Differences in 5'untranslated regions highlight the importance of translational regulation of dosage sensitive genes.

BACKGROUND: Untranslated regions (UTRs) are important mediators of post-transcriptional regulation. The length of UTRs and the composition of regulatory elements within them are known to vary substantially across genes, but little is known about the reasons for this variation in humans. Here, we set out to determine whether this variation, specifically in 5'UTRs, correlates with gene dosage sensitivity. RESULTS: We investigate 5'UTR length, the number of alternative transcription start sites, the potential for alternative splicing, the number and type of upstream open reading frames (uORFs) and the propensity of 5'UTRs to form secondary structures. We explore how these elements vary by gene tolerance to loss-of-function (LoF; using the LOEUF metric), and in genes where changes in dosage are known to cause disease. We show that LOEUF correlates with 5'UTR length and complexity. Genes that are most intolerant to LoF have longer 5'UTRs, greater TSS diversity, and more upstream regulatory elements than their LoF tolerant counterparts. We show that these differences are evident in disease gene-sets, but not in recessive developmental disorder genes where LoF of a single allele is tolerated. CONCLUSIONS: Our results confirm the importance of post-transcriptional regulation through 5'UTRs in tight regulation of mRNA and protein levels, particularly for genes where changes in dosage are deleterious and lead to disease. Finally, to support gene-based investigation we release a web-based browser tool, VuTR, that supports exploration of the composition of individual 5'UTRs and the impact of genetic variation within them.

Systematic identification of disease-causing promoter and untranslated region variants in 8,040 undiagnosed individuals with rare disease.

Background: Both promoters and untranslated regions (UTRs) have critical regulatory roles, yet variants in these regions are largely excluded from clinical genetic testing due to difficulty in interpreting pathogenicity. The extent to which these regions may harbour diagnoses for individuals with rare disease is currently unknown. Methods: We present a framework for the identification and annotation of potentially deleterious proximal promoter and UTR variants in known dominant disease genes. We use this framework to annotate de novo variants (DNVs) in 8,040 undiagnosed individuals in the Genomics England 100,000 genomes project, which were subject to strict region-based filtering, clinical review, and validation studies where possible. In addition, we performed region and variant annotation-based burden testing in 7,862 unrelated probands against matched unaffected controls. Results: We prioritised eleven DNVs and identified an additional variant overlapping one of the eleven. Ten of these twelve variants (82%) are in genes that are a strong match to the individual's phenotype and six had not previously been identified. Through burden testing, we did not observe a significant enrichment of potentially deleterious promoter and/or UTR variants in individuals with rare disease collectively across any of our region or variant annotations. Conclusions: Overall, we demonstrate the value of screening promoters and UTRs to uncover additional diagnoses for previously undiagnosed individuals with rare disease and provide a framework for doing so without dramatically increasing interpretation burden.

Syncope and profound bradycardia associated with intrauterine contraceptive procedures.

There has been recent interest in this Journal concerning the occurrence of profound bradycardia with impaired consciousness during insertion of intrauterine contraceptive devices or systems. Questions have been raised regarding the requirement for medication for reversal of the condition, the role of the nurse practitioner in the light of this, and the effects upon sexual and reproductive health care service delivery. We present three cases where this condition affected patients under our care and suggest that although very infrequent, it is important. Medication for treatment and staff trained to administer it should always be available.

Competency-based medical education: theory to practice.

Although competency-based medical education (CBME) has attracted renewed interest in recent years among educators and policy-makers in the health care professions, there is little agreement on many aspects of this paradigm. We convened a unique partnership - the International CBME Collaborators - to examine conceptual issues and current debates in CBME. We engaged in a multi-stage group process and held a consensus conference with the aim of reviewing the scholarly literature of competency-based medical education, identifying controversies in need of clarification, proposing definitions and concepts that could be useful to educators across many jurisdictions, and exploring future directions for this approach to preparing health professionals. In this paper, we describe the evolution of CBME from the outcomes movement in the 20th century to a renewed approach that, focused on accountability and curricular outcomes and organized around competencies, promotes greater learner-centredness and de-emphasizes time-based curricular design. In this paradigm, competence and related terms are redefined to emphasize their multi-dimensional, dynamic, developmental, and contextual nature. CBME therefore has significant implications for the planning of medical curricula and will have an important impact in reshaping the enterprise of medical education. We elaborate on this emerging CBME approach and its related concepts, and invite medical educators everywhere to enter into further dialogue about the promise and the potential perils of competency-based medical curricula for the 21st century.

Competency-based medical education: implications for undergraduate programs.

