An ovine hepatorenal fibrocystic model of a Meckel-like syndrome associated with dysmorphic primary cilia and TMEM67 mutations.

Meckel syndrome (MKS) is an inherited autosomal recessive hepatorenal fibrocystic syndrome, caused by mutations in TMEM67, characterized by occipital encephalocoele, renal cysts, hepatic fibrosis, and polydactyly. Here we describe an ovine model of MKS, with kidney and liver abnormalities, without polydactyly or occipital encephalocoele. Homozygous missense p.(Ile681Asn; Ile687Ser) mutations identified in ovine TMEM67 were pathogenic in zebrafish phenotype rescue assays. Meckelin protein was expressed in affected and unaffected kidney epithelial cells by immunoblotting, and in primary cilia of lamb kidney cyst epithelial cells by immunofluorescence. In contrast to primary cilia of relatively consistent length and morphology in unaffected kidney cells, those of affected cyst-lining cells displayed a range of short and extremely long cilia, as well as abnormal morphologies, such as bulbous regions along the axoneme. Putative cilia fragments were also consistently located within the cyst luminal contents. The abnormal ciliary phenotype was further confirmed in cultured interstitial fibroblasts from affected kidneys. These primary cilia dysmorphologies and length control defects were significantly greater in affected cells compared to unaffected controls. In conclusion, we describe abnormalities involving primary cilia length and morphology in the first reported example of a large animal model of MKS, in which we have identified TMEM67 mutations.

Predicting perioperative mortality after oesophagectomy: a systematic review of performance and methods of multivariate models.

Predicting risk of perioperative mortality after oesophagectomy for cancer may assist patients to make treatment choices and allow balanced comparison of providers. The aim of this systematic review of multivariate prediction models is to report their performance in new patients, and compare study methods against current recommendations. We used PRISMA guidelines and searched Medline, Embase, and standard texts from 1990 to 2012. Inclusion criteria were English language articles reporting development and validation of prediction models of perioperative mortality after open oesophagectomy. Two reviewers screened articles and extracted data for methods, results, and potential biases. We identified 11 development, 10 external validation, and two clinical impact studies. Overestimation of predicted mortality was common (5-200% error), discrimination was poor to moderate (area under receiver operator curves ranged from 0.58 to 0.78), and reporting of potential bias was poor. There were potentially important case mix differences between modelling and validation samples, and sample sizes were considerably smaller than is currently recommended. Steyerberg and colleagues' model used the most 'transportable' predictors and was validated in the largest sample. Most models have not been adequately validated and reported performance has been unsatisfactory. There is a need to clarify definition, effect size, and selection of currently available candidate predictors for inclusion in prediction models, and to identify new ones strongly associated with outcome. Adoption of prediction models into practice requires further development and validation in well-designed large sample prospective studies.

Biallelic DICER1 mutations occur in Wilms tumours.

DICER1 is an endoribonuclease central to the generation of microRNAs (miRNAs) and short interfering RNAs (siRNAs). Germline mutations in DICER1 have been associated with a pleiotropic tumour predisposition syndrome and Wilms tumour (WT) is a rare manifestation of this syndrome. Three WTs, each in a child with a deleterious germline DICER1 mutation, were screened for somatic DICER1 mutations and were found to bear specific mutations in either the RNase IIIa (n = 1) or the RNase IIIb domain (n = 2). In the two latter cases, we demonstrate that the germline and somatic DICER1 mutations were in trans, suggesting that the two-hit hypothesis of tumour formation applies for these examples of WT. Among 191 apparently sporadic WTs, we identified five different missense or deletion somatic DICER1 mutations (2.6%) in four individual WTs; one tumour had two very likely deleterious somatic mutations in trans in the RNase IIIb domain (c.5438A>G and c.5452G>A). In vitro studies of two somatic single-base substitutions (c.5429A>G and c.5438A>G) demonstrated exon 25 skipping from the transcript, a phenomenon not previously reported in DICER1. Further we show that DICER1 transcripts lacking exon 25 can be translated in vitro. This study has demonstrated that a subset of WTs exhibits two 'hits' in DICER1, suggesting that these mutations could be key events in the pathogenesis of these tumours.

