QJM: monthly journal of the Association of Physicians

Published by Oxford University Press (OUP)
Online ISSN: 1460-2393
Print ISSN: 1460-2725
Publications
Clinical decision‐making used to be based on physicians' experience and authority. Now this is no longer enough. The dissemination of the practice of evidence‐based medicine (EBM) has closely appended science to art.1 Clinicians worldwide have access to powerful, precise and up‐to‐date information sources on which to base both diagnosis and treatment. Medical textbooks, which until recently, referred to tests as being ‘positive’ or ‘negative’ and to treatments as being ‘useful’ or ‘ineffective’ for a given condition, are being transformed. They are less likely to contain these vague adjectives, whose meanings are uncertain,2 or the tables that cite extremely rare causes on the same footing as highly common ones. An analytical, quantitative and critical approach to medical data is on the rise. Factual, numeric information, often derived from the scientific examination of large numbers of patients, is now widely available, through modern textbooks, journal articles and electronic databases. Many of these databases can be accessed and searched in real time, and they are often continuously updated. As a result, EBM, which is the use of this type of information as the basis of decision‐making, is becoming a paradigm of correct medical practice.3 More and more, it underlies clinical thinking, and it affects and improves many medical decisions. The potential benefits of EBM are numerous and well described.4,,5 Nevertheless, concerns have been published,6–,9 and enthusiasm for this recently unearthed treasure trove should not be undiscerning. Although there is wide agreement as to the immense value of the practice of EBM in the science and art of clinical decision‐making, its clinical usefulness could be enhanced if clinicians understood the gaps that exist between the research evidence and the care of the individual patient, and dealt with them effectively. First, the characteristics of patients studied …
 
It was back in the early 1980s. My thoracic surgical colleague asked if I could help him with one of his patients who had developed breathing problems after a lobectomy. The man was on a respirator, the consequence (it turned out) of a post-operative attack of asthma. By the time he had recovered, the pathologist reported the resected lobe to have contained not cancer but pneumoconiotic massive fibrosis. By chance, I happened to be researching miners’ diseases, so I asked him which coalmine he had worked in. He replied that he had been a shale miner, an occupation in which pneumoconiosis was thought not to have occurred. Well, now it seemed it had, and a trawl through the pathology records of the local hospital led to the discovery of a number of other examples, some of which had been associated with lung cancer. This coincided with the early-1980s oil crisis. The US government was looking towards exploiting the vast oil reserves locked in shale in the Rocky Mountains in Colorado and was anxious to make an assessment of any risks to workers. Exploitation of oil shale had started after the discovery of deposits in Scotland in the mid-19th century by James Young, a Glasgow chemist. This had led to the 1876 description by Joseph Bell, an Edinburgh surgeon and Conan Doyle's model for Sherlock Holmes, …
 
Age-adjusted prevalence rates for four major risk factors in adult population of Salamis, Greece, in 2002 and 2006. 
rates of self-reported myocardial infarction and effects of potential risk factors in adult population of Salamis, Greece, in 2002 and 2006
To examine trends in the prevalence of myocardial infarction (MI) and conventional risk factors in Greek adults between 2002 and 2006. Repeated cross-sectional study. Self-reported data from surveys given in Salamis during two election days in 2002 and 2006 were analysed. The same sampling method and procedures were used on both surveys. The study sample included 2805 and 3478 subjects (> or =20 years) in 2002 and 2006, respectively, with similar age and sex distribution to the target population. The prevalence of MI increased from 4.1% (men, 6.3%; women, 1.9%) in 2002 to 4.8% (men, 7.3%; women, 2.2%) in 2006 (P = 0.18). At the same time, prevalence rates of major risk factors were as follows: diabetes increased from 8.7% to 10.3% (P = 0.037), hypertension from 20.1% to 25.7% (P < 0.001) and hypercholesterolemia (cholesterol >240 mg/dl or the use of cholesterol-lowering medication) increased from 17.5% to 22.3% (P < 0.001). Prevalence of current smokers in 2002 (defined as persons who smoked > or =5 cigarettes/day) was 37.0% and in 2006 (defined as those who smoked > or =1 cigarettes/day) was 40.1%. Logistic regression analysis showed that the aforementioned risk factors were significantly associated with MI in both surveys; the factor that showed the greatest magnitude of association with MI was hypercholesterolemia, followed by diabetes, hypertension and smoking. These findings show that, in the Greek population, prevalence of MI continues to rise (at approximately 4% per year). This trend seems to be driven by a persistently high prevalence of smoking and the rapidly increasing burden of diabetes, hypertension and hypercholesterolemia.
 
Adult bone mineral status is modified by early environmental influences, but the mechanism of this phenomenon is unknown. Intestinal calcium absorption and vitamin D metabolism are integrally involved in bone metabolism and may be programmed during early life. To examine the early-life influences on calcium absorption and its control in 322 post-menopausal female twins. Intestinal calcium absorption was assessed by the stable strontium (Sr) method. Serum PTH, 25(OH) and 1,25(OH)(2) vitamin D were measured and recalled birth weight recorded. Fractional intestinal Sr absorption (alpha Sr) was correlated with serum 1,25(OH)(2) vitamin D (p<0.001), but not with 25(OH) vitamin D. Birth weight was inversely associated with serum 1,25(OH)(2) vitamin D (p=0.04), the association being independent of serum calcium, phosphate, creatinine and PTH. Birth weight was inversely correlated with alpha Sr (p=0.03), this association being independent of age, season, customary calcium intake and serum 25(OH) vitamin D; however, when serum 1,25(OH)(2) vitamin D was added into the model, the association became non-significant, suggesting that the association was partially mediated via serum 1,25(OH)(2) vitamin D. We found a significant inverse association between birth weight and intestinal calcium absorption that is partially explained by an association between serum 1,25(OH)(2) vitamin D and birth weight. This suggests a mechanism whereby the intra-uterine environment might affect adult skeletal status.
 
Clinical parameters on arrival in the ED 
Disposition of patients following presentation to the Emergency Department following self-reported GHB or GBL ingestion. 
Gamma-hydroxybutyrate (GHB) is used as a recreational drug, with significant associated morbidity and mortality; it is therefore a class C drug under the Misuse of Drugs Act (1971). However, its precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4BD) remain legally available despite having similar clinical effects. The aim of this study was to determine whether the relative proportions of self-reported ingestions of GHB or its precursors GBL and 1,4BD were similar to those seen in analysis of seized drugs. Retrospective review of our clinical toxicology database to identify all cases of self-reported recreational GHB, GBL and 1,4BD use associated with ED presentation in 2006. Additionally all seized substances on people attending local club venues were analysed by a Home Office approved laboratory to identify any illicit substances present. In 2006, there were a total of 158 ED presentations, of which 150 (94.9%) and 8 (5.1%) were GHB and GBL self-reported ingestions respectively; 96.8% (153) were recreational use. Of the 418 samples seized, 225 (53.8%) were in liquid form; 85 (37.8%) contained GHB and 140 (62.2%) contained GBL. None of the seized samples contained 1,4BD and there were no self-reported 1,4BD ingestions. Self-reported GHB ingestion was much more common than GBL ingestion, whereas GBL was more commonly found in the seized samples. These differences suggest that GBL use may be more common than previously thought and we suggest that there should be further debate about the legal status of the precursors of GHB.
 
