MVMRmode: Introducing an R package for plurality valid estimators for multivariable Mendelian randomisation.

BACKGROUND: Mendelian randomisation (MR) is the use of genetic variants as instrumental variables. Mode-based estimators (MBE) are one of the most popular types of estimators used in univariable-MR studies and is often used as a sensitivity analysis for pleiotropy. However, because there are no plurality valid regression estimators, modal estimators for multivariable-MR have been under-explored. METHODS: We use the residual framework for multivariable-MR to introduce two multivariable modal estimators: multivariable-MBE, which uses IVW to create residuals fed into a traditional plurality valid estimator, and an estimator which instead has the residuals fed into the contamination mixture method (CM), multivariable-CM. We then use Monte-Carlo simulations to explore the performance of these estimators when compared to existing ones and re-analyse the data used by Grant and Burgess (2021) looking at the causal effect of intelligence, education, and household income on Alzheimer's disease as an applied example. RESULTS: In our simulation, we found that multivariable-MBE was generally too variable to be much use. Multivariable-CM produced more precise estimates on the other hand. Multivariable-CM performed better than MR-Egger in almost all settings, and Weighted Median under balanced pleiotropy. However, it underperformed Weighted Median when there was a moderate amount of directional pleiotropy. Our re-analysis supported the conclusion of Grant and Burgess (2021), that intelligence had a protective effect on Alzheimer's disease, while education, and household income do not have a causal effect. CONCLUSIONS: Here we introduced two, non-regression-based, plurality valid estimators for multivariable MR. Of these, "multivariable-CM" which uses IVW to create residuals fed into a contamination-mixture model, performed the best. This estimator uses a plurality of variants valid assumption, and appears to provide precise and unbiased estimates in the presence of balanced pleiotropy and small amounts of directional pleiotropy.

The Relative Importance of Factors That Applicants Weigh When Ranking Adult Reconstruction Fellowships as Well as Their Perspectives on Robotic-Assisted Arthroplasty.

BACKGROUND: Orthopedic Surgery Fellowship programs offer highly specialized training that varies based on the training environment and surgical experience. Additionally, for Adult Reconstruction programs, robotic-assisted surgery exposure has been a widely discussed topic. The purpose of this study was to determine the relative value of various factors to Adult Hip and Knee Fellowship applicants, and their perceptions of robotic-assisted arthroplasty. METHODS: We surveyed 780 applicants who applied to our fellowship to matriculate in 2020 to 2024. We received 158 responses (20.3% response rate). We assessed factors concerning people and perceptions, logistics, salary and benefits, program reputation and curriculum, and surgical experience. Additionally, we surveyed fellows' attitudes toward using robotic surgery and its impact on patient outcomes. RESULTS: The highest-rated factors were Level of Hands-On Operative Experience (4.83), Revision Hip Volume (4.72), Revision Knee Volume (4.71), Multiple Surgical Exposures to the Hip (4.59), and Clinical Case Variety (4.59). Respondents who were postfellowship matriculation placed significantly more value on Exposure to Multiple Attendings with Surgical Diversity (P = .01), and Anterior Hip Volume (P = .04), and less value on Geographic Location (P = .04) and Patient-Specific Instrumentation (P = .02) than prematriculates. Overall, 65% of applicants plan to or currently use robotics, 7.6% do not, and 27.2% said "Maybe". Those who plan to or currently use robotics most cited procedure fidelity, patient-preference, and marketability as reasons to use robotics. CONCLUSIONS: Hands-on surgical experience and revision volume were the most important factors for fellowship applicants. Applicants placed lower importance on robotics exposure and their perspectives on robotics in their future practice were highly variable. Our results will inform fellowship programs and future applicants what previous applicants have valued in their training to help guide fellowship program structure, resource management, as well as recruitment.

CVS Health's Acquisition of Oak Street Health Reconfirms Market Viability of Private Equity Investment in Value-Based Payment Models for Primary Care.

For over a decade and for the foreseeable future, federal agencies have made efforts to promote value-based care through various incentive schemes, such as the recent "Regulatory Sprint to Coordinated Care." Federal incentive schemes and other "macro tailwinds" have brought in private equity investors, especially in the context of primary care for Medicare beneficiaries. Oak Street Health and its private equity backers were pioneers in this space, applying buy-and-build strategies to create "next-generation" primary care networks "that focus largely or entirely on Medicare Advantage enrollees." Although Oak Street Health persuasively established a workable "playbook" for private equity investment in value-based care, and forecasts have been favorable, the ultimate market viability of this value-based playbook hinges on whether or not private equity investors can locate corporate buyers. The market viability of such a strategy has now been reconfirmed by the acquisition of Oak Street Health by CVS Health ("CVS"), announced February 8, 2023, and closed May 2, 2023, especially given that the incentives and the efficiencies associated with this deal are likely to be applicable to large-scale vertically integrated "payvider" corporations more generally. This Recent Transaction Comment examines CVS's acquisition of Oak Street Health to consider what factors might lead vertically integrated health care corporations to acquire value-based primary care networks in the future, and what knock on effects such acquisitions might have on future private equity buyouts in health care.