PAX2 is an antiapoptotic molecule with deregulated expression in medulloblastoma.

PAX2 is a paired box transcription factor possessing a fundamental role in the embryogenesis of hindbrain and urinary tract. PAX genes are proto-oncogenes, PAX2 expression may contribute to the pathogenesis of renal cell carcinoma. Because of the expression of PAX2 in the developing hindbrain and its essential role in cerebellar development, it has been hypothesized that PAX2 may also be involved in medulloblastoma tumorigenesis. We investigated the expression pattern of PAX2 and various genes of the neuronal lineage in medulloblastoma and glioma cell lines. We found high expression of PAX2 mRNA and PAX2 protein in medulloblastoma cells and some glioma cell lines independent of their neuronal lineage gene expression signature. Gene suppression of PAX2 decreased the expression of the PAX2 transcriptional target GDNF in Daoy cells and had a profound cytotoxic effect in vitro on Daoy medulloblastoma and T98G glioma cells. Expression of PAX2 was then assessed in two separate medulloblastoma tissue microarrays with a total of 61 patient samples by immunohistochemistry. PAX2 expression was detected in the majority of medulloblastoma samples and correlated with less differentiated histology. Therefore, PAX2 is a biomarker for a more aggressive medulloblastoma phenotype and may represent a novel therapeutic target.

Impact of CONSORT extension for cluster randomised trials on quality of reporting and study methodology: review of random sample of 300 trials, 2000-8.

OBJECTIVE: To assess the impact of the 2004 extension of the CONSORT guidelines on the reporting and methodological quality of cluster randomised trials. DESIGN: Methodological review of 300 randomly sampled cluster randomised trials. Two reviewers independently abstracted 14 criteria related to quality of reporting and four methodological criteria specific to cluster randomised trials. We compared manuscripts published before CONSORT (2000-4) with those published after CONSORT (2005-8). We also investigated differences by journal impact factor, type of journal, and trial setting. DATA SOURCES: A validated Medline search strategy. Eligibility criteria for selecting studies Cluster randomised trials published in English language journals, 2000-8. RESULTS: There were significant improvements in five of 14 reporting criteria: identification as cluster randomised; justification for cluster randomisation; reporting whether outcome assessments were blind; reporting the number of clusters randomised; and reporting the number of clusters lost to follow-up. No significant improvements were found in adherence to methodological criteria. Trials conducted in clinical rather than non-clinical settings and studies published in medical journals with higher impact factor or general medical journals were more likely to adhere to recommended reporting and methodological criteria overall, but there was no evidence that improvements after publication of the CONSORT extension for cluster trials were more likely in trials conducted in clinical settings nor in trials published in either general medical journals or in higher impact factor journals. CONCLUSION: The quality of reporting of cluster randomised trials improved in only a few aspects since the publication of the extension of CONSORT for cluster randomised trials, and no improvements at all were observed in essential methodological features. Overall, the adherence to reporting and methodological guidelines for cluster randomised trials remains suboptimal, and further efforts are needed to improve both reporting and methodology.

PAX8 promotes tumor cell growth by transcriptionally regulating E2F1 and stabilizing RB protein.

The retinoblastoma protein (RB)-E2F1 pathway has a central role in regulating the cell cycle. Several PAX proteins (tissue-specific developmental regulators), including PAX8, interact with the RB protein, and thus regulate the cell cycle directly or indirectly. Here, we report that PAX8 expression is frequent in renal cell carcinoma, bladder, ovarian and thyroid cancer cell lines, and that silencing of PAX8 in cancer cell lines leads to a striking reduction in the expression of E2F1 and its target genes, as well as a proteasome-dependent destabilization of RB protein, with the RB1 mRNA level remaining unaffected. Cancer cells expressing PAX8 undergo a G(1)/S arrest and eventually senesce following PAX8 silencing. We demonstrate that PAX8 transcriptionally regulates the E2F1 promoter directly, and E2F1 transcription is enhanced after RB depletion. RB is recruited to the PAX8-binding site, and is involved in PAX8-mediated E2F1 transcription in cancer cells. Therefore, our results suggest that, in cancer, frequent and persistent expression of PAX8 is required for cell growth control through transcriptional activation of E2F1 expression and upregulation of the RB-E2F1 pathway.