Number and proportion of patients receiving branded drugs at time of discharge from hospital 
Cost implications of different combinations of secondary prevention medication 
Combination therapy with three classes of drug, antiplatelet, cholesterol and blood pressure lowering treatment markedly reduce the risk of recurrent cardiovascular events in patients with coronary heart disease (CHD). Within each class, generic and branded (patented) drugs are available which have similar efficacy but differ in cost. (i) To assess the extent to which preventive medical drugs are prescribed in patients with CHD and to examine the reasons for drug omissions and (ii) to assess the relative use of branded and generic drugs and the reasons for drug selection. The medication charts and hospital notes of consecutive patients undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) at a large cardiothoracic centre were reviewed over a 3-month period. Interviews with patients, attending cardiologists and general practitioners were undertaken to establish why drugs were and were not prescribed. Among 1008 patients (755 who had PCI and 253 who had CABG) the use of aspirin, statins, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), beta blockers and calcium channel blockers were, respectively, 97, 98, 81, 76 and 18%. The combination of any 4 classes of drug were used in 65% of patients. Almost all patients who did not receive aspirin or a statin had clinical contraindications and were on alternative drugs. In about 12% of patients without an ACE inhibitor (or ARB) and 7% of patients without a beta blocker, no reason to withhold such treatment was identified. Branded drugs were used in 52% of patients; the most commonly prescribed being atorvastatin in 33%. Clinical reasons for using branded rather than generic drugs were identified in 13% of cases. Our results show a high rate of use of secondary preventive cardiac medications in patients undergoing coronary revascularization procedures, but the use of ACE inhibitors or beta blockers is still overlooked in about 1 in 10 patients. Branded drugs are prescribed in about half of all patients undergoing PCI and CABG, but in almost 90% of cases, a generic equivalent could have been used to achieve similar risk reduction. If our results reflect wider practice, an estimated 11 million pounds a year would be saved by the National Health Service by switching to generic alternative drugs.
 
11b-HSD mRNA is expressed in the non-pigmented epithelium (NPE) (A) (Â400), with minimal chromagen precipitation in the control sections: DIG-labelled antisense probe in the presence of 60-fold excess of unlabelled probe (B), DIG-labelled sense cRNA probe (C) and use of no probe (D). Indirect fluorescent in situ hybridization confirmed expression in the NPE, but there was also evidence of expression in the PE although full expression was masked by the pigment (E) (Â630). There was minimal fluorescence with the control DIG-labelled sense cRNA probe (F).  
Cortisol and cortisone levels in aqueous humour from 40 controls (oe), and 38 patients (g) with primary open angle glaucoma. (A) all patients, (B) males, (C) females. Results are shown as means AE SEM. Although cortisol levels exceed those of cortisone in each case, there was no statistical significance between glaucoma and controls.  
Changes in urinary corticosteroid metabolites after the administration of CBX (n ¼ 7) or placebo (n ¼ 7) confirming systemic inhibition of 11b-HSD1 (A) and 11b-HSD2 (B). Results are shown as means AE SD. (oe, stage I—baseline; g, stage II—treatment: CBX or placebo as indicated; *p < 0.05; **p < 0.001).  
Change in IOP in patients with ocular hypertension after oral carbenoxolone (CBX) or placebo. The reduction was highly significant when patients (n ¼ 20) were treated with CBX, but not when patients were taking placebo or during the intermediate washout stage. (A) Right eye; (B) left eye. (IOP in mmHg; boxes, 99%CI; þ, mean; whiskers, range).  
Model for 11b-HSD1 as a potential target for lowering intraocular pressure (IOP). The 11b-HSD1 expressed in the non-pigmented epithelium (NPE) provides the basis for a cortisol-generating system that induces sodium transport across the ciliary epithelial bi-layer, and the production of aqueous humour. Selective inhibition of this isozyme could potentially lower IOP. PE, pigmented epithelium; MR, mineralocorticoid receptor; GR, glucocorticoid receptor; ENaC, epithelial sodium channel.  
Intraocular pressure (IOP) is maintained by a balance between aqueous humour (AH) production (dependent on sodium transport across a ciliary epithelial bi-layer) and drainage (predominantly through the trabecular meshwork). In peripheral epithelial tissues, sodium and water transport is regulated by corticosteroids and the 11beta-hydroxysteroid dehydrogenase (11beta-HSD) isozymes (11beta-HSD1 activating cortisol from cortisone, 11beta-HSD2 inactivating cortisol to cortisone). To analyse expression of 11beta-HSD in the human eye and investigate its putative role in AH formation. Multipart prospective study, including a randomized controlled clinical trial. The expression of 11beta-HSD1 in normal human anterior segments was evaluated by in situ hybridization (ISH). RT-PCR for 11beta-HSDs, glucocorticoid and mineralocorticoid receptors (GR, MR) was performed on human ciliary body tissue. AH cortisol and cortisone concentrations were measured by radioimmunoassay on specimens taken from patients with primary open-angle glaucoma (POAG) and age-matched controls. Randomized, placebo-controlled studies of healthy volunteers and patients with ocular hypertension (OHT, raised IOP but no optic neuropathy) assessed the effect of oral carbenoxolone (CBX, an inhibitor of 11beta-HSD) on IOP. ISH defined expression of 11beta-HSD1 in the ciliary epithelium, while RT-PCR analysis of ciliary body tissue confirmed expression of 11beta-HSD1, with additional GR and MR, but not 11beta-HSD2 expression. In both POAG patients and controls, AH concentrations of cortisol exceeded those of cortisone. The CBX-treated healthy volunteers who demonstrated the largest change in urinary cortisol metabolites, indicative of 11beta-HSD1 inhibition, had the greatest fall in IOP. Patients with OHT showed an overall reduction of IOP by 10% following CBX administration, compared to baseline (p<0.0001). CBX lowers IOP in patients with ocular hypertension. Our data suggest that this is mediated through inhibition of 11beta-HSD1 in the ciliary epithelium. Selective and topical inhibitors of 11beta-HSD1 could provide a novel treatment for patients with glaucoma.
 
A wide variety of neuroendocrine tumours express somatostatin receptors, and can be visualized by radiolabelled somatostatin analogue scintigraphy. To investigate the value of [111In]-octreotide scintigraphy (Octreoscan), 48 patients (37 with proven carcinoid, pancreatic endocrine and medullary carcinoma of thyroid tumours, 11 with neuroendocrine syndromes multiple endocrine neoplasia (MEN-I) and Zollinger-Ellison syndrome (ZES) were examined with 111In-DTPA-D-Phe1-octreotide. Scintigrams were obtained at 24 and 48 h, and the results were compared with CT and magnetic resonance imaging (MRI). Thirty-five of 48 patients had positive [111In]-octreotide scintigraphy (23/25 (92%) carcinoids, 8/9 (89%) PETs, 4/11 (36%) MEN-I & ZES). Of the 42 lesions located by conventional imaging techniques, 37 (88%) were also identified by Octreoscan. Unexpected lesions (40 sites), not detected by CT or MR imaging were found in 24/48 (50%) patients. [111In]-octreotide scintigraphy has a higher sensitivity for tumour detection, and is superior to MR imaging and CT scanning in the identification of previously unsuspected extraliver and lymph node metastases. It may also be helpful for the localization of clinically suspected tumours in patients with MEN-I and ZES.
 
Blood pressure, proteinuria and serum creatinine (SCr) were examined in 119 985 adults, aged 40 years and older, who attended annual health examinations both in 1993 and 3 years later. Renal function was assessed from SCr; changes in individuals' renal function were estimated using the slope of the regression line for the reciprocal of the SCr level vs. time (slope of rSCr) over the 3-year period. Age-dependent SCr concentration increments were observed; however, there was no significant age-dependent change in the slope of rSCr. SCr in hypertensives on anti-hypertensive medication was significantly higher than that in untreated hypertensives, borderline hypertensives and normotensives. The slopes of rSCr in hypertensives (treated, untreated and borderline) were steeper than normotensives in males, and that in untreated hypertensives was steeper than other groups in females. In hypertensives with proteinuria, SCr was higher and renal function deteriorated more rapidly, compared with hypertensives without proteinuria. Hypertension with proteinuria appears to be an important indicator for progressive decline in renal function, this trend being more obvious in males. Renal function decreases with age; however, the rate of decline is constant. The influences of proteinuria and blood pressure on renal function are different in males and females.
 