Clinical validity assessment of genes frequently tested on intellectual disability/autism sequencing panels.

PURPOSE: Neurodevelopmental disorders (NDDs), such as intellectual disability (ID) and autism spectrum disorder (ASD), exhibit genetic and phenotypic heterogeneity, making them difficult to differentiate without a molecular diagnosis. The Clinical Genome Resource Intellectual Disability/Autism Gene Curation Expert Panel (GCEP) uses systematic curation to distinguish ID/ASD genes that are appropriate for clinical testing (ie, with substantial evidence supporting their relationship to disease) from those that are not. METHODS: Using the Clinical Genome Resource gene-disease validity curation framework, the ID/Autism GCEP classified genes frequently included on clinical ID/ASD testing panels as Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Known Disease Relationship. RESULTS: As of September 2021, 156 gene-disease pairs have been evaluated. Although most (75%) were determined to have definitive roles in NDDs, 22 (14%) genes evaluated had either Limited or Disputed evidence. Such genes are currently not recommended for use in clinical testing owing to the limited ability to assess the effect of identified variants. CONCLUSION: Our understanding of gene-disease relationships evolves over time; new relationships are discovered and previously-held conclusions may be questioned. Without periodic re-examination, inaccurate gene-disease claims may be perpetuated. The ID/Autism GCEP will continue to evaluate these claims to improve diagnosis and clinical care for NDDs.

Cost-Effectiveness of Earlier Transition to Angiotensin Receptor Neprilysin Inhibitor in Patients With Heart Failure and Reduced Ejection Fraction.

BACKGROUND: Angiotensin receptor neprilysin inhibitor (ARNi) therapy improves clinical outcomes in patients with heart failure and reduced left ventricular ejection fraction. However, ARNi therapy uptake remains modest, potentially in part due to perceived cost considerations of early transition from angiotensin converting enzyme inhibitor or angiotensin receptor blocker therapy. METHODS: We constructed a decision-analytic Markov model to assess cost-effectiveness of 3 different ARNi initiation strategies according to timing of initiation: (1) de novo, or immediate initiation at baseline, (2) Early or after 3 months, or (3) Late, or after 9 months. Initiation strategies were compared with (4) current care, with utilization of ARNi derived from a large observational database. Total costs, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) were estimated over a 5-year time horizon in the base case analysis. RESULTS: Current care was associated with the lowest total cost (CAD$26,664) and accrued benefit (3.28 QALYs). The de novo strategy yielded an ICER of $34,727 per QALY gained, whereas Early and Late initiation strategies yielded a less favourable ICER per QALY gained of $35,871 and $40,234, respectively. The model was most sensitive to the cost of ARNi therapy. CONCLUSION: A strategy of de novo ARNi initiation is economically attractive and becomes less favourable as the delay of initiation increases. Our results suggest that ARNi therapy should be initiated as soon as possible for patients with heart failure and reduced left ventricular ejection fraction.

CONTEXTE: Le traitement par un antagoniste des récepteurs de l'angiotensine/inhibiteur de la néprilysine (ARNI) améliore les résultats cliniques chez les patients présentant une insuffisance cardiaque et une fraction d'éjection ventriculaire gauche réduite. L'adoption d'un tel traitement demeure toutefois modeste, peut-être en partie à cause des perceptions quant au coût associé à la substitution précoce d'un inhibiteur de l'enzyme de conversion de l'angiotensine ou d'un antagoniste des récepteurs de l'angiotensine. MÉTHODOLOGIE: Nous avons mis au point un modèle de Markov appliqué à l'analyse décisionnelle afin d'évaluer le rapport coût-efficacité de trois stratégies d'instauration d'un traitement par un ARNI, selon le moment de la mise en route : 1) instauration de novo, c'est-à-dire instauration immédiate dès le départ; 2) instauration précoce (après trois mois); ou 3) instauration tardive (après neuf mois). Les stratégies d'instauration ont été comparées à 4) la norme de soins actuelle, l'utilisation des ARNI étant dérivée d'une importante base de données observationnelles. Dans l'analyse du scénario de référence, les coûts totaux, les années de vie pondérées par la qualité (QALY pour quality-adjusted life-years) et le rapport coût-efficacité différentiel (RCED) ont été estimés sur une période de cinq ans. RÉSULTATS: La norme de soins actuelle était associée au coût le plus faible (26 664 $CAD) et à un bienfait cumulé (3,28 QALY). La stratégie de novo a donné lieu à un RCED de 34 727 $ par QALY gagnée, tandis que les RCED des stratégies d'instauration précoce et tardive étaient moins favorables et s'établissaient respectivement à 35