North of England and Scotland Study of Tonsillectomy and Adeno-tonsillectomy in Children(NESSTAC): a pragmatic randomised controlled trial with a parallel non-randomised preference study.

OBJECTIVES: To examine the clinical effectiveness and cost-effectiveness of tonsillectomy/adeno-tonsillectomy in children aged 4-15 years with recurrent sore throats in comparison with standard non-surgical management. DESIGN: A pragmatic randomised controlled trial with economic analysis comparing surgical intervention with conventional medical treatment in children with recurrent sore throats (trial) and a parallel non-randomised cohort study (cohort study). SETTING: Five secondary care otolaryngology departments located in the north of England or west of Scotland. PARTICIPANTS: 268 (trial: 131 allocated to surgical management; 137 allocated to medical management) and 461 (cohort study: 387 elected to have surgical management; 74 elected to have medical management) children aged between 4 and 15 years on their last birthday with recurrent sore throats. Participants were stratified by age (4-7 years, 8-11 years, 12-15 years). INTERVENTIONS: Treatment was tonsillectomy and adeno-tonsillectomy with adenoid curettage and tonsillectomy by dissection or bipolar diathermy according to surgical preference within 12 weeks of randomisation. The control was non-surgical conventional medical treatment only. MAIN OUTCOME MEASURES: The primary clinical outcome was the reported number of episodes of sore throat in the 2 years after entry into the study. Secondary clinical outcomes included: the reported number of episodes of sore throat; number of sore throat-related GP consultations; reported number of symptom-free days; reported severity of sore throats; and surgical and anaesthetic morbidity. In addition to the measurement of these clinical outcomes, the impact of the treatment on costs and quality of life was assessed. RESULTS: Of the 1546 children assessed for eligibility, 817 were excluded (531 not meeting inclusion criteria, 286 refused) and 729 enrolled to the trial (268) or cohort study (461). The mean (standard deviation) episode of sore throats per month was in year 1 - cohort medical 0.59 (0.44), cohort surgical 0.71 (0.50), trial medical 0.64 (0.49), trial surgical 0.50 (0.43); and in year 2 - cohort medical 0.38 (0.34), cohort surgical 0.19 (0.36), trial medical 0.33 (0.43), trial surgical 0.13 (0.21). During both years of follow-up, children randomised to surgical management were less likely to record episodes of sore throat than those randomised to medical management; the incidence rate ratios in years 1 and 2 were 0.70 [95% confidence interval (CI) 0.61 to 0.80] and 0.54 (95% CI 0.42 to 0.70) respectively. The incremental cost-effectiveness ratio was estimated as 261 pounds per sore throat avoided (95% confidence interval 161 pounds to 586 pounds). Parents were willing to pay for the successful treatment of their child's recurrent sore throat (mean 8059 pounds). The estimated incremental cost per quality-adjusted life-year (QALY) ranged from 3129 pounds to 6904 pounds per QALY gained. CONCLUSIONS: Children and parents exhibited strong preferences for the surgical management of recurrent sore throats. The health of all children with recurrent sore throat improves over time, but trial participants randomised to surgical management tended to experience better outcomes than those randomised to medical management. The limitations of the study due to poor response at follow-up support the continuing careful use of 'watchful waiting' and medical management in both primary and secondary care in line with current clinical guidelines until clear-cut evidence of clinical effectiveness and cost-effectiveness is available. TRIAL REGISTRATION: Current Controlled Trials ISRCTN47891548.

When and how to update systematic reviews.

