benefit research and its safe dissemination. Open-access publishing has many different definitions,5 but it is based on the idea that research findings should be made available immediately to everyone, via the author, without payment. This is a high ideal and sounds unimpeachable. The benefits include instant dissemination of research results to scientists and the public, increased ease of retrievability, and reduced costs to research institutions. But like other ideas that were thought to be self-evidently beneficial at the time,6 there may be downsides and unintended consequences. The benefits have not been proven to be so beneficial that the balance of benefit to harm is favourable. For example, instant wide-spread dissemination of research results may not be beneficial if the results are used inappropriately or misinterpreted before their true value has been established over a period of reflection and careful testing—was the immediate wide-spread dissemination of Wakefield's work on the measles, mumps and rubella (MMR) vaccine beneficial? The argument about reduced costs is a slippery one. What open access actually proposes is a redistribution of costs. Bookshops and libraries give everyone open access to their contents, but someone has to pay: for the bookshop—the customer; for the library—the taxpayer. Publishing scientific work in learned journals isn't free: either subscribers (individuals or institutions) pay, in which case only they have immediate access; or authors (individuals or institutions acting on their behalf) pay, in which case everyone can have immediate access. A few journals have other sources of funding—such as advertising and the support of their sponsoring institutions—and can afford to give free access to research papers immediately without charging authors. Most others cannot, but many are willing to do so after a variable period. The potential disadvantages of open access publishing are many. I have reviewed them elsewhere.7 They include concerns about peer review, quality control, research in developing countries and by junior researchers, and the future of learned societies. These concerns are shared by the Royal Society8 and these and other issues were recently debated in the House of Commons, in the light of the Science and Technology Committee's 10th Report of Session 2003-04. Although the title of that debate (taken from the report) was misleading—nothing is `free for all'—it at least lacked hyphens, and the discussion was well informed, lively, and civilized.9 The debate about open-access publishing has been fruitful. The view that all research should be universally available free as soon as it is published has been replaced by more reasonable proposals, for example to make it available 6-12 months after publication, which some journals already do anyway. However, the proposal that institutions such as universities and grant-giving bodies should create freely accessible archives of their own material has been criticized,10 partly because of fears about flooding the system with confusing non-definitive versions. `More research is needed'—a common cry.11 Well, it is happening. For example, Research Councils UK and the Royal Society, in collaboration with publishers, are studying the impact that self-publishing and self-archiving will have.9 Let us have more research, not more vox pop. Then we can reach a verdict after obtaining the evidence, rather than the other way round.

When I use a word: Consultation

Abstract: In his account of the Persian wars, Herodotus tells how the Lydian king Croesus consulted the Delphic oracle, asking whether he should go to war with Persia. If Croesus attacks the Persians, said the oracle, he will destroy a mighty empire. Croesus confidently marched on Cappadocia, but it was his own mighty empire that he destroyed by doing so, not that of the enemy king, Cyrus. Other oracular pronouncements were equally ambiguous. According to Ennius, “Aio te Romanos vincere posse” (quoted by Shakespeare in Henry VI, Part 2) was the answer that Pyrrhus, king of Epirus, received when he asked about making war with Rome: “I assert that you can conquer the Romans/the Romans can conquer you.” The lesson is clear: listen carefully to those whom you consult—they may not be saying what you would like them to say. It is a lesson that seems to have been forgotten. The word consult comes from the Latin verbs consulere (supine consultum) and consultare, both of which mean to apply to someone for advice or information. Consultare also means to consult an oracle. The Oxford English Dictionary gives several definitions for “consult,” including “to have especial respect or beneficial reference to (a person's good, interest, convenience, etc.) in forming plans;... To ask advice of, seek counsel from; to have recourse to for instruction, guidance, or professional advice... to seek permission or approval from (a person) for a proposed action.” My concern that modern methods of consultation do not conform to this description received another dig in the ribs recently when an organisation enthusiastic to introduce author pays, “open access” publishing, and institutional repositories (with apparently little regard for the various deleterious effects that these policies may have (BMJ 2005;330: 759. [PubMed]) including damage to learned societies that publish their own journals) proclaimed that it would “discuss with the learned societies ways in which they can adapt to and exploit new models of publication.” To me this is rather like a doctor telling her patient that she will see him through his terminal illness, helping him to adapt to the inevitable. The patient may have consulted the doctor, but the doctor has not consulted the patient. One way of getting the answer you want is to ask the right question. My local council (a word, incidentally, that comes from concilium; not to be confused with counsel), keen to introduce charges for allowing me to park outside my own house, recently sent me a consultation questionnaire. Did I agree that there should be a consistent policy about such charges throughout the city? My gut reaction was “yes,” because surely consistency is desirable. Well actually it isn't always. What is good and necessary in some parts of town may be harmful in others. So, should the same policy be applied throughout? I answered “no,” but it won't do any good—I suspect that they have already decided what they're going to do. All too often today consultation seems to mean, as Paul Glasziou suggested to me when we discussed it, “This is what we intend to do; tell us how much you agree.” I therefore propose a novel Likert scale for responding to modern consultations: Agree/Agree strongly/Agree very strongly/Agree enthusiastically/Couldn't agree more. I also note that another meaning of the Latin word consulere, listed in the Oxford Latin Dictionary, is “[with male, duriter, and similar] to plan harm (to), act mischievously, prejudicially, etc (towards)... [and with contra] to take steps against.”