Changes in educational thinking and in medical program accreditation provide an opportunity to reconsider approaches to undergraduate medical education. Current developments in competency-based medical education (CBME), in particular, present both possibilities and challenges for undergraduate programs. CBME does not specify particular learning strategies or formats, but rather provides a clear description of intended outcomes. This approach has the potential to yield authentic curricula for medical practice and to provide a seamless linkage between all stages of lifelong learning. At the same time, the implementation of CBME in undergraduate education poses challenges for curriculum design, student assessment practices, teacher preparation, and systemic institutional change, all of which have implications for student learning. Some of the challenges of CBME are similar to those that can arise in the implementation of any integrated program, while others are specific to the adoption of outcome frameworks as an organizing principle for curriculum design. This article reviews a number of issues raised by CBME in the context of undergraduate programs and provides examples of best practices that might help to address these issues.

Identifying the policy implications of competency-based education.

At their 2009 consensus conference, the International CBME Collaborators proposed a number of central tenets of CBME in order to advance the field of medical education. Although the proposed conceptualization of CBME offers several advantages and opportunities, including a greater emphasis on outcomes, a mechanism for the promotion of learner-centred curricula, and the potential to move away from time-based training and credentialing in medicine, it is also associated with several significant barriers to adoption. This paper examines the concepts of CBME through a broad educational policy lens, identifying considerations for medical education leaders, health care institutions, and policy-makers at both the meso (program, institutional) and macro (health care system, inter-jurisdictional, and international) levels. Through this analysis, it is clear that CBME is associated with a number of complex challenges and questions, and cannot be considered in isolation from the complex systems in which it functions. Much more work is needed to engage stakeholders in dialogue, to debate the issues, and to identify possible solutions.

Can the male-to-female ratio of gonorrhoea in one sexually transmissible infection treatment facility be solely used to judge its efficiency?

BACKGROUND: This facility has for a long time audited its efficacy in contact tracing (case finding) and found results comparable with national guidelines. In addition, we consistently measure control of the disease using three indices. A departure from the norm in one of these (the male-to-female ratio) prompted us to explore whether local case finding, and therefore control, was lacking resulting in the identification of a statistical anomaly. We have learnt a lesson, which may be of use to others who critically evaluate their work. METHODS: Review of statutory clinic quarterly returns and manually-held contact tracer data, comparison of representative quarters (Wilcoxson sign rank test) and detailed inspection of sampled case-to-case contact tracing efficiency. RESULTS: Evidence was found challenging our belief that male-to-female ratios are at face value an inevitably accurate surrogate for case finding or infection control. In our clinic, we identified recording anomalies giving rise to false concerns that case finding was less efficient than usual. CONCLUSIONS: Although the heterosexual male:female ratio for gonorrhoea is one readily available and proxy measure of disease control and tracing efficiency, its sole use should be interpreted with caution. A time lag across quarters between patient and partner attendance and other recording anomalies may mislead. Ratios should therefore be interpreted in the context of partner notification outcomes, which give a more reliable measure of efficiency. The use of the ratio in critical evaluation of a unit's efficiency should be but one part of a package of measures.

HIV infection.

INTRODUCTION: Infection with the human immunodeficiency virus (HIV) usually leads to 8-10 years of asymptomatic infection before immune function deteriorates and AIDS develops. Without treatment, about 50% of infected people will die of AIDS over 10 years. With treatment, prognosis depends on age, CD4 cell count, and initial viral load. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of preventive interventions? What are the effects of different antiretroviral drug treatment regimens in HIV infection? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 17 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: combination treatments containing either CCR5 inhibitors or fusion inhibitors; early diagnosis and treatment of sexually transmitted diseases (STDs); early and delayed antiretroviral treatment using triple antiretroviral regimens; non-nucleoside reverse transcriptase inhibitor (NNRTI) based triple regimens; nucleoside reverse transcriptase inhibitor (NRTI) and protease inhibitor-based triple regimens (standard, and boosted); post-exposure prophylaxis in healthcare workers; and presumptive mass treatment of sexually transmitted diseases (STDs).

Evaluation, using two assessment instruments, of the American and British national guidelines for the management of sexually transmissible and genital infections.

BACKGROUND: The objective of the present study was to compare, utilising two guideline assessment instruments, six corresponding clinical practice guidelines of the British Association for Sexual Health and HIV and the Centres for Disease Control. METHODS: Three raters independently assessed the recently published guidelines for gonorrhoea, chlamydial infection, early syphilis, pelvic inflammatory disease, bacterial vaginosis and HIV testing using two instruments, the Cluzeau and the AGREE (Appraisal of Guidelines for Research and Evaluation instrument). The Cluzeau scores were a simple percentage comparison; the AGREE scores were a standardised score for each guideline development domain. Differences were assessed using the Wilcoxson signed ranks test. Inter-rater variability was calculated on the Cluzeau instrument utilising the intragroup correlation method. RESULTS: The British Association for Sexual Health and HIV guidelines scored higher than the Centres for Disease Control guidelines in many of the assessed domains. There were significant differences between the two in many of the scores (P = 0.026-0.028). Inter-rater concordance was high to very high at 0.70-0.83. CONCLUSIONS: There were often major differences in scores between the two guideline groups. It is necessary for wider discussion within the profession to consider the significance of these findings.