In apparently localized amyloidosis, there is no appropriate test to determine whether systemic deposits exist. We studied the value of serum amyloid P component (SAP) scintigraphy and labial salivary gland (LSG) biopsy on patients with apparently localized amyloidosis in 12 patients who had neither clinical nor biological evidence of systemic amyloidosis. All patients had an LSG biopsy and echocardiography. Iodine-123-labelled serum amyloid P component (123I-SAP) scintigraphy was performed in all patients. Whole-body scintigraphy was done, and tissue retention was evaluated at 24 h and 48 h. Of these 12 patients, three had amyloidosis in their LSG and had abnormal 123I-SAP scintigraphy; these three had a secondary clinical history of systemic amyloidosis. Three other patients had abnormal 123I-SAP scintigraphy without detectable systemic amyloid deposits, but one had a previous history of bilateral carpal tunnel syndrome treated with infiltration. 123I-SAP scintigraphy in association with LSG biopsy may be helpful in determining the localized or systemic character of amyloid disease.
 
Vertebral osteomyelitis (VO) is associated with considerable morbidity and its incidence seems to be increasing. Haematogenous spread is an important aetiological factor. The objective was to describe a series of patients with VO and to search for a relationship between preceding bacteraemia and subsequent VO with the same pathogen. Design and methods: A retrospective study of all treated cases of VO in a tertiary hospital over a 10-year period. There were 129 cases of VO (involving 125 patients) that received antimicrobial treatment. Eighty-three (66%) were male and the mean age was 59.5 years (range 1 month to 87 years). The vertebral level involved was lumbar in 66 (53%) cases and thoracic in 35 (28%) cases. Seventy-four cases (59%) had a microbiologically confirmed aetiology. The diagnostic yield from procedures was 46 and 36% from blood culture and bone biopsy, respectively. Staphylococcus aureus was the most common pathogen [38 of 74 (51%) cases]. Nine of 38 (24%) cases of Staphylococcus aureus VO had a preceding bacteraemia with the same pathogen in the previous year. Staphylococcus aureus is an important pathogen causing bacteraemia with the ability to cause metastatic complications including VO. The high proportion of cases developing VO following a documented bacteraemia, sometimes many months previously, reinforce the importance of adequate aggressive treatment for bacteraemia. VO must be considered in all patients presenting with back pain up to a year after bacteraemia. Previous bacteraemias with relevant pathogens can help guide antibiotic treatment at presentation of VO and if biopsy cannot be obtained.
 
( a ) CT scan abdomen showing B/L adnexal lesions (arrows). ( b ) Contrast-enhanced MRI brain showing enhancing lesions in right frontoparietal lobe and an additional lesion in left frontal lobe (arrows). 
### Learning Point for Clinicians Tuberculosis should be kept as a possibility in patients with multisystem disease, especially in developing countries like India. A simple test like CT guided FNAC can help detect infection with M. tuberculosis and hence a major surgery can be avoided CA-125 is an epithelial marker derived from coelomic epithelium. It is elevated in 90% of advanced ovarian cancers and has a sensitivity of 57–80% and specificity of 100%. Therefore, CA-125 is an important investigation in evaluating a pelvic mass. However, any process that disrupts the epithelial lining of the peritoneum has the potential to raise its level. Therefore, it can be elevated in many non-neoplastic conditions such as hepatitis, pancreatitis, menstruation etc.1 We illustrate a patient who presented with elevated CA-125 levels but was ultimately diagnosed as …
 
Plasma total homocysteine (tHcy), folate and red blood cells (RBC) folate levels in the studied population 
Distribution of MTHFR 677C£T genotypes and allele frequencies in South European countries 
Methylenetetrahydrofolate reductase (MTHFR) is one of the main regulatory enzymes of homocysteine metabolism. Elevated plasma total homocysteine (tHcy) is a major risk for cardiovascular disease. A common 677C-->T mutation in the MTHFR gene results in decreased enzymic activity, and contributes to increased plasma tHcy, in association with low plasma folate. A recently described 1298A-->C mutation in the MTHFR gene clearly reduces MTHFR activity (although to a lesser extent than the 677C-->T) but its effect on plasma tHcy levels is not yet clear. To investigate the frequency of these two MTHFR polymorphisms in a Portuguese population, and to correlate the MTHFR genotype with the biochemical phenotype at the level of homocysteine and folate concentrations. Prospective population survey. We studied 117 healthy volunteers (71 females, 46 males). The 677C-->T and 1298A-->C mutations were screened by PCR-RFLP. Levels of plasma tHcy and folate, and red blood cell folate, were determined. The allele frequencies of the 677C-->T and 1298A-->C mutations were 0.33 and 0.28, respectively. Homozygotes for the 677C-->T mutation had significantly elevated plasma tHcy and RBC folate levels and significantly lowered plasma folate concentrations than subjects without the mutation. The 1298A-->C mutation showed a significant effect on plasma tHcy, but not on plasma folate or RBC folate levels. The observed 677T allele frequency is not consistent with the idea of a north-south gradient as previously suggested. The 1298A-->C mutation is common in Portugal. Both MTHFR mutations showed effects on plasma tHcy levels.
 
A 13-year-old male adolescent presented to our clinic because of cessation of growth discovered during an annual health examination. He had no relevant medical and surgical history, but had a 4-year history of heavy resistance training (8 h/week). There was no history of performance-enhancing agent intake, besides carbohydrate-electrolyte drink during exercise in the past 12 months. Parents reported the onset of his puberty, primarily identified as testicular enlargement, shortly after age 10. Parents denied genetic diseases in the family. Father (195cm tall) reported starting puberty approximately at age 11, while mother (175 cm tall) had menarche at 10.5 years. Examination revealed adult-like pubic hair quality, extending across pubis but sparing medial thighs, with testes long axis measuring 4.5 cm. Facial hair reached upper lip. The patient had an athletic body physique: height = 183.0 cm, weight = 77.6 kg; muscle mass = 52.9%. CDC height for age calculation revealed Z-score of 3.3 and 99.9th percentile. Growth velocity curve showed a tall stature (95th percentile) for the past 5 years of height measurement, with annual growth velocity decline from 8 to 2 cm per year. No limb length discrepancy has been found. An X-ray of the left hand and wrist done at chronological age of 13 years (Figure 1) revealed advanced skeletal age closest to 18.0 years; all the epiphyses except that of the radius have fused with their shafts. Laboratory evaluation revealed a serum total testosterone of 743.2 ng/dl (normal range: 7–800 ng/dl), free testosterone of 25.8 ng/dl and Dehydroepiandrosterone (DHEA) sulfate of 211.6 mg/dl (reference values for free testosterone and DHEA sulfate have not been established for patients under age 16), estradiol of 26.9 pg/ml (normal range: 0–38 pg/ml), and free thyroxin of 1.3 ng/dl (normal range: 0.7–2.0 ng/dl). Chromosomal analysis showed normal karyotype.
 
Survival post-stent of those that died during study period. 
Endoscopic oesophageal stent insertion is a widely used procedure to alleviate dysphagia caused by malignant strictures of the oesophagus and gastric cardia. It can, however, be associated with significant complications, mortality and morbidity. Aim and method: This retrospective case note study was undertaken to assess success rates, complications and mortality of oesophageal stenting when undertaken in a UK District General Hospital (DGH) setting. Patients who underwent oesophageal stenting for malignant disease from January 2000 to January 2006 were included. Of the 137 patients studied, oesophageal adenocarcinoma was present in 57% of patients, squamous cell oesophageal carcinoma in 37% and gastric adenocarcinoma in 6%. Indications for stent insertion were: presence of non-resectable tumours (65%), co-morbidities that contraindicated surgery (25%), refusal by patients for surgery for potentially resectable disease (6%) and a need for enhanced oral nutrition prior to surgery (4%). Prior to stenting 86.4% of patients suffered from advanced dysphagia. A significant improvement in symptoms was seen in 94% of patients. Discharge from hospital was within 48 h in 45% of cases. Chest pain was experienced by 13.9% of patients and serious acute stent-related complications (perforation or bleeding) occurred in 5.8% of patients. Overall 41.6% of patients had at least one complication. Mortality was 4.4% at 7 days and 24.8% at 30 days. Oesophageal stent insertion proved to be an effective palliation of dysphagia in group studied. It is a relatively safe procedure with a low rate of serious acute complications (5.8%) and can be done as a short stay in many patients.
 