The diagnosis of art: Diastrophic dysplasia and Hephaistos

Abstract: The Greek god Hephaistos was, according to Homer, the son of Zeus and Hera. But Hesiod, in his Theogony, says that he was the parthenogenetic son of Hera. A skolion to the Iliad reconciles these two accounts by suggesting that Hera concealed the identity of Hephaistos’s father because he was conceived before she and Zeus were married. This befits the modesty for which Hera was known, but it is surprising that Zeus, not a priggish god, nowhere trumpets his paternity. Perhaps he was ashamed of his disabled son. Hephaistos was born lame in both feet, according to an epithet that various authors gave him—‘Amphiguēeis’. We learn in the Homeric Hymn to Apollo that Hera threw him out of heaven soon after his birth because he was deformed, but the Iliad recounts that Zeus threw Hephaistos out of Olympos because he defended Hera from him. As Milton describes, comparing him with Lucifer, Hephaistos fell for a day, eventually landing on Lemnos, where he was cared for by the Sintians. Milton says that he built Pandaemonium, Satan’s palace. Later, in revenge for this ill treatment by his mother, Hephaistos fashioned a magic throne, which held her fast when she sat on it. Only when Dionysos made him drunk did he dissolve the spell. He is also credited with making Achilles’ armour and Harmonia’s necklace and with fashioning Pandora from clay. Hephaistos married Aphrodite, and of his offspring, Palaimonios is described by Apollonios as being crippled and Periphetes by Apollodoros as being weak in the feet. Why was Hephaestus lame? We shall propose a diagnosis based on the history and physical examination, using the 6th century BC water-vase illustrated here (Figure 1). We note that depictions of the god changed with time from short and deformed to tall and normal,1 and that depending on the history and examination one chooses to adopt, different diagnoses are possible—that is the fun of the game. We shall assume that Hephaistos was lame from birth, that both feet were affected, and that his affection was hereditary. We shall also invoke other features in the figure shown here—the abnormal upper limbs, the short stature, and some facial features. We rule out bilateral congenital talipes equinovarus;2 it has a strong multifactorial hereditary component but no upper limb features or short stature. The latter also rules out arthrogryposis, in which bilateral rigid congenital talipes equinovarus occurs, and which could explain the elbows fixed in flexion. Another suggested diagnosis, achondroplasia, would not explain the foot deformities; this diagnosis is based on earlier images of the god, evoking Egyptian depictions of deities such as Ptah, Bes and Harpocrates.1 We also rule out an acquired peripheral neuropathy secondary to arsenic poisoning, an affection of smelters.3 It may be that this afflicted models for the artists who depicted Hephaistos, if for example they were smelters who had been exposed to arsenic, but it does not fit the history we have proposed. Furthermore, it is more likely that Hephaistos became a smith because he hobbled rather than the other way round; in primitive societies a lame man with strong arms would be highly suited for smithery, other common occupations being ruled out. The diagnosis that we favour, after Silverman,4 is diastrophic dysplasia, short-limbed dwarfism with bilateral rigid foot deformities, such as hindfoot equinovarus and forefoot adductus resembling clubfeet; upper limb involvement with contractures of the elbows leading to loss of extension but no loss of power; and progressive scoliosis, hip, and knee flexion contractures, which can cause stooping and limping. It has an autosomal recessive pattern of inheritance, and may have been passed on to his children. There are lethal and severe variants, but there is also a mild variant, with a normal lifespan. Perhaps the blot below Hephaistos’ left eye is a haemangioma, another feature of the disease. And his ear may be misshapen (it is different from the ears of the others in the picture), due to typical cystic change. An alternative diagnosis is pseudodiastrophic dysplasia, in which elbow dislocations are prominent,5 but very few cases have been described.