A prospective, randomized, double-blind trial to evaluate the role of a short reducing course of oral corticosteroid therapy in the treatment of chronic prostatitis/chronic pelvic pain syndrome.

OBJECTIVES: To assess the validity of our observational experience that a short course of oral prednisolone therapy might be of value in the management of symptoms of chronic pelvic pain syndrome (CPPS) in men. PATIENTS AND METHODS: Twenty-one men with CPPS (inflammatory or non-inflammatory) for > or =6 months, and who had failed to improve with standard antibiotic therapy, were randomized to receive either a 1-month reducing course of oral prednisolone (nine) or an equivalent placebo regimen (12 men). The outcome measures used were the McGill Pain Questionnaire, the Hospital Anxiety and Depression Scale (HADS), General Health Questionnaire-30 (GHQ-30) and the National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI), which were completed at baseline and 3 months. RESULTS: Outcomes were analysed for the 18 patients (six treated, 12 placebo) who completed the 3 months of follow-up. At both baseline and 3 months, respectively, there was no statistically significant difference between the groups in the NIH-CPSI total score (P = 0.48 and 0.62; Mann-Whitney U-test), or in the HADS (anxiety, P = 0.85 and 0.67; depression P = 0.96 and 0.74), and there was no significant improvement or deterioration over time. Although not statistically significant, there was a trend to improvement in the depression score for the active group (P = 0.13). However, the clinical significance is doubtful, as both baseline and follow-up depression scores were within the normal range. No patient had clinically negative changes in depression. A 3-month follow-up analysis was not possible for the McGill Pain Questionnaire or GHQ-30 as not all patients completed the questionnaire. CONCLUSIONS: Whilst the study showed no clinical benefit of using corticosteroids in the management of CPPS, the few patients recruited limited the validity of firm conclusions from the data. There was a trend towards an improvement of depression levels amongst subjects. The study highlights the difficulties of recruitment and illustrates the complex psychological profiles of patients with CPPS.

The characterisation of a recent syphilis outbreak in Sheffield, UK, and an evaluation of contact tracing as a method of control.

OBJECTIVE: To explore the factors around and the success of contact-tracing in a recent major outbreak of infectious syphilis in Sheffield, and to evaluate the effectiveness of it, our hitherto standard strategy of control. METHOD: Retrospective chart review RESULTS: Over a period of 18 months, an outbreak of 21 cases was, on closer inspection, the result of several, discrete "micro" outbreaks in different groups. Two major patterns emerged, a relatively straightforward and more accessible cluster in heterosexual persons (a "spread" network), and more sporadic, "starburst" networks in men who have sex with men. CONCLUSION: Our traditional method of control, contact-tracing, was seen to be most effective in the spread network in heterosexuals. In the face of an apparent outbreak, clinicians should explore the nature and parameters of their local epidemic and engage a mixture of control methods. These may include, but not excusively so, contact-tracing to interrupt transmission by case-finding and by treatment.

Monkey see, monkey do: a critique of the competency model in graduate medical education.

BACKGROUND: Graduate medical education in the UK is in danger of being subsumed in a minimalist discourse of competency. ARGUMENT: While accepting that competence in a doctor is a sine qua non, the author criticises the construction of a graduate and specialist medical education based solely upon a competency model. Many competency models follow the concepts of either academic competence or operational competence, both of which have lately been subject to criticism. CONCLUSION: The author discusses the need for replacing such criterion-referenced models in favour of a model that engages the higher order competence, performance and understanding which represent professional practice at its best.

Good wine may need to mature: a critique of accelerated higher specialist training. Evidence from cognitive neuroscience.

CONTEXT: Higher specialist training in the UK is to be further shortened in the absence of any valid educational evidence for the wisdom of this move. Some practitioners/teachers are becoming increasingly concerned at this. THESIS AND DISCUSSION: Whereas the optimum length of time for such training is as yet undetermined, there is much in medical practice that resonates with the thinking of recent authors, who recommend slow incubation and facilitated reflection on experience, which steeps the learner in a hidden curriculum of practice, and entrains intuitive, "slow mode" thinking. This engagement necessarily takes time. The author has surveyed some of the recent literature on problem solving, cognitive neuroscience, artificial intelligence and learning for practice, and discusses his conclusions. These are unsettling. CONCLUSION: Further truncation of the length of higher specialist training must be supported by robust educational evidence that supports this reduction. The author advises caution.