The ABCD and ABCD2 scores have been validated for use as predictors of stroke in community populations up to 90 days after a transient ischemic attack (TIA). TIA outpatient clinics may see a selective group of patients who have not had an early stroke but may be at raised risk in the medium to long term and therefore benefit from preventive treatment. To describe the prognostic values of the ABCD and ABCD2 scores on long-term stroke risk. Retrospective cohort study of TIA clinic outpatients followed for up to 14 years. Absolute and relative stroke risks, Kaplan-Meier survival curves and cumulative stroke incidence were calculated. Receiver Operating Characteristic curves (ROCs) and areas under the curve were calculated for both scores. Seven hundred and ninety-five patients were included and 138 (17.3%) experienced a stroke within 13.8 years follow-up after first TIA clinic visit, a crude risk of 26.3 per 1000 person-years. Compared with baseline scores of 0-2, risk ratios for ABCD of 3-4 were 2.95 (95% CI 1.52-6.40), and for 5-6 were 3.42 (95% CI 1.72-7.54); for the ABCD2, risk ratios for 3-4 were 2.68 (95% CI 1.37-5.84), and for 5-7 were 3.55 (95% CI 1.80-7.79). Scores of > or = 3 for either ABCD or ABCD2 predicted raised stroke risks at 90 days, 1, 5 and 10 years. Areas under the curve were 0.619 (95% CI 0.571-0.668) and 0.630 (95% CI 0.582-0.677) for the ABCD and ABCD2 scores, respectively. ABCD and ABCD2 scores of > or = 3 may be clinically useful in identifying TIA outpatients at raised risk of stroke in the medium to long term.
 
The mean values of pan-CSF 14-3-3 (14-3-3-P) protein and its five major isoforms ( b , g , e , Z and z ) levels between bacterial and aseptic meningitis at the time of admission. § P 1⁄4 0.049, bacterial meningitis vs. aseptic meningitis groups; k P 1⁄4 0.032, bacterial meningitis vs. aseptic meningitis groups; l P 1⁄4 0.028, bacterial meningitis vs. aseptic meningitis groups; x P 1⁄4 0.04, bacterial meningitis vs. aseptic meningitis groups. 
Increased levels of cerebrospinal fluid (CSF) 14-3-3 proteins have been reported in acute bacterial meningitis. We tested the hypothesis that CSF 14-3-3 protein levels are substantially increased in acute bacterial meningitis and decreased after anti-microbial therapy, and that CSF 14-3-3 protein levels can predict treatment outcomes. We examined serial pan-CSF 14-3-3 (14-3-3-P) protein and five major isoform (beta, gamma, epsilon, eta, zeta) levels in 29 adult community-acquired bacterial meningitis (ACABM) patients. The CSF 14-3-3 protein levels were also evaluated in 12 aseptic meningitis patients during the study period. All of the meningitis patients had a positive result on admission. Levels of CSF 14-3-3 protein in ACABM cases were significantly increased initially, and substantially decreased thereafter. Most of those who survived (survivors = 25 and non-survivors = 4) had nearly cleared their 14-3-3 protein from the CSF before discharge. Conversely, patients who died never cleared their CSF 14-3-3 protein. The median value of CSF 14-3-3-P and 14-3-3 gamma, 14-3-3 eta and 14-3-3 epsilon isoforms on admission in the bacterial meningitis group were 173.7, 137.7, 42.2 and 9.1, respectively, which were statistically significant than those of the aseptic meningitis group (48.4, 39.6, 2.5 and 0, respectively). Stepwise logistic regression analysis showed only CSF 14-3-3 gamma isoform on admission was independently associated with outcome (P = 0.05, OR = 0.991). Serial 14-3-3 protein gamma isoform actually meets the major requirements for outcome prediction in the treatment of ACABM patients. Assay of the 14-3-3 protein gamma isoform should be added as a neuro-pathologic marker among the panel of conventional CSF parameters.
 
Muscle biopsy from biceps brachii of Patient 1 obtained at 2 months (both magnification Â400): (a) The modified Gomori trichrome stain showing marked fiber-size variation and numerous ragged-red fibers. (b) Histochemical staining of COX showing virtually absence in all muscle fibers except for the intrafusal spindle (arrow).  
### Learning Point for Clinicians Childhood-onset mitochondrial encephalomyopathies usually present with a progressive course with a fatal outcome. These assumed irreversible conditions prompt clinicians and parents to face end-of-life decisions for a young child. However, this unfortunate situation can be overcome via a molecular diagnosis that can grant a favorable prognosis with continuing intensive supportive care. ### Patient 1 A 6-week-old boy was admitted to the pediatric intensive care unit (PICU) for frequent choking and apnea, requiring gavage feeding and assisted ventilation. He developed generalized weakness and sucking difficulties soon after birth. He exhibited profound hypotonia and hyporeflexia. The serum lactate was 9.6 mmol/l (normal reference: 0.5–2.2) and the creatine kinase (CK) 700 U/l (normal reference: 200). Muscle biopsy from the biceps brachii suggested a …
 
Thomas Addison was first to describe adrenocortical failure in 1855. Despite advances in the treatment of this condition, the diagnosis is still often delayed and sometimes missed with potentially fatal consequences. From the same institution where Thomas Addison performed his original autopsy studies, we present four recent cases highlighting the wide clinical spectrum and discuss how modern biochemical and immunological tests could be utilized in early diagnosis and aetiological classification.
 
The picture (Figure 1) showing a markedly virilized central figure with an infant at the breast was painted in 1631 by Jose Ribera, a Spaniard living in Naples. It was commissioned by Ribera’s patron, the Duke of Alcala and in due course returned to Spain. It was exhibited in Paris and in the Royal Academy of San Fernando in the early 19th century and hung for many years in the Hospital Tavera in Toledo. It is now in the Museo del Prado, Madrid. Figure 1. La mujer barbuda by Ribera, 1631. The central figure poses a conundrum but a case for the diagnosis of the underlying medical condition which would explain all the features seen can be made from evidence in the picture. The medical history of this real named person is given in the Latin inscription on the stone tablets in the picture, enhanced in Figure 2. The inscription translates as follows: Look, a great miracle of nature. Magdalena Ventura from the town of Accumulus in Samnium, in the vulgar tongue Abruzzo in the Kingdom of Naples, aged 52 and what is unusual is when she was in her 37th year she began to go through puberty and thus a full growth of beard appeared such that it seems rather that of a bearded gentleman than a woman who had previously lost three sons whom she had borne to her husband, Felici de Amici, whom you see next to her. Joseph de Ribera, a Spaniard, marked by the cross of Christ, a second Apelles of his own time, by order of Duke Ferdinand II of Alcala, Viceroy at Naples, depicted in a marvellously lifelike way. 17th February 1631.Magdalena Ventura’s features show frontal balding, a luxuriant beard, coarse skin but no acne, masculine face and large but not acromegalic hands. …
 
Statins represent the largest selling class of cardiovascular drug in the world. Previous randomized trials (RCTs) have demonstrated important clinical benefits with statin therapy. We combined evidence from all RCTs comparing a statin with placebo or usual care among patients with and without prior coronary heart disease (CHD) to determine clinical outcomes. We searched independently, in duplicate, 12 electronic databases (from inception to August 2010), including full text journal content databases, to identify all statin versus inert control RCTs. We included RCTs of any statin versus any non-drug control in any populations. We abstracted data in duplicate on reported major clinical events and adverse events. We performed a random-effects meta-analysis and meta-regression. We performed a mixed treatment comparison using Bayesian methods. We included a total of 76 RCTs involving 170,255 participants. There were a total of 14,878 deaths. Statin therapy reduced all-cause mortality, Relative Risk (RR) 0.90 [95% confidence interval (CI) 0.86-0.94, P ≤ 0.0001, I(2)=17%]; cardiovascular disease (CVD) mortality (RR 0.80, 95% CI 0.74-0.87, P<0.0001, I(2)=27%); fatal myocardial infarction (MI) (RR 0.82, 95% CI 0.75-0.91, P<0.0001, I(2)=21%); non-fatal MI (RR 0.74, 95% CI 0.67-0.81, P ≤ 0.001, I(2)=45%); revascularization (RR 0.76, 95% CI 0.70-0.81, P ≤ 0.0001); and a composite of fatal and non-fatal strokes (0.86, 95% CI 0.78-0.95, P=0.004, I(2)=41%). Adverse events were generally mild, but 17 RCTs reported on increased risk of development of incident diabetes [Odds Ratio (OR) 1.09; 95% CI 1.02-1.17, P=0.001, I(2)=11%]. Studies did not yield important differences across populations. We did not find any differing treatment effects between statins. Statin therapies offer clear benefits across broad populations. As generic formulations become more available efforts to expand access should be a priority.
 