The diagnosis of art: Rachmaninov's hand span

Abstract: In 1943 the Russian virtuoso pianist, composer, and conductor Sergei Vasilievich Rachmaninov (1873-1943) became ill in the middle of a concert tour and was admitted to a hospital in Los Angeles. When cancer was diagnosed, he looked at his hands and whispered, ‘My dear hands... Farewell, my poor hands.’ Were his hands the key to his suffering? Rachmaninov is perhaps best known for his second, C minor, piano concerto, popularized in the films Brief Encounter (1945) and The Seven Year Itch (1955); the adagio sostenuto provided inspiration for Eric Carmen's 1976 pop song All By Myself, later covered by Celine Dion and mimed with passion by Renee Zellweger in the opening scenes of Bridget Jones's Diary in 2001. The third, D minor, piano concerto, already popular, was given further exposure by David Helfgott, as portrayed in Shine (1996). In his lifetime Rachmaninov's prelude in C sharp minor was so popular as a concert encore that he grew to hate it. And works such as the Rhapsody on a Theme of Paganini and the Symphonic Dances cemented his popularity. His technical perfection was legendary. It was said that his large hands were able to span a twelfth (an octave and a half or, for example, a stretch from middle C to high G). The size of his hands may have been a manifestation of Marfan's syndrome, their size and slenderness typical of arachnodactyly.1,2 However, Rachmaninov did not clearly exhibit any of the other clinical characteristics typical of Marfan's, such as scoliosis, pectus excavatum, and eye or cardiac complications. Nor did he express any of the clinical effects of a Marfan-related syndrome, such as Beal's syndrome (congenital contractural arachnodactyly), Ehlers-Danlos syndrome, homocystinuria, Stickler syndrome, or Sphrintzen-Goldberg syndrome. There is no indication that his immediate family had similar hand spans, ruling out familial arachnodactyly. Rachmaninov did not display any signs of digital clubbing or any obvious hypertrophic skin changes associated with pachydermoperiostitis. Acromegaly is an alternative diagnosis. From photographs of Rachmaninov in the 1920s and his portrait by Konstantin Somov in 1925 (Figure 1), at a time when he was recording his four piano concerti, the coarse facial features of acromegaly are not immediately apparent. However, a case can be made from later photographs. Figure 1 Portrait of Sergei Rachmaninov (1925) by Konstantin Somov; oil on canvas. The State Russian Museum, St. Petersburg, Russia Rachmaninov's repeated bouts of depression3 are also consistent with a diagnosis of acromegaly. On 27 March 1897, his First Symphony was poorly received in an under-rehearsed performance conducted by an inebriated Aleksandr Glazunov. This event, from which Rachmaninov fled in horror, is said to have triggered his first major episode of depression, which temporarily brought his composing career to a standstill: ‘all my hopes, all belief in myself, had been destroyed.’ It would not be until the latter half of 1900 that he returned to composition, with the help of a hypnotist, Dr Nikolai Dahl, to whom he dedicated his Second Piano Concerto, the second and third movements of which he brilliantly performed in December of that year. His second major bout of depression began during the Second World War, when he was living near Los Angeles, probably related to worries over the safety of one of his daughters and grief over the deaths of relatives and friends in the war. During a heavy concert schedule in Russia in 1912, he interrupted his schedule because of stiffness in his hands. This may have been due to overuse, although carpal tunnel syndrome or simply swelling and puffiness of the hands associated with acromegaly may have been the cause. In 1942, Rachmaninov made a final revision of his troublesome Fourth Concerto but composed no more new music. A rapidly progressing melanoma forced him to break off his 1942-1943 concert tour after a recital in Knoxville, Tennessee. A little over five weeks later he died in the house he had bought the year before on Elm Drive in Beverly Hills. Melanoma is associated with acromegaly4,5 and may have been a final clue to Rachmaninov's diagnosis. But then again, perhaps he just had big hands.