BACKGROUND: Systematic reviews are most helpful if they are up-to-date. We did a systematic review of strategies and methods describing when and how to update systematic reviews. OBJECTIVES: To identify, describe and assess strategies and methods addressing: 1) when to update systematic reviews and 2) how to update systematic reviews. SEARCH STRATEGY: We searched MEDLINE (1966 to December 2005), PsycINFO, the Cochrane Methodology Register (Issue 1, 2006), and hand searched the 2005 Cochrane Colloquium proceedings. SELECTION CRITERIA: We included methodology reports, updated systematic reviews, commentaries, editorials, or other short reports describing the development, use, or comparison of strategies and methods for determining the need for updating or updating systematic reviews in healthcare. DATA COLLECTION AND ANALYSIS: We abstracted information from each included report using a 15-item questionnaire. The strategies and methods for updating systematic reviews were assessed and compared descriptively with respect to their usefulness, comprehensiveness, advantages, and disadvantages. MAIN RESULTS: Four updating strategies, one technique, and two statistical methods were identified. Three strategies addressed steps for updating and one strategy presented a model for assessing the need to update. One technique discussed the use of the "entry date" field in bibliographic searching. Statistical methods were cumulative meta-analysis and predicting when meta-analyses are outdated. AUTHORS' CONCLUSIONS: Little research has been conducted on when and how to update systematic reviews and the feasibility and efficiency of the identified approaches is uncertain. These shortcomings should be addressed in future research.

WITHDRAWN: Selective serotonin reuptake inhibitors (SSRIs) versus other antidepressants for depression.

BACKGROUND: The relatively new class of antidepressant, the selective serotonin reputake inhibitors (SSRIs), may be better tolerated than the older tricyclic antidepressants. This review compares the efficacy of SSRIs with other antidepressants. OBJECTIVES: To examine the relative efficacy of selective serotonin reuptake inhibitors (SSRIs) compared to other antidepressants. SEARCH STRATEGY: The search strategy included a search of (a) Electronic bibliographic databases (MEDLINE, EMBASE); (b) reference lists of related reviews (c) reference lists of all located studies (d) contact with the manufacturer and (e) the Cochrane Group register of controlled trials SELECTION CRITERIA: Randomised controlled trials comparing selective serotonin reuptake inhibitors with other kinds of antidepressants in the treatment of patients with depressive disorders. The outcome measures assessed included measures of the severity of depression. DATA COLLECTION AND ANALYSIS: Data were collected from each study the main outcome measurefrom each study. These included: mean Hamilton depression rating scale, mean Montgomery & Asberg depression rating scale, Clinical Global Impression rating scale. An analysis of standardised mean difference of these scales was performed using Review Manager 3.1 software. The presence of heterogeneity of treatment effect was assessed MAIN RESULTS: Ninety-eight trials contributed data to the analysis of the relative efficacy of SSRIs and related drugs with comparator antidepressants (Figure 3 & Appendix 3). Analysis of efficacy was based upon 5044 patients treated with an SSRI or related drug, and 4510 treated with an alternative antidepressant. The standardised effect size for SSRIs and related drugs together versus alternative antidepressants using a fixed effects model was 0.035 (95% CI -0.006 to 0.076; Q = 149.25, df = 97, p < 0.001). AUTHORS' CONCLUSIONS: There are no clinically significant differences in effectiveness between selective serotonin reuptake inhibitors and tricyclic antidepressants. Treatment decisions need to be based on considerations of relative patient acceptability, toxicity and cost.

WITHDRAWN: Treatment discontinuation with selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants (TCAs).

BACKGROUND: Selective serotonin reuptake inhibitors are thought to have better discontinuation rates (i.e. less people dropping out) than tricyclic and heterocyclic antidepressant drugs. It is important to quantify the drop-out rates of different antidepressant drugs in order to have a better understanding of the relative tolerability of these drugs. OBJECTIVES: To assess the comparative tolerability of selective serotonin reuptake inhibitors and tricyclic/heterocyclic antidepressant drugs. SEARCH STRATEGY: We searched the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Registers (1997 to 1999), MEDLINE (1966 to 1999), EMBASE (1974 to 1999) We also searched specialist journals, the reference lists of relevant papers and previous systematic reviews, conference abstracts and government documents. Representatives of the pharmaceutical industry were contacted. SELECTION CRITERIA: Parallel group randomised controlled trials comparing selective serotonin reuptake inhibitors with tricyclic or heterocyclic antidepressants in people with depression. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and a third reviewer checked any cases of disagreement. MAIN RESULTS: We included 136 trials. The selective serotonin reuptake inhibitors showed less participants dropping out compared to the tricyclic/heterocyclic group (odds ratio 1.21, 95% confidence interval 1.12 to 1.30). A statistically significant difference was found in total drop-outs between the selective serotonin reuptake inhibitors and the old tricyclics as well as the newer tricyclics. When the selective serotonin reuptake inhibitors were compared to the heterocyclic antidepressants, there was a non significant difference favouring the selective serotonin reuptake inhibitors. The poor tolerability profile of the old tricyclics was explained by differences in drop-outs for side-effects, but not for inefficacy. AUTHORS' CONCLUSIONS: Whilst selective serotonin reuptake inhibitors do appear to show an advantage over tricyclic drugs in terms of total drop-outs, this advantage is relatively modest. This has implications for pharmaco-economic models, some of which may have overestimated the difference of drop-out rates between selective serotonin reuptake inhibitors and tricyclic antidepressants. These results are based on short-term randomised controlled trials, and may not generalise into clinical practice.

Qualitative methods in a randomised controlled trial: the role of an integrated qualitative process evaluation in providing evidence to discontinue the intervention in one arm of a trial of a decision support tool.

OBJECTIVE: To understand participants' experiences and understandings of the interventions in the trial of a computerised decision support tool in patients with atrial fibrillation being considered for anti-coagulation treatment. DESIGN: Qualitative process evaluation carried out alongside the trial: non-participant observation and semistructured interviews. PARTICIPANTS: 30 participants aged >60 years taking part in the trial of a computerised decision support tool. RESULTS: Qualitative evidence provided the rationale to undertake a decision to discontinue one arm of the trial on the basis that the intervention in that arm, a standard gamble values elicitation exercise was causing confusion and was unlikely to produce valid data on participant values. CONCLUSIONS: Qualitative methods used alongside a trial allow an understanding of the process and progress of a trial, and provide evidence to intervene in the trial if necessary, including evidence for the rationale to discontinue an intervention arm of the trial.

PAX2 inactivation enhances cisplatin-induced apoptosis in renal carcinoma cells.

Renal cell carcinoma (RCC) is the most common kidney malignancy and has a poor prognosis owing to its resistance to chemotherapy. RCC cells overexpress the transcription factor, PAX2, normally expressed in fetal kidney but downregulated at birth. Since Pax2 suppresses apoptosis during renal development, we reasoned that PAX2 may confer resistance to cisplatin-induced apoptosis in RCC. Here, we show that PAX2 confers resistance to cisplatin-induced apoptosis in normal kidney cells and fetal kidney explants. Human embryonic kidney 293 cells transfected with a PAX2 expression vector and exposed to cisplatin (40 microM) exhibited 45 +/- 15% as much caspase-3 cleavage compared to control cells. Conversely, murine collecting duct cells stably transfected with PAX2 antisense cDNA had twofold increase in cisplatin-induced apoptosis. Murine fetal (embryonic day 15) kidney explants from PAX2(1Neu)+/- mice exposed to cisplatin (25 microM x 24 h) had 50% increased apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling staining). We then show that RCC cells (CAKI-1 (human, Caucasian, kidney, carcinoma) and ACHN (human, Caucasian, kidney, adenocarcinoma)) express PAX2 protein. PAX2-small interfering RNA (100 nM) reduces endogenous PAX2 protein (10% of baseline) and induces apoptosis (Annexin-V staining). Pax2 knockdown sensitized RCC cells to cisplatin-induced apoptosis, killing 50-60% of cisplatin-resistant ACHN and CAKI-1 cells. These findings suggest that PAX2 confers resistance to cisplatin-induced apoptosis in non-transformed kidney cells and fetal kidney explants. Similarly, Pax2 overexpression in RCC cells contributes to cisplatin resistance. Conceivably, a therapeutic strategy that inactivates Pax2 in vivo might enhance the efficacy of conventional cytotoxic drugs against RCC.

Congenital polycystic kidney disease in lambs.

AIM: To describe the pathology and inheritance of a congenital polycystic kidney disease (PKD) of sheep. METHODS: Mode of inheritance of PKD was investigated by evaluation of results of the disorder from planned matings in two consecutive years within subsets of a flock that had a high prevalence of PKD in lambs. Gross pathological and histopathological studies were based on tissues derived from this study. Haematoxylin and eosin (H&E)-stained paraffin sections of kidney, liver, extrahepatic biliary and pancreatic ducts, pancreas and epididymis were used to describe the lesions. RESULTS: Twenty-five lambs affected by PKD, of both sexes, were born, numbers in accord with those expected for an autosomal recessive disorder in the population studied. In all cases for which tissues were available, the renal, bile ductal (intrahepatic and extrahepatic), pancreatic and epididymal tissues had widespread dysplastic changes and associated cyst formation. CONCLUSIONS: The findings of renal cysts in conjunction with cysts in other organs are unifying features in many of the human and animal forms of PKD and suggest a related pathogenic and genetic base consistent with an autosomal recessive disorder.

What do we know about how to do audit and feedback? Pitfalls in applying evidence from a systematic review.

BACKGROUND: Improving the quality of health care requires a range of evidence-based activities. Audit and feedback is commonly used as a quality improvement tool in the UK National Health Service [NHS]. We set out to assess whether current guidance and systematic review evidence can sufficiently inform practical decisions about how to use audit and feedback to improve quality of care. METHODS: We selected an important chronic disease encountered in primary care: diabetes mellitus. We identified recommendations from National Institute for Clinical Excellence (NICE) guidance on conducting audit and generated questions which would be relevant to any attempt to operationalise audit and feedback in a healthcare service setting. We explored the extent to which a systematic review of audit and feedback could provide practical guidance about whether audit and feedback should be used to improve quality of diabetes care and, if so, how audit and feedback could be optimised. RESULTS: National guidance suggests the importance of securing the right organisational conditions and processes. Review evidence suggests that audit and feedback can be effective in changing healthcare professional practice. However, the available evidence says relatively little about the detail of how to use audit and feedback most efficiently. CONCLUSION: Audit and feedback will continue to be an unreliable approach to quality improvement until we learn how and when it works best. Conceptualising audit and feedback within a theoretical framework offers a way forward.

Effectiveness and efficiency of guideline dissemination and implementation strategies.

OBJECTIVES: To undertake a systematic review of the effectiveness and costs of different guideline development, dissemination and implementation strategies. To estimate the resource implications of these strategies. To develop a framework for deciding when it is efficient to develop and introduce clinical guidelines. DATA SOURCES: MEDLINE, Healthstar, Cochrane Controlled Trial Register, EMBASE, SIGLE and the specialised register of the Cochrane Effective Practice and Organisation of Care (EPOC) group. REVIEW METHODS: Single estimates of dichotomous process variables were derived for each study comparison based upon the primary end-point or the median measure across several reported end-points. Separate analyses were undertaken for comparisons of different types of intervention. The study also explored whether the effects of multifaceted interventions increased with the number of intervention components. Studies reporting economic data were also critically appraised. A survey to estimate the feasibility and likely resource requirements of guideline dissemination and implementation strategies in UK settings was carried out with key informants from primary and secondary care. RESULTS: In total, 235 studies reporting 309 comparisons met the inclusion criteria; of these 73% of comparisons evaluated multifaceted interventions, although the maximum number of replications of a specific multifaceted intervention was 11 comparisons. Overall, the majority of comparisons reporting dichotomous process data observed improvements in care; however, there was considerable variation in the observed effects both within and across interventions. Commonly evaluated single interventions were reminders, dissemination of educational materials, and audit and feedback. There were 23 comparisons of multifaceted interventions involving educational outreach. The majority of interventions observed modest to moderate improvements in care. No relationship was found between the number of component interventions and the effects of multifaceted interventions. Only 29.4% of comparisons reported any economic data. The majority of studies only reported costs of treatment; only 25 studies reported data on the costs of guideline development or guideline dissemination and implementation. The majority of studies used process measures for their primary end-point, despite the fact that only three guidelines were explicitly evidence based (and may not have been efficient). Respondents to the key informant survey rarely identified existing budgets to support guideline dissemination and implementation strategies. In general, the respondents thought that only dissemination of educational materials and short (lunchtime) educational meetings were generally feasible within current resources. CONCLUSIONS: There is an imperfect evidence base to support decisions about which guideline dissemination and implementation strategies are likely to be efficient under different circumstances. Decision makers need to use considerable judgement about how best to use the limited resources they have for clinical governance and related activities to maximise population benefits. They need to consider the potential clinical areas for clinical effectiveness activities, the likely benefits and costs required to introduce guidelines and the likely benefits and costs as a result of any changes in provider behaviour. Further research is required to: develop and validate a coherent theoretical framework of health professional and organisational behaviour and behaviour change to inform better the choice of interventions in research and service settings, and to estimate the efficiency of dissemination and implementation strategies in the presence of different barriers and effect modifiers.

Leptospirosis in febrile men ingesting Agouti paca in South America.

To explore the relationship between the ingestion of Agouti paca (AP) and human leptospirosis in Guyana, 19 febrile men who said they had hunted and eaten A. paca were screened for malaria, using bloodsmears, and for leptospirosis, using an enzyme immuno-assay that detects Leptospira -specific IgM. Those found positive for anti-Leptospira IgM were then evaluated further, with a microscopical agglutination test based on a limited panel of serovars from three pathogenic species of Leptospira. Although six of the 18 patients who provided suitable samples for the serology were found seropositive for acute leptospirosis, only three of the 19 patients were found smear-positive for malaria. A clinical-decision model, based on medical histories, the results of physical examinations, and the use of routine urine dipsticks, and enabling prediction of the serological results, was developed. This model, which had 83% sensitivity and 100% specificity for leptospirosis, indicated that, in the absence of serology, most febrile patients reporting AP ingestion could be correctly treated if each was checked for malaria using traditional bloodsmears. The smear-positives should be treated with antimalarial drugs whereas the smear-negatives should be treated for leptospirosis if they had any of the following: a skin rash; lymphadenopathy; abnormal urine sediment (proteinuria or haematuria); and/or no previous history of malaria. In the present study, the relative risk of leptospirosis among the patients who were smear-negative for malaria and fulfilled at least one of these four criteria was 13 (P = 0.0007). In Guyana at least, leptospirosis appears to be common among men who hunt, prepare and ingest AP. Vaccines may be the best, practical form of protection among such men.

Assessing the long-term effect of educational reminder messages on primary care radiology referrals.

AIM: To investigate whether the effect of educational reminder messages for knee and lumbar spine radiographs varied over a 12 month period. MATERIALS AND METHODS: In a previous randomized, controlled trial, educational reminder messages attached to x-ray reports were shown to be effective in reducing the number of radiograph requests by general practitioners for knee and lumbar spine radiographs. In this study, all radiology departments from the previous trial were asked for monthly referral records for the 12 month intervention period for knee and lumbar spine radiographs for each general practice. Poisson regression was used to test for a change over time in the number of referrals between control and intervention practices. RESULTS: Data were obtained for 66% of the general practices in the main trial. The number of referrals for both knee and lumbar spine radiographs remained consistently and statistically significantly lower in the educational reminder messages group compared with the control group (relative risk=0.65 and 0.64, respectively). There was no evidence that this difference increased or decreased throughout the 12 month period. CONCLUSIONS: The effect of educational reminder messages was produced as soon as the intervention was delivered and maintained throughout the intervention period. There was no evidence of the effect of the intervention wearing off.