Dr William MacMichael was Registrar of the Royal College of Physicians from 1824 to 1829. He describes the art of medicine as practised by five celebrated Royal Physicians, each of whom carried the famous cane now preserved in the Royal College of Physicians. MacMichael was born at Bridgnorth, Shropshire and attended Christ Church, Oxford, where he obtained his BM (1808) and DM (1816). He received post-graduate training in Edinburgh, St Bartholomew's and as a Radcliffe Travelling Fellow throughout Europe. He became FRS (1817), FRCP (1818), Censor (1820), Registrar of the College (1824), Physician to the Middlesex Hospital (1822–31) and Physician to George IV (1829) and to William IV (1829). He published ‘The Gold-Headed Cane’ in 1827, making an inanimate object, …
 
A 60-year-old ex-smoker of 20 pack years was further evaluated following a few month history of malaise, weight loss and abnormal chest radiograph. Initial computed tomography (CT) showed (Figure 1) was suggestive of primary lung cancer. CT-guided fine needle aspiration of the mass revealed numerous neutrophils with no evidence of malignancy. Given a possible diagnosis of lung cancer, positron …
 
Aim: To describe the main characteristics and the treatment of cryptococcosis in patients with sarcoidosis. Design: Multicenter study including all patients notified at the French National Reference Center for Invasive Mycoses and Antifungals. Methods: Retrospective chart review. Each case was compared with two controls without opportunistic infections. Results: Eighteen cases of cryptococcosis complicating sarcoidosis were analyzed (13 men and 5 women). With 2749 cases of cryptococcosis registered in France during the inclusion period of this study, sarcoidosis accounted for 0.6% of all the cryptococcosis patients and for 2.9% of the cryptococcosis HIV-seronegative patients. Cryptococcosis and sarcoidosis were diagnosed concomitantly in four cases; while sarcoidosis was previously known in 14/18 patients, including 12 patients (67%) treated with steroids. The median rate of CD4 T cells was 145 per mm3 (range: 55–1300) and not related to steroid treatment. Thirteen patients had cryptococcal meningitis (72%), three osteoarticular (17%) and four disseminated infections (22%). Sixteen patients (89%) presented a complete response to antifungal therapy. After a mean follow-up of 6 years, no death was attributable to cryptococcosis. Extra-thoracic sarcoidosis and steroids were independent risk factors of cryptococcosis in a logistic regression model adjusted with the sex of the patients. Conclusions: Cryptococcosis is a significant opportunistic infection during extra-thoracic sarcoidosis, which occurs in one-third of the cases in patients without any treatment; it is not associated to severe CD4 lymphocytopenia and has a good prognosis.
 
Clinical profile of HCC 
Hematological, biochemical and endoscopic profile of HCC 
Etiological work up of HCC (n = 191) 
TNM and Okuda staging of HCC and its correlation with serum AFP 
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The outcome of the disease is related to the stage of presentation. A comprehensive analysis of patients with this disease is not available in India. Retrospective chart review of 246 patients with HCC was done. One hundred ninety-one patients (male 160, female 31; median age 52 years, range 9-85 years) fulfilling diagnostic criteria for HCC adopted by Barcelona-2000 EASL conference were analyzed for clinical, etiological, radiological and cytohistological profile. Underlying cirrhosis was seen in 60% cases with hepatitis B being the most common etiologic agent. HCC caused new onset ascites and recent worsening in three-fourth cases with ascites. Paraneoplastic syndrome was a rare event in HCC in India. Diagnostic level of serum AFP was seen in only 46% with significant difference between cirrhosis HCC patients compared with non-cirrhosis HCC patients (53% vs. 26%; P = 0.046). Most cases (83%) presented at advanced stage (Okuda III or IV) and cytohistology was the best method to diagnose HCC. Vascular invasion was seen in half the patients (53%) by the time they presented with extrahepatic spread of tumor in 13% cases. The prevalence of advanced stage HCC makes most of the detectable lesions unsuitable for curative resection. However, universal hepatitis B vaccination program may become the most effective preventive measure to control this disease in India.
 
Few data link childhood mental ability (IQ) with risk of accidents, and most published studies have methodological limitations. To examine the relationship between scores from a battery of mental ability tests taken in childhood, and self-reported accidents between the ages of 16 and 30 years. In the British Cohort study, a sample of 8172 cohort members born in Great Britain in 1970 had complete data for IQ score assessed at 10 years of age and accident data self-reported at age 30 years. The relationship between childhood IQ score and later risk of accident was complex, differing according to sex and the type of accident under consideration. Women with higher childhood IQ were more likely than those with lower scores to report having had an accident(s) while at work, in a vehicle, engaging in sports, and in unspecified circumstances. Adjustment for markers of socioeconomic position weakened or eliminated some of these relations, but higher childhood IQ remained associated with increased risk of sporting and unspecified accidents. Men with higher childhood IQ scores were less likely than those with lower scores to report accidents at work, but more likely to report accidents at home, playing sports or in unspecified circumstances. After adjustment for socioeconomic circumstances, higher childhood IQ in men remained associated with an increased risk of accidents at home or in unspecified circumstances. The relationship between childhood mental ability and accidents in adulthood is complex. As in other studies, socioeconomic position has an inconsistent relationship with non-fatal accident type.
 
Background: Overt hypothyroidism and thyrotoxicosis have widespread systemic effects and are associated with increased mortality. Most death certificates that include them do not have the thyroid disease coded as the underlying cause of death. Aim: To describe regional (1979–2010) and national (1995–2010) trends in mortality rates for acquired hypothyroidism and thyrotoxicosis, analysing all certified causes of death (termed ‘mentions’) and not just the underlying cause. Design: Analysis of death registration data. Methods: Analysis of data for the Oxford region (mentions available from 1979) and English national data (mentions available from 1995). The data were grouped in periods defined by different national rules for selecting the underlying cause of death (1979–83, 1984–92, 1993–2000 and 2001–10) and were also analysed as single calendar years. Results: Mentions mortality for acquired hypothyroidism in the Oxford region declined significantly from 1979 to 2010: the average annual percentage change (AAPC) was −2.6% (95% confidence intervals −3.5, −1.8). Most of the decrease occurred during the 1980s. The AAPC in rates for later years in England (1995–2010) was non-significant at 0.2% (−0.7, 1.0). Mortality rates for thyrotoxicosis decreased significantly: the AAPC was −2.8% (−4.1, −1.5) in the Oxford region and −3.8% (−4.7, −3.0) in England. In England, between 2001 and 2010, hypothyroidism or thyrotoxicosis was coded as the underlying cause of death on, respectively, 17 and 24% of death certificates that included them. Conclusions: Mortality rates for hypothyroidism and thyrotoxicosis have fallen substantially. The fall is probably wholly or mainly a result of improved care.
 
Trends in acceptance rate in the UK and individual countries over the last two decades. Data from EDTA, four National Surveys and the Scottish and UK Renal Registries. 
Changes in renal unit haemodialysis (HD) facilities in the UK, 1993-2002 
Prevalent numbers by modality with time. Data from EDTA Registry Reports (1982 and 1986), National Renal Reviews (1993-98) and Scottish and UK Renal Registry Reports (1993-2002). 
International comparisons of RRT 
Following the introduction of dialysis and transplantation for the treatment of established renal failure (ERF) 40 years ago, the UK failed to match the achievements of many other countries. To review progress with treatment for ERF in the UK in the past 20 years. Review of four cross-sectional national studies, and 1997-2002 annual UK Renal Registry data. Data on UK patients on renal replacement treatment (RRT) were collated from three sources: European Registry reports for 1982-1990, surveys carried out within the UK in 1993, 1996, 1998 and 2002, and the UK Renal Registry database (1997-2002). Trends in acceptance and prevalence rates, median age, cause of ERF, and treatment modality were analysed and compared with current data from other countries. The UK annual acceptance rate for RRT increased from 20 per million population (pmp) in 1982 to 101 pmp in 2002. This growth was largely in those aged over 65 years, and in those with co-morbidity. Annual acceptance rates for ERF due to diabetes rose from 1.6 to 18 pmp. The prevalence of RRT increased from 157 pmp in 1982 to 626 pmp in 2002. Hospital haemodialysis has become the main modality, and is increasingly being provided in satellite units. Although rising, UK acceptance and prevalence rates are still lower than in many developed countries. Despite significant expansion in RRT services for adults in the UK over the last 20 years, there is evidence of unmet need, and need is expected to rise, due to demographic changes and trends in type 2 diabetes. Continuing growth in the already substantial investment in RRT will be needed, unless efforts to prevent the occurrence of ERF are successful.
 
Details of cases who died in the 10 years after developing acute Q fever 
Demographics and response rate in controls. 
Characteristics of matched cases and controls seen in hospital 
Some patients exposed to Q fever (Coxiella burnetii infection) may develop chronic fatigue. To determine whether subjects involved in the West Midlands Q fever outbreak of 1989 had increased fatigue, compared to non-exposed controls, 10 years after exposure. Matched cohort study comparing cases to age-, sex- and smoking-history-matched controls not exposed to Q fever. A postal questionnaire was sent to subjects at home, followed by further assessment in hospital, including a physical examination and blood tests. Of 108 Q-exposed subjects, 70 (64.8%) had fatigue, 37 idiopathic chronic fatigue (ICF) (34.3%), vs. 29/80 (36.3%) and 12 (15.0%), respectively, in controls. In 77 matched pairs, fatigue was commoner in Q-exposed subjects than in controls: 50 (64.9%) vs. 27 (35.1%), p<0.0001. ICF was found in 25 (32.5%) of Q-exposed patients and 11(14.3%) of controls (p=0.01). There were 36 (46.8%) GHQ cases in Q-exposed subjects, vs. 18 (23.4%) controls (p=0.004). A matched analysis of those more intensively studied showed fatigue in 48 (66.7%) Q-exposed patients and 25 (34.7%) controls, (p<0.0001), ICF in 25 (34.7%) Q-exposed and 10 (13.9%) controls (p=0.004), and chronic fatigue syndrome (CFS) in 14 (19.4%) Q-exposed patients and three (4.2%) controls (p=0.003). Thirty-four (47.2%) Q-exposed patients were GHQ cases compared to 17 (23.6%) controls (p=0.004). Subjects who were exposed to Coxiella in 1989 had more fatigue than did controls, and some fulfilled the criteria for CFS. Whether this is due to ongoing antigen persistence or to the psychological effects of prolonged medical follow-up is uncertain.
 
In 1989, an outbreak of Q fever (C. burnetii infection) with 147 confirmed cases occurred in Solihull, West Midlands. Three patients developed cardiomyopathy in the subsequent 10 years. The cohort has been followed up with respect to the development of fatigue and, in this instance, cardiac effects after the original infection. To determine whether persisting fatigue after Q fever represented sub-clinical cardiomyopathy. Prospective follow-up study. All traceable subjects from the original outbreak, and community age-, sex- and smoking-matched controls, were studied. Questionnaires for idiopathic fatigue, 12-lead ECG, echocardiography, spirometry and shuttle walk distance were undertaken, and a subset with CDC-defined chronic fatigue syndrome had gated cardiac scans. Of the original cohort, 19 had died, three had emigrated and 10 were untraceable. Of the remaining 115, 108 responded to a mailed questionnaire and 87 were investigated further, of whom 85 provided complete data. Two developed aortic valve vegetations, one of whom died. Chronic fatigue syndrome was found in 20% of cases and 5.3% of controls (including those with co-morbidities), falling to 8.2% and 0 when excluding those with co-morbidities. There were no significant differences in ECG and echocardiographic investigations or shuttle-walk distance between those with fatigue and those without. Six of the seven patients with CFS had gated cardiac scans: all were within normal limits. These findings do not support the existence of a sub-clinical cardiomyopathy in the patients in this cohort who suffer from fatigue after acute Q fever, although endocarditis can occur after acute infection.
 
Discharges for overdose by gender 1990–1999.  
Poisoning discharges per 100 000 population by age and gender, 1990-1999
Trends in overdose discharge for paracetamol, antidepressants and opioid overdose and misuse by gender.
Discharges involving antidepressants by age and gender per 100 000 population 1990-1999
Discharges involving opioids coded as poisoning or misuse by age and gender per 100 000 population 1990-1999
Overdose is one of the commonest causes of medical admissions to UK hospitals. In Scotland (pop. 5.1 million), all NHS hospital discharge data is uniquely linked to enable identification of individuals re-presenting with the same diagnosis. Aim: To examine trends in discharges for poisoning, in particular paracetamol, antidepressants and opioids from 1990-99. Retrospective analysis. Discharge data from the Scottish Morbidity Record (SMR01) and mortality data from the General Register Office for Scotland (GROS) were analysed for 1990-99 by age and gender for the relevant codes. Overall discharge rates increased until 1997, after which they fell. This pattern was seen in paracetamol-related discharges, but not for antidepressants or for opioids. Overdose was more common in females, except for opioids. Discharges related to opioids increased in an exponential manner over the decade, five-fold in women and six-fold in men in 10 years. Increases in opioid-related presentations are of major concern. Changes in paracetamol pack-size have been associated with reduced discharge rates. In Scotland the age group with the highest rate of discharge (15-24 years) with paracetamol overdose is not the one with the highest mortality.
 
To describe incidence, aetiology and outcome data for Scotland since the inception of the Scottish Liver Transplant Unit (SLTU) in 1992. Acute liver failure (ALF) is a rare but frequently fatal condition. Few studies have adequate patient numbers to draw convincing conclusions over demographic features, aetiology and outcome. Statistical analysis of prospectively collected data on aetiology, demographic, clinical and outcome of all admissions, including those with ALF, to the SLTU. Incidence data presented for admissions and ALF. Descriptive frequencies for aetiology, clinical, demographic and outcome data presented; including split analysis for paracetamol and non-paracetamol aetiologies. Univariate and multivariate analysis of admission factors predictive of outcome is described. Nine hundred and forty-nine patients were admitted to the SLTU between 1992 and 2009. Five hundred and twenty-four patients had ALF. The annual incidence of ALF in the Scottish population is 0.62 per 100,000 and paracetamol overdose (POD) was the largest causative factor; responsible for 0.43 cases of ALF per 100,000 population per year. The odds ratio (OR) of transplantation or death was 0.47 in the POD group compared to other aetiologies; yet of not being a transplant candidate having met the Kings College Hospital poor prognostic criteria OR was 4.9. Of admissions listed for transplant 76.0% were transplanted. Of those listed and not transplanted mortality was approaching 100% and 76.1% of those transplanted survived to discharge. This large, prospective, single centre study with a defined geographical area and well-recorded population provides accurate data regarding ALF between 1992 and 2009.
 
Coeliac disease (CD) results from mucosal exposure to dietary gluten in genetically predisposed individuals, although other environmental factors may be involved. The seroprevalence of CD is approximately 1%, with a high ratio of undiagnosed to diagnosed cases, leading to the concept of a 'coeliac iceberg'. To provide contemporary estimates of the incidence of diagnosed CD and the size of the submerged 'coeliac iceberg', and to seek evidence of disease clustering. Prospective observational study in a defined local population. Data were collected prospectively for all biopsy-proven cases diagnosed at Poole Hospital, 1993-2002. Age-specific incidence was calculated and point prevalence estimated for cases within the defined study zone. Evidence of disease clustering was sought using a space-time scan statistic based on a Poisson model. The overall incidence of CD was 8.7 cases/100,000/year (95%CI 7.4-10.1), with a median age at diagnosis of 53 years. Incidence increased progressively during the study period, and the estimated point prevalence of biopsy-proven CD rose from 0.18% to 0.4%. An area of significant space-time clustering was identified, with an incidence of 22.9 cases/100,000/year (95%CI 16.1-31.6), but there was no evidence of seasonality. The submerged component of the 'coeliac iceberg' may be diminishing due to increasing case ascertainment, with a projected ratio of undiagnosed to diagnosed cases as low as 1.5:1. Our identification of clustering must be interpreted with caution, but suggests that an additional environmental factor may influence the pathogenesis of CD.
 
Kidney stone disease has an estimated prevalence of around 10%. Genetic as well as environmental factors are thought to play an important role in the pathogenesis of renal stones. The aim of our study was to analyse and report the main characteristics of patients with kidney stones attending a large UK metabolic stone clinic in London between 1995 and 2012. A cross-sectional study. Analysis of data from stone formers attending the University College and Royal Free Hospitals' metabolic stone clinic from 1995 to 2012. Demographic, clinical, dietary and biochemical characteristics have been summarized and analysed for men and women separately; trends over time have also been analysed. Of the 2861 patients included in the analysis, 2016 (70%) were men with an average age of 47 years (range 18-87 years) and median duration of disease of 6 years (range 0-60 years). The prevalence of low urine volume, hypercalciuria, hyperoxaluria, hyperuricosuria and hypocitraturia was 5.6%, 38%, 7.9%, 18% and 23%, respectively. The prevalence of several risk factors for stones increased over time. The majority of stones were mixed, with around 90% composed of calcium salts in varying proportion. Our findings in a large cohort of patients attending a London-based stone clinic over the past 20 years show differences in distributions of risk factors for stones for men and women, as well as metabolic profiles and stone composition. The impact of most risk factors for stones appeared to change over time. © The Author 2014. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
 
A large cohort of rhesus-negative women in Ireland were inadvertently infected with hepatitis C virus following exposure to contaminated anti-D immunoglobulin in 1977-8. This major iatrogenic episode was discovered in 1994. We studied 36 women who had been infected after their first pregnancy, and compared them to an age- and parity-matched control group of rhesus-positive women. The presence of hepatitis C antibody was confirmed in all 36 by enzyme-linked immunosorbent assay and by recombinant immunoblot assay, while 26 (72%) of the cohort were HCV-RNA-positive (type 1b) on PCR testing. In the 20 years post-infection, all members of the study group had at least one pregnancy, and mean parity was 3.5. They had a total of 100 pregnancies and 85 of these went to term. There were four premature births, one being a twin pregnancy, and 11 spontaneous miscarriages. One miscarriage occurred in the pregnancy following HCV infection. There were two neonatal deaths due to severe congenital abnormalities in the PCR-positive women. Of the children born to HCV-RNA positive mothers, only one (2.3%) tested positive for the virus. Significant portal fibrosis on liver biopsy was confined to HCV-RNA-positive mothers apart from one single exception in the antibody-positive HCV-RNA-negative group. Comparison with the control group showed no increase in spontaneous miscarriage rate, and no significant difference in obstetric complications; birth weights were similar for the two groups.
 
To resolve whether haemoglobin A1c(HbA1c) levels in normal subjects increase with age, we measured HbA1c in 399 patients undergoing routine oral glucose tolerance test (OGTT). The OGTT results categorized the patients into 127 normal, 94 impaired glucose tolerance (IGT) and 178 diabetic. None of these groups showed a significant correlation between HbA1c and age and we cannot, therefore, see a need for age-specific reference ranges for HbA1c. Some of the confusion in the literature may have arisen from less rigorous categorization of subjects than we used, resulting in the inclusion of some individuals with IGT or diabetes in the 'normal' groups of other studies. The prevalence of such abnormality would be expected to be greater amongst older subjects, falsely suggesting a correlation between HbA1c and age, and we were able to demonstrate this with our own data when insufficiently rigorous criteria were applied for the selection of normal subjects.
 
Costs of individual treatments in 2000 
Base case cost-effectiveness estimates (£/LYG) for selected treatmets (maximum minimum values based on the uncertainty around the cost, effectiveness and DPP estimates. 
Discounted cost-effectiveness ratios for statins used as primary prevention: comparison of men and women categorized by 10-year age groups. 
Discounted cost-effectiveness ratios for all treatment scenarios, grouped by 10-year age bands 
Discounted incremental costs and benefits categorised by specific treatments 
Coronary heart disease (CHD) in the UK affects approximately 3 million people, with >100,000 deaths annually. Mortality rates have halved since the 1980s, but annual NHS treatment costs for CHD exceed 2 billion pounds. To examine the cost-effectiveness of specific CHD treatments in England and Wales. The IMPACT CHD model was used to calculate the number of life-years gained (LYG) from specific cardiological interventions from 2000 to 2010. Cost-effectiveness ratios (costs per LYG) were generated for each specific intervention, stratified by age and sex. The robustness of the results was tested using sensitivity analyses. In 2000, medical and surgical treatments together prevented or postponed approximately 25,888 deaths in CHD patients aged 25-84 years, thus generating approximately 194,929 extra life-years between 2000 and 2010 (range 143,131-260,167). Aspirin and beta-blockers for secondary prevention following myocardial infarction or revascularisation, for angina and heart failure were highly cost-effective (< 1000 pounds per LYG). Other secondary prevention therapies, including cardiac rehabilitation, ACE inhibitors and statins, were reasonably cost-effective (1957 pounds, 3398 pounds and 4246 pounds per LYG, respectively), as were CABG surgery (3239 pounds-4601 pounds per LYG) and angioplasty (3845 pounds-5889 pounds per LYG). Primary angioplasty for myocardial infarction was intermediate (6054 pounds-12,057 pounds per LYG, according to age), and statins in primary prevention were much less cost-effective (27,828 pounds per LYG, reaching 69,373 pounds per LYG in men aged 35-44). Results were relatively consistent across a wide range of sensitivity analyses. The cost-effectiveness ratios for standard CHD treatments varied by over 100-fold. Large amounts of NHS funding are being spent on relatively less cost-effective interventions, such as statins for primary prevention, angioplasty and CABG surgery. This merits debate.
 
Antiepileptic drugs are increasingly used in patients with psychiatric disorders who are at increased risk of self-harm. This might increase the likelihood that these agents are used as a means of overdose. This study was designed to examine the rate of occurrence of antiepileptic drug overdose between 2000 and 2007. A retrospective observational study examined patterns of antiepileptic drug overdose in patients admitted to the Edinburgh Poisons Unit, and compared prescription data for the corresponding region. Data were compared using chi-square trend tests. There were 18 010 admissions to the Toxicology Unit, and 613 patients ingested at least one antiepileptic drug (3.4%). The most frequently implicated were carbamazepine, sodium valproate, phenytoin and lamotrigine, which corresponded with those most commonly prescribed. Women were more likely to ingest lamotrigine than men (P < 0.0001), and less likely to ingest sodium valproate (P = 0.0234). Patients that ingested antiepileptic drugs were more likely to be admitted to hospital for >1 day (22% vs. 8%, P < 0.0001) and need transfer to a psychiatric facility (14% vs. 7%, P < 0.0001). Patients that ingested antiepileptic drugs required more intensive medical and psychiatric intervention compared to ingestion of other agents. Significant gender differences were noted in the specific antiepileptic drug ingested. Further work is required to establish whether this discrepancy may be explained by gender-based prescribing practices.
 
Background: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) can lead to end-stage renal disease in patients with renal involvement. Objective: This study evaluated the survival of AAV patients on chronic dialysis in France. Methods: Between 2002 and 2011, a total of 425 AAV patients started chronic dialysis and were registered in the Renal Epidemiology and Information Network. We analysed survival censored for renal transplantation, recovery of renal function and loss to follow-up. AAV patients were compared with 794 matched non-AAV patients on chronic dialysis. Results: A total of 166 (39%) patients with microscopic polyangiitis and 259 (61%) patients with granulomatosis with polyangiitis were registered. Within a median follow-up of 23 months, 58 (14%) patients received a renal allograft and 19 (4%) recovered renal function. Median survival on dialysis was 5.35 years (95% CI, 4.4–6.3) and survival rates at 3 months, 1, 3 and 5 years were 96%, 85%, 68% and 53%, respectively. A total of 143 (41%) patients died after a median of 16 months. Causes of death were cardiovascular (29%), infections (20%), malnutrition (13%), malignancies (4%), AAV relapse (2%), miscellaneous (14%) and unknown (18%). Multivariate logistic regression identified three independent risk factors associated with AAV patients’ mortality: age (HR = 1.05/year, P < 0.001), peripheral artery disease (HR = 2.62, P = 0.003) and frailty (HR = 2.43, P < 0.001). Survival of AAV patients did not differ from non-AAV controls, but infectious mortality was higher in AAV patients (20% vs. 8%, P < 0.001). Conclusion: Survival of AAV patients in chronic dialysis, although poor, was comparable to survival of non-AAV controls on dialysis. There was a similar burden of cardiovascular mortality, but higher infectious mortality.
 
Demographics of people with COPD on 25 February 2003 
Demographics of people with COPD on 25 February 2005 
Recorded spirometry data by age, sex, Townsend score and region 
Distribution of COPD severity by spirometry and associated mortlaity 
Prescriptions for combination inhalers by age, sex, Townsend score and region for 2003 and 2005 
The introduction of the NICE guideline on COPD and the inclusion of COPD in the new Quality and Outcomes Framework (QOF) were designed to improve the care of people with COPD in primary care in the UK. We have investigated whether these initiatives have had an impact on the prevalence of COPD, the recording of spirometry data and the use of combined inhaled corticosteroid/long-acting beta-agonist inhalers. We analysed data from The Health Improvement Network for the year before and after the introduction of the NICE guideline. Data were analysed using logistic regression. The prevalence of COPD in 2003 was 1.27%, and this increased by 14-1.45% in 2005. The risk of COPD was strongly related to age, male gender, socioeconomic disadvantage and living in the North of England, Scotland and Wales. People with COPD had an increased mortality (adjusted rate ratio for 2003 is 2.38, 95% confidence interval 2.30-2.47). The presence of recorded spirometry data in people with COPD increased from 18% in 2003 to 62% in 2005, and FEV1 was consistently a strong predictor of survival. The use of combination inhalers in people with moderate to severe COPD also increased markedly during the study. Following the introduction of the NICE guideline for COPD and the new QOF, there has been an increase in the prevalence of COPD in general practice and a large increase in spirometry data and prescriptions for combination inhalers. This represents significant progress for people with COPD.
 
OECD trends in teenage suicide. Source: OECD–Social Policy Division–Directorate of Employment, Labour and Social Affairs. CO4.4: Teenage suicide (15–19 years old) adapted from WHO (2011), WHO Mortality Database. 15 OECD-33 refers to countries of the OECD, with the exception of Turkey as there is no data available). Russia, China, Brazil and South Africa are ‘enhanced engagement OECD Countries’. There is no data available for China circa 2008. 15 
Chart CO4.1.A: falling suicide rates for most OECD countries. Source: OECD–Social Policy Division–Directorate of Employment, Labour and Social Affairs. 15 Suicides per 100 000 persons 15–19 years old, OECD-33 average from 1990 to 
Frequency of suicide and open verdicts in the UK and Ireland by age (in years) UK and Ireland, 2000–2006. Source: Malone et al . Ageing towards 21 as a risk factor for Young Adult Suicide in UK and Ireland. 23 
To review the past decade of research on teenage suicide with a particular emphasis on epidemiologic trends by age, gender, and indigenous ethnicity. A review of research literature from 2003-2014 was conducted via a comprehensive search of relevant Psychological and Medical databases. Wide gaps in our knowledge base exist concerning the true extent of teenage suicide due to lack of data, particularly in developing countries, resulting in a Western bias. The gender paradox of elevated suicidality in females with higher completed suicide rates in males is observed in teenage populations worldwide, with the notable exceptions of China and India. Native and indigenous ethnic minority teens are at significantly increased risk of suicide in comparison to general population peers. Often those with the highest need for mental health care, (such as the suicidal adolescent), have least access to therapeutic support. Globally, suicide in teenagers remains a major public health concern. Further focused research concerning completed suicides of youth under the age of 18 is required across countries and cultures to understand more about risk as children progress through adolescence. Gender and ethnic variations in suicidality are embedded within cultural, historical, psychological, relational, and socio-economic domains. Worldwide, the absence of child/adolescent-specific mental health policies, may delay the development of care and suicide prevention. It is vital that clinicians adopt a holistic approach that incorporates an awareness of age and gender influences, and that cultural competency informs tailored and evaluated intervention programmes. © The Author 2015. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
 
Patient process of care and outcome for 192 units participating in both the 2003 and 2008 National COPD clinical audits 
The 2003 UK Chronic Obstructive Pulmonary Disease (COPD) audit revealed wide variability between hospital units in care delivered. To assess whether processes of care, patient outcomes and organization of care have improved since 2003. A UK national audit was performed in 2008 to survey the organization and delivery of clinical care provided to patients admitted to hospital with COPD. All UK acute hospital Trusts (units) were invited to participate. Each unit completed cross-sectional resource and organization questionnaires and a prospective clinical audit comprising up to 60 consecutively admitted cases of COPD exacerbation. Comparison between 2003 and 2008 includes aggregated statistics for units participating in both audit rounds. A total of 192 units participated in both audit rounds (6197 admissions in 2003 and 8170 in 2008). In 2008, patients were older and of a poorer functional class. Overall mortality was unchanged but adjusting for age and performance status, inpatient mortality (P = 0.05) and 90-day mortality (P = 0.001) were both reduced in 2008. More patients were discharged under a respiratory specialist (P < 0.01), treated with non-invasive ventilation if acidotic (P < 0.001) and accepted onto early discharge schemes (P < 0.01) while median length of stay fell from 6 to 5 days (P < 0.001). Within these mean data, however, there remains considerable inter-unit variation in organization, resources and outcomes. Overall improvements in resources and organization are accompanied by reduced mortality, shorter admissions and greater access to specialist services. There remains, however, considerable variation in the quality of secondary care provided between units.
 
Admission wards for patients with acute myocardial infarction 
Numbers having cardiac arrest on cardiac care units and medical wards 44 h after admission for acute myocardial infarction 
Coronary care units were developed in the 1960s as specially equipped and staffed areas where patients with acute myocardial infarction could be monitored and offered rapid resuscitation from life-threatening arrhythmias. Awareness of the morbidity and mortality of the wider spectrum of acute coronary ischaemia was unrecognized at that time. To examine the relative frequencies with which thrombolytic treatment and resuscitation from cardiac arrest are provided for patients with myocardial infarction in cardiac care units (CCUs), emergency departments (EDs) and other medical wards. Observational study. We analysed records from the National Audit of Myocardial Infarction Project (MINAP) for 61 688 patients admitted to 230 acute hospitals in England and Wales during 2003, and who received a final diagnosis of myocardial infarction, for locations of initiation of thrombolytic therapy and of first cardiac arrest within hospital. Overall, 84% of 27 881 patients with ST-segment-elevation infarction, but only 42% of 30 382 patients with non-ST-elevation infarction, were admitted to a CCU. Of those receiving thrombolytic treatment for ST-elevation infarction, 68.3% of 21 595 did so in the ED. Within the first 4 h after arrival, the majority of episodes of cardiac arrest occurred in the ED: 709 (57%) vs. 488 (39%) in CCU, and 49 (4%) in medical wards. The traditional role of the CCU in providing early resuscitation and thrombolytic treatment for patients with ST elevation infarction has largely been devolved to the ED. The role of the CCU should be re-evaluated, and the service re-designed to provide specialist care for all presentations of acute coronary syndrome.
 
Top-cited authors
Paul Dargan
  • King's College London
Mario Amore
  • Università degli Studi di Genova
Andrea Aguglia
  • Università degli Studi di Genova
Andrea Amerio
  • Azienda Ospedaliera Universitaria San Martino di Genova
Gianluca Serafini
  • Università degli Studi di Genova