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Rationale: Pulmonary arterial hypertension (PAH) is characterized by structural remodeling of pulmonary arteries and arterioles. Underlying biological processes are likely reflected in a perturbation of circulating proteins. Objectives: To quantify and analyze the plasma proteome of patients with PAH using inherited genetic variation to inform on underlying molecular drivers. Methods: An aptamer-based assay was used to measure plasma proteins in 357 patients with idiopathic or heritable PAH, 103 healthy volunteers, and 23 relatives of patients with PAH. In discovery and replication subgroups, the plasma proteomes of PAH and healthy individuals were compared, and the relationship to transplantation-free survival in PAH was determined. To examine causal relationships to PAH, protein quantitative trait loci (pQTL) that influenced protein levels in the patient population were used as instruments for Mendelian randomization (MR) analysis. Measurements and Main Results: From 4,152 annotated plasma proteins, levels of 208 differed between patients with PAH and healthy subjects, and 49 predicted long-term survival. MR based on cis-pQTL located in proximity to the encoding gene for proteins that were prognostic and distinguished PAH from health estimated an adverse effect for higher levels of netrin-4 (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16-2.08) and a protective effect for higher levels of thrombospondin-2 (OR, 0.83; 95% CI, 0.74-0.94) on PAH. Both proteins tracked the development of PAH in previously healthy relatives and changes in thrombospondin-2 associated with pulmonary arterial pressure at disease onset. Conclusions: Integrated analysis of the plasma proteome and genome implicates two secreted matrix-binding proteins, netrin-4 and thrombospondin-2, in the pathobiology of PAH.

Item does not contain fulltext Although several examples of frameworks dealing with students' unprofessional behaviour are available, guidance on how to deal locally or regionally with dysfunctional residents is limited (Hickson et al. in Acad Med 82(11):1040-1048, 2007b; Leape and Fromson in Ann Intern Med 144(2):107-115, 2006). Any 'rules' are mostly unwritten, and often emerge by trial and error within the specialty training programme (Stern and Papadakis in N Engl J Med 355(17):1794-1799, 2006). It is nevertheless of utmost importance that objectives, rules and guidelines comparable to those existing in undergraduate training (Project Team Consilium Abeundi van Luijk in Professional behaviour: teaching, assessing and coaching students. Final report and appendices. Mosae Libris, 2005; van Mook et al. in Neth J Crit Care 16(4):162-173, 2010a) are developed for postgraduate training. And that implicit rules are made explicit. This article outlines a framework based on the lessons learned from contemporary postgraduate medical training programmes.

Setting the many parameters available to the operator in a QoS-enabled IP network in order to achieve peak performance is a highly non-trivial task. Individual settings are not independent; and their consequences depend upon the traffic and application mix, the behaviour of higher-level protocols, the remainder of the network, and the customer's response. To complicate matters further, settings which optimise mean achievable bandwidth for large files may be very different from those best for Web-browsing applications; and within a single class the preferred values to minimise mean or median delays may be different from those which minimise different percentiles. To study the behaviour of all these, a range of techniques needs to be employed. This paper gives examples of analytic, simulation and experimental approaches, and shows how they are all needed for an in-depth understanding.

We all recognise the importance of good communication, and in medical education we invest much effort in teaching students how to maximise their communication skills. The objective is always to talk and listen in ways that minimise the potential for misunderstanding. Roberts and colleagues provide a fascinating study of doctors talking to each other in an examination setting. Although this is a relatively small study, the methodologically exacting paper offers an example of the everyday practice of medical examinations writ large. The importance of the study is twofold. Firstly, it shows the value of discourse analysis in understanding how human interactions go wrong, leading to the entirely unintended potential for discrimination. In the context of oral examinations, the interpretation of answers through the culture and language of institutional discourse can lead to misunderstandings by examiners and candidates. This misinterpretation adversely affects some groups of candidates and can lead to indirect discrimination. Although ethnicity was used as an example in this study, the findings could equally apply to candidates from working class backgrounds and, in some instances, to female candidates. Secondly, and equally importantly, the paper raises some fundamental questions about the use of the oral examination as an assessment tool. Examiners need to be aware of the ways in which the complex interactions involved in oral exams can affect the performance of candidates. Such awareness can only be achieved through improving the training of examiners. The board of examiners of the Royal College of General Practitioners should be congratulated on sponsoring the study. But what of the other royal colleges that use oral examinations in their assessment procedures and whose examination candidates include many who have been trained overseas? Are these candidates getting rough justice? Only the Royal College of General Practitioners has carried out and published a systematic analysis of the failure rate of ethnic minority candidates and then sought to understand why some groups are disadvantaged.1-1 If the royal colleges are hoping to use their qualifications as a minimum requirement for embarking on consultant training, they need to satisfy candidates that the process is fair and the criteria used for assessment are as explicit as possible.1-2 Medical schools using oral examinations as an important part of the assessment process need to ensure that the examiners are adequately trained. It is only a matter of time before these issues are tested in the courts. Forthcoming legislation will make it possible for candidates and students to force such changes on professional bodies and higher education institutions. Students have an expectation that when they are assessed, cultural differences between examined and examiner will not determine a pass or fail. In the litigious culture of the United States, the final medical examinations do not include oral exams precisely because of the potential for these problems. The lessons for the United Kingdom must be—get it right or don't do it at all.

Bacterial meningitis in adults (those aged over 15 years) is an uncommon but serious condition. The principles of prevention and treatment are easy to state but, unlike recommendations in guidelines for other conditions, the evidence base for many of our recommendations is lacking or a subject of controversy. The British Infection Society therefore convened a working party comprising clinicians, microbiologists, epidemiologists, general practitioner (GP) and Public Health representatives to assess current evidence and issue a clinically based consensus paper on the management of adult patients with suspected bacterial meningitis which would be useful for non-specialist physicians. The Working Party was aware that they had to make several recommendations using incomplete evidence. evidence from childhood meningitis, or from animal models. The grading of levels of evidence, adapted from AHCPR 1992 ’ . is given in Table I and the grading for our recommendations in Table II. We have included management of septicaemic presentations of meningococcal infection although such patients may not have meningitis. Adults with a meningitic presentation of meningococcal sepsis may have had a relatively mild bacteraemic phase and have a mortality rate of 5% or less whereas those who present with meningococcal septicaemia or sepsis unaccompanied by meningitis may have a mortality rate of 15-40% We have not included advice on management of meningitis following trauma or neurosurgery (except for recommendations for antibiotic treatment of pneumococcal meningitis).

Contains fulltext : 80009.pdf (Publisher’s version ) (Closed access) OBJECTIVES: The aim of this study is to make an inventory of the changes that are needed to make an interactive computer based training program (ICBT) with a specific educational content, acceptable to professional communities with different linguistic,cultural and health care backgrounds in different European countries. METHODS: Existing educational software, written in two languages was reviewed by GPs and primary care professionals in three different countries. Reviewers worked through the program using a structured critical reading grid. RESULTS: A 'simple' translation of the program is not sufficient. Minor changes are needed to take account of linguistic differences and medical semantics. Major changes are needed in respect of the existing clinical guidelines in every country related to differences in the existing health care systems. CONCLUSIONS: ICTB programs cannot easily be used in different countries and cultures. The development of a structured educational program needs collaboration between educationalists, domain experts, information technology advisers and software engineers. Simple validation of the content by local expert groups will not guarantee the program's exportability. It is essential to involve different national expert groups at every phase of the development process in order to disseminate it in other countries.

Ischemic-induced cell injury results in rapid duration-dependent actin-depolymerizing factor (ADF)/cofilin-mediated disruption of the apical microvilli microfilament cores. Because intestinal microvillar microfilaments are bound and stabilized in the terminal web by the actin-binding protein tropomyosin, we questioned whether a protective effect of tropomyosin localization to the terminal web of the proximal tubule microfilament cores is disrupted during ischemic injury. With tropomyosin-specific antibodies, we examined rat cortical sections under physiological conditions and following ischemic injury by confocal microscopy. In addition, Western blot analysis of cortical extracts and urine was undertaken. Our studies demonstrated the presence of tropomyosin isoforms in the proximal tubule microvillar terminal web under physiological conditions and their dissociation in response to 25 min of ischemic injury. This correlated with the excretion of tropomyosin-containing plasma membrane vesicles in urine from ischemic rats. In addition, we noted increased tropomyosin Triton X-100 solubility following ischemia in cortical extracts. These studies suggest tropomyosin binds to and stabilizes the microvillar microfilament core in the terminal web under physiological conditions. With the onset of ischemic injury, we propose that tropomyosin dissociates from the microfilament core providing access to microfilaments in the terminal web for F-actin binding, severing and depolymerizing actions of ADF/cofilin proteins.

Ischemic injury induces actin cytoskeleton disruption and aggregation, but mechanisms affecting these changes remain unclear. To determine the role of actin-depolymerizing factor (ADF)/ cofilin participation in ischemic-induced actin cytoskeletal breakdown, we utilized porcine kidney cultured cells, LLC-PKA4.8, and adenovirus containing wild-type (wt), constitutively active, and inactive Xenopus ADF/cofilin linked to green fluorescence protein [XAC(wt)-GFP] in an ATP depletion model. High adenoviral infectivity (70%) in LLC-PKA4.8cells resulted in linearly increasing XAC(wt)-GFP and phosphorylated (p)XAC(wt)-GFP (inactive) expression. ATP depletion rapidly induced dephosphorylation, and, therefore, activation, of endogenous pcofilin as well as pXAC(wt)-GFP in conjunction with the formation of fluorescent XAC(wt)-GFP/actin aggregates and rods. No significant actin cytoskeletal alterations occurred with short-term ATP depletion of LLC-PKA4.8cells expressing GFP or the constitutively inactive mutant XAC(S3E)-GFP, but cells expressing the constitutively active mutant demonstrated nearly instantaneous actin disruption with aggregate and rod formation. Confocal image three-dimensional volume reconstructions of normal and ATP-depleted LLC-PKA4.8cells demonstrated that 25 min of ATP depletion induced a rapid increase in XAC(wt)-GFP apical and basal signal in addition to XAC-GFP/actin aggregate formation. These data demonstrate XAC(wt)-GFP participates in ischemia-induced actin cytoskeletal alterations and determines the rate and extent of these ATP depletion-induced cellular alterations.

The performance procedures of the General Medical Council are aimed at identifying seriously deficient performance in a doctor. The performance procedures require the medical record to be of a standard that enables the next doctor seeing the patient to give adequate care based on the available information. Setting standards for microbiological record keeping has proved difficult. Over one fifth of practising medical microbiologists (including virologists) in the UK (139 of 676) responded to a survey undertaken by the working group developing the performance procedures for microbiology, to identify current practice and to develop recommendations for agreement within the profession about the standards of the microbiological record. The cumulative frequency for the surveyed recording methods used indicated that at various times 65% (90 of 139) of respondents used a daybook, 62% (86 of 139) used the back of the clinical request card, 57% (79 of 139) used a computer record, and 22% (30 of 139) used an index card system to record microbiological advice, suggesting wide variability in relation to how medical microbiologists maintain clinical records.

An essential element of practice performance assessment involves combining the results of various procedures in order to see the whole picture. This must be derived from both objective and subjective assessment, as well as a combination of quantitative and qualitative assessment procedures. Because of the severe consequences an assessment of practice performance may have, it is essential that the procedure is both defensible to the stakeholders and fair in that it distinguishes well between good performers and underperformers.Large samples of behaviour are always necessary because of the domain specificity of competence and performance. The test content is considerably more important in determining which competency is being measured than the test format, and it is important to recognise that the process of problem-solving process is more idiosyncratic than its outcome. It is advisable to add some structure to the assessment but to refrain from over-structuring, as this tends to trivialise the measurement.A practice performance assessment should use multiple instruments. The reproducibility of subjective parts should not be increased by over-structuring, but by sampling through sources of bias. As many sources of bias may exist, sampling through all of them may not prove feasible. Therefore, a more project-orientated approach is suggested using a range of instruments. At various timepoints during any assessment with a particular instrument, questions should be raised as to whether the sampling is sufficient with respect to the quantity and quality of the observations, and whether the totality of assessments across instruments is sufficient to see 'the whole picture'. This policy is embedded within a larger organisational and health care context.

From July 1997, the General Medical Council (GMC) has had the power to investigate doctors whose performance is considered to be seriously deficient. Assessment procedures have been developed for all medical specialties to include peer review of performance in practice and tests of competence. Peer review is conducted by teams of at least two medical assessors and one lay assessor. A comprehensive training programme for assessors has been developed that simulates the context of a typical practice-based assessment and has been tailored for 12 medical specialties. The training includes the principles of assessment, familiarization with the assessment instruments and supervised practice in assessment methods used during the peer review visit. High fidelity is achieved through the use of actors who simulate third party interviewees and trained doctors who role play the assessee. A subgroup of assessors, selected to lead the assessment teams, undergo training in handling group dynamics, report writing and in defending the assessment report against legal challenge. Debriefing of assessors following real assessments has been strongly positive with regard to their preparedness and confidence in undertaking the assessment.

Background The assessment of performance in the real world of medical practice is now widely accepted as the goal of assessment at the postgraduate level. This is largely a validity issue, as it is recognised that tests of knowledge and in clinical simulations cannot on their own really measure how medical practitioners function in the broader health care system. However, the development of standards for performance-based assessment is not as well understood as in competency assessment, where simulations can more readily reflect narrower issues of knowledge and skills. This paper proposes a theoretical framework for the development of standards that reflect the more complex world in which experienced medical practitioners work. Methods The paper reflects the combined experiences of a group of education researchers and the results of literature searches that included identifying current health system data sources that might contribute information to the measurement of standards. Conclusion Standards that reflect the complexity of medical practice may best be developed through an ‘expert systems’ analysis of clinical conditions for which desired health care outcomes reflect the contribution of several health professionals within a complex, three-dimensional, contextual model. Examples of the model are provided, but further work is needed to test validity and measurability.