Bishop Auckland Hospital

BACKGROUND: Antibiotic-associated diarrhoea (AAD) occurs most frequently in older (≥65 years) inpatients exposed to broad-spectrum antibiotics. When caused by Clostridium difficile, AAD can result in life-threatening illness. Although underlying disease mechanisms are not well understood, microbial preparations have been assessed in the prevention of AAD. However, studies have been mostly small single-centre trials with varying quality, providing insufficient data to reliably assess effectiveness. We aimed to do a pragmatic efficacy trial in older inpatients who would be representative of those admitted to National Health Service (NHS) and similar secondary care institutions and to recruit a sufficient number of patients to generate a definitive result. METHODS: We did a multicentre, randomised, double-blind, placebo-controlled, pragmatic, efficacy trial of inpatients aged 65 years and older and exposed to one or more oral or parenteral antibiotics. A computer-generated randomisation scheme was used to allocate participants (in a 1:1 ratio) to receive either a multistrain preparation of lactobacilli and bifidobacteria, with a total of 6 × 10(10) organisms, one per day for 21 days, or an identical placebo. Patients, study staff, and specimen and data analysts were masked to assignment. The primary outcomes were occurrence of AAD within 8 weeks and C difficile diarrhoea (CDD) within 12 weeks of recruitment. Analysis was by modified intention-to-treat. This trial is registered, number ISRCTN70017204. FINDINGS: Of 17,420 patients screened, 1493 were randomly assigned to the microbial preparation group and 1488 to the placebo group. 1470 and 1471, respectively, were included in the analyses of the primary endpoints. AAD (including CDD) occurred in 159 (10·8%) participants in the microbial preparation group and 153 (10·4%) participants in the placebo group (relative risk [RR] 1·04; 95% CI 0·84-1·28; p=0·71). CDD was an uncommon cause of AAD and occurred in 12 (0·8%) participants in the microbial preparation group and 17 (1·2%) participants in the placebo group (RR 0·71; 95% CI 0·34-1·47; p=0·35). 578 (19·7%) participants had one or more serious adverse event; the frequency of serious adverse events was much the same in the two study groups and none was attributed to participation in the trial. INTERPRETATION: We identified no evidence that a multistrain preparation of lactobacilli and bifidobacteria was effective in prevention of AAD or CDD. An improved understanding of the pathophysiology of AAD is needed to guide future studies. FUNDING: Health Technology Assessment programme; National Institute for Health Research, UK.

In a 12-month prospective study incorporating four neighbouring district general hospitals, 228 patients required a total of 236 admissions with intestinal obstruction. The aetiological factors included adhesions 75 (32 per cent), malignant disease 61 (26 per cent), strangulated hernias 59 (25 per cent), volvulus 10 (4 per cent), acquired megacolon 6 (3 per cent), pseudo-obstruction 4 (2 per cent), faecal impaction 6 (3 per cent) and miscellaneous 15 (6 per cent). The peak incidence for obstruction due to adhesions, malignant disease and strangulated hernias each occurred in the eighth decade. Surgery was performed within 48 h of admission in 29 per cent adhesive obstructions (22), 30 per cent obstructions due to malignant disease (18) and 68 per cent strangulated hernias (40)--bowel resection rates in these three groups were 13.5, 50 and 29 per cent, respectively. The overall mortality was 11.4 per cent (26 deaths) and postoperative mortality was 12.3 per cent (19 deaths). During the 12-month study period, 228 patients required a total of 2993 inpatient hospital days as a result of intestinal obstruction. Postoperative adhesions have become the commonest cause of intestinal obstruction but strangulated hernias and intra-abdominal malignant disease still account for 50 per cent of all cases and mortalities. Obstruction due to strangulated hernias and intra-abdominal malignant disease typically occurs in the elderly age group where a more aggressive policy of elective surgical intervention is likely to be associated with increased postoperative morbidity and mortality.

Healthcare budgets worldwide are facing increasing pressure to reduce costs and improve efficiency, while maintaining quality. Laboratory testing has not escaped this pressure, particularly since pathology investigations cost the National Health Service £2.5 billion per year. Indeed, the Carter Review, a UK Department of Health-commissioned review of pathology services in England, estimated that 20% of this could be saved by improving pathology services, despite an average annual increase of 8%-10% in workload. One area of increasing importance is managing the demands for pathology tests and reducing inappropriate requesting. The Carter Review estimated that 25% of pathology tests were unnecessary, representing a huge potential waste. Certainly, the large variability in levels of requesting between general practitioners suggests that inappropriate requesting is widespread. Unlocking the key to this variation and implementing measures to reduce inappropriate requesting would have major implications for patients and healthcare resources alike. This article reviews the approaches to demand management. Specifically, it aims to (a) define demand management and inappropriate requesting, (b) assess the drivers for demand management, (c) examine the various approaches used, illustrating the potential of electronic requesting and (d) provide a wider context. It will cover issues, such as educational approaches, information technology opportunities and challenges, vetting, duplicate request identification and management, the role of key performance indicators, profile composition and assessment of downstream impact of inappropriate requesting. Currently, many laboratories are exploring demand management using a plethora of disparate approaches. Hence, this review seeks to provide a 'toolkit' with the view to allowing laboratories to develop a standardised demand management strategy.

Shortfin mako sharks were aged by counting growth bands in sectioned vertebrae (n = 256), and assuming annual band-pair deposition. No systematic ageing bias was present and count precision was high. 0+ juveniles were identified from length–frequency plots and assigned ages based on a theoretical birth date of 1 October and their date of capture. A Schnute generalised growth model fitted to the combined vertebral and 0+ data described the growth patterns best. Shortfin makos grow very rapidly initially, increasing by ~39 cm fork length in their first year. Thereafter, males and females grow at similar but slower rates until about age 7 years, after which the relative growth of males declines. Longevity estimates were 29 and 28 years for males and females respectively. Natural mortality (M) is probably in the range of 0.10–0.15. Median ages at maturity were 7–9 years for males and 19–21 years for females. Comparisons of growth curves reported here and elsewhere suggest no regional differences in growth rates. The shortfin mako is a late-maturing species with moderate longevity and low natural mortality. With these life history characteristics and an unknown stock size and structure worldwide, management should be of a precautionary nature.

Demand for laboratory testing is increasing disproportionately to medical activity, and the tests involved are becoming increasingly complex. When this phenomenon is seen in parallel with declining teaching of laboratory medicine in the medical curriculum, a need emerges to manage demand to avoid unnecessary expenditure and improve the use of laboratory services: 'the right test in the right patient at the right time.' Various methods have been tried to manage demand, with success depending on the medical context, type of health service and preintervention situation. Because many factors contribute to demand, and the different settings in which these exist, it is not realistic to meta-analyse the studies and we are limited to trying to identify trends in results in particular situations. The studies suggest that education combined with facilitating interventions, such as feedback, prompts and changes to laboratory request forms are the most successful. From the perspective of a whole health service, it is important that results are not exaggerated by assessing benefits in terms of total rather than marginal cost. It would be desirable, although difficult, to include the impact on downstream clinical activity caused or avoided by the interventions. Advances in information and web technology may make the elusive goal of achieving substantial demand control more achievable.

Although severe hyperkalaemia is life threatening and a medical emergency, spurious hyperkalaemia (pseudohyperkalaemia) is common in blood samples taken in primary care, often because of sampling conditions and storage and transport problems

This best practice review examines four series of common primary care questions in laboratory medicine: (i) "minor" blood platelet count and haemoglobin abnormalities; (ii) diagnosis and monitoring of anaemia caused by iron deficiency; (iii) secondary hyperlipidaemia and hypertriglyceridaemia; and (iv) glycated haemoglobin and microalbumin use in diabetes. The review is presented in question-answer format, referenced for each question series. The recommendations represent a précis of guidance found using a standardised literature search of national and international guidance notes, consensus statements, health policy documents and evidence-based medicine reviews, supplemented by Medline Embase searches to identify relevant primary research documents. They are not standards, but form a guide to be set in the clinical context. Most of the recommendations are based on consensus rather than evidence. They will be updated periodically to take account of new information.

The direct urease test was used in 462 patients with normal upper digestive tracts, 108 with duodenal ulcers and 43 with gastric ulcers who attended for upper digestive endoscopy in a prospective study. There was a strong association between Helicobacter pylori infection and current cigarette smoking in patients with normal endoscopy (49.6% vs 35.5%, P < 0.01). The associations of peptic ulcer both with H. pylori infection and cigarette smoking were also confirmed. The excess of peptic ulcer disease in cigarette smokers may be explained by their increased susceptibility to H. pylori infection.

BACKGROUND: It has been suggested that gallstone disease is now commoner, and that this might explain an increase in cholecystectomy rates, though conclusive evidence has been lacking. METHODS: All the non-forensic necropsy results for Dundee 1953-98 were examined to assess the prevalence of gallstone disease. The NHS Scotland annual cholecystectomy figures were extracted from their earliest availability in 1961 up to the present. The subgroup of patients from Dundee was analysed separately, as were laparoscopic procedures, which were recorded from 1991. RESULTS: Gallstone disease was much commoner in 1974-98 than in 1953-73. Increasing age was the main determinant of gallstone disease. Though gallstone disease was commoner in women than men aged 40-89, there was no sex difference under 40 or over 90 years. Cholecystectomy became much commoner in the 1960s when frequency of gallstone disease did not change. It increased further in the 1970s, peaking in 1977-8. There was a gradual fall in rates in the 1980s when gallstone prevalence remained high. There was a further moderate rise in the 1990s after the wide introduction of laparoscopic cholecystectomy. Cholecystectomy is now much commoner in young women and this change started in the 1960s. By contrast, cholecystectomy in men has become more prevalent in the older age group. CONCLUSIONS: Gallstones were definitely more common in both sexes at all ages over 40 in the last 25 years. Changes in the cholecystectomy rates are only partly explained by changes in gallstone prevalence, and are more determined by surgical practice.

Insulin assays are utilized in various clinical scenarios, including the assessment of insulin therapy compliance or of suspected insulin overdose. In an interpretative exercise carried out by UK National External Quality Assessment Service (NEQAS), serum sent to the participating laboratories was spiked with 30 pmol/L of the short-acting insulin analogue Human Actrapid. Only two out of 24 participant laboratories had sufficient assay cross-reactivity with Actrapid to interpret the results as suggestive of insulin administration. The development of specific insulin assays has led to deterioration in the ability to detect non-compliance or overdose with recombinant insulin treatment. Clinicians should be aware of this significant limitation, which could lead to misdiagnosis.

Several hypotheses have been put forward to explain the pathogenesis of Parkinson's disease (PD) and recently it has been suggested that alterations in iron homeostasis may be implicated. Because of the central role of the transferrin receptor in providing access of iron to cells, we have studied the distribution and density of transferrin receptors using [3H]-transferrin ([3H]-Tf) binding and tritium film autoradiography in the normal and PD midbrain. High levels of [3H]-Tf binding were found in the dorsal raphé, oculomotor nucleus and periaqueductal grey whilst lower levels of [3H]-Tf binding were found in the tegmentum, red nucleus and substantia nigra. Significant reductions in binding were found in the substantia nigra, red nucleus and oculomotor nucleus in PD, the reductions in [3H]-Tf binding being similar to the loss of nigral neurons in PD. The data suggest that the increased iron content of surviving nigral neurons may reflect a compensatory metabolic response rather than abnormal transferrin receptor expression.

Abstract The author is grateful for the attention given to his book The Resurrection of the Son of God by the four reviewers. David Bryan is right to highlight the Enoch literature as a more fertile source of resurrection ideas than the book allowed for; but he has overstated his objection. Granted that the stream of thought represented by resurrection is more diverse even than RSG allowed, the book's argument did not hinge on the wide spread of resurrection belief at the time but on the meaning of 'resurrection', i.e. a two-stage post-mortem existence, the second stage being a new embodiment. Bryan's suggested elevation of Enoch, Elijah and others as precursors of the exaltation of Jesus fails in that these figures neither die nor are resurrected. James Crossley's counter-proposal—resurrection stories grew from 'visions' which gave rise to the idea of an empty tomb as an attempt to 'vindicate' the 'ideas and beliefs of Jesus'—fails on several counts, not least because it ignores Jesus' kingdom-proclamation which was not the promulgation of ideas and beliefs but the announcement that Israel's God was going to do something that would claim his sovereignty over the world. Michael Goulder revives the highly contentious hypothesis that the early Church was polarized between the Jerusalem apostles, who believed in a non-bodily resurrection, and Pauline Christians for whom the resurrection was bodily. The claim that Mark 16.1-8 is full of contradictions and impossibilities is rejected. Larry Hurtado warns against downplaying the role of experience both in the Christian life and in describing the devotion and liturgy of the early Church. While cautioning against the use of the word 'metaphor' to mean 'less than fully real', I acknowledge the force of the argument, and suggest the cognitive processes I propose and the devotional life sketched by Hurtado are complementary.

<i>Glycation of haemoglobin to produce HbA_1c occurs throughout the 120 day average lifespan of the red blood cell. Repeat testing in less than 120 days or situations that shorten this lifespan will produce HbA_1c results that do not fully reflect current diabetic control</i>

<i>Microcytic anaemia is often assumed to indicate iron deficiency, but up to 20-30% of patients will have another diagnosis, particularly anaemia of chronic inflammation or myelodysplasia. Measurement of serum ferritin offers the best means of confirming iron deficiency, although in some cases a trial of iron may be required.</i>

AIMS: To examine whether variations in pathology test requesting between different general practices can be accounted for by sociodemographic or other descriptive indicators of the practice. METHOD: This was a comparative analysis of requesting patterns across a range of pathology tests representing 95% of those requested in general practice, in 22 general practices in a single district, serving a population of 165 000. Spearman correlation coefficients were calculated and both the top and bottom fifths of activity were displayed graphically to detect trends at the extremes of the ranges. RESULTS: The proportion of women of childbearing age, median practice Townsend scores, or the existence of specialist miniclinics within the practice did not have a demonstrable impact on requesting patterns. A weak correlation was found between the proportion of elderly patients and creatinine/electrolyte testing but not for the other two tests examined for this patient group. CONCLUSIONS: The large differences observed in general practice pathology requesting probably result mostly from individual variation in clinical practice and are therefore potentially amenable to change.

This article describes how benchmarking can be used to assess laboratory performance. Two benchmarking schemes are reviewed, the Clinical Benchmarking Company's Pathology Report and the College of American Pathologists' Q-Probes scheme. The Clinical Benchmarking Company's Pathology Report is undertaken by staff based in the clinical management unit, Keele University with appropriate input from the professional organisations within pathology. Five annual reports have now been completed. Each report is a detailed analysis of 10 areas of laboratory performance. In this review, particular attention is focused on the areas of quality, productivity, variation in clinical practice, skill mix, and working hours. The Q-Probes scheme is part of the College of American Pathologists programme in studies of quality assurance. The Q-Probes scheme and its applicability to pathology in the UK is illustrated by reviewing two recent Q-Probe studies: routine outpatient test turnaround time and outpatient test order accuracy. The Q-Probes scheme is somewhat limited by the small number of UK laboratories that have participated. In conclusion, as a result of the government's policy in the UK, benchmarking is here to stay. Benchmarking schemes described in this article are one way in which pathologists can demonstrate that they are providing a cost effective and high quality service.

CONTEXT: A diagnosis of Addison's disease means lifelong dependence on daily glucocorticoid and mineralocorticoid therapy and is associated with increased morbidity and mortality as well as a risk of unexpected adrenal crisis. OBJECTIVE: The objective of the study was to determine whether immunomodulatory therapy at an early stage of autoimmune Addison's disease could lead to preservation or improvement in adrenal steroidogenesis. DESIGN AND INTERVENTION: This was an open-label, pilot study of B lymphocyte depletion therapy in new-onset idiopathic primary adrenal failure. Doses of iv rituximab (1 g) were given on d 1 and 15, after pretreatment with 125 mg iv methylprednisolone. PATIENTS AND MAIN OUTCOME MEASURES: Six patients (aged 17-47 yr; four females) were treated within 4 wk of the first diagnosis of idiopathic primary adrenal failure. Dynamic testing of adrenal function was performed every 3 months for at least 12 months. RESULTS: Serum cortisol levels declined rapidly and were less than 100 nmol/liter (3.6 μg/dl) in all patients by 3 months after B lymphocyte depletion. Serum cortisol and aldosterone concentrations remained low in five of the six patients throughout the follow-up period. However, a single patient had sustained improvement in both serum cortisol [peak 434 nmol/liter (15.7 μg/dl)] and aldosterone [peak 434 pmol/liter (15.7 ng/dl)] secretion. This patient was able to discontinue steroid medications 15 months after therapy and remains well, with improving serum cortisol levels 27 months after therapy. CONCLUSION: New-onset autoimmune Addison's disease should be considered as a potentially reversible condition in some patients. Future studies of immunomodulation in autoimmune Addison's disease may be warranted.

BACKGROUND: Direct (non-extracted) testosterone immunoassays may give spuriously high results in women. The presumed interferents may be removed if testosterone is extracted into an organic phase before being measured. We aimed to clarify possible causes and effects of interference in testosterone measurement in women. METHODS: Women who had a blood sample referred to Hope Hospital Clinical Biochemistry laboratory for measurement of serum testosterone concentration over a six-month period were studied. Clinical and treatment data were recorded. A difference (direct-minus-extracted testosterone) of less than 1.0 nmol/L was used to define a group with low interference. A difference of 2.5 nmol/L or more was used to define a group with significant interference. RESULTS: The distribution of interference in 1271 serum samples from female patients was unimodal. There were no group differences in clinical presentation or treatment. The median degree of interference was 1.4 nmol/L. In 42 female patients with varying degrees of interference, identified on routine assay, regression analysis showed strong association between dehydroepiandrosterone sulphate (DHEA-S) and interference (direct-minus-extracted testosterone) (r = 0.77, P < 0.001). CONCLUSIONS: Given that DHEA-S is present in very variable amounts in blood, it is possible that even with a low cross reactivity, DHEA-S or one of its metabolites significantly interferes in the testosterone assay when at higher concentrations.

Pathology has struggled to define and implement changes to improve requesting practices, yet, with the increasing transfer of care from secondary to primary care, our workloads are increasing out of proportion to health care activity. Conversely, some tests appear to be considerably under-used by some general practitioners. Aspects of service reconfiguration such as rationalization of low-volume testing and joint equipment and reagent procurement may release some savings, although any such financial benefits are likely to be quickly nullified by the continued rise in activity and do not contribute to quality of test use. With very large differences between general practices in their use of pathology tests, this review looks at methods for changing pathology requesting activity and calls for involvement from professional organizations to support such initiatives.

Although guidance exists for the use of many laboratory tests in a wide range of clinical situations, this guidance is spread among a range of literature sources, and is often directed at laboratory specialists rather than test users. Individual general practices display large variations in standardised test requesting, yet much of their testing activity involves a relatively small range of tests. This paper describes a methodological approach to review the available evidence and guidance and to extract relevant primary research work to examine a range of testing scenarios in general practice, with the aim of formulating guidance based on the best available evidence or consensus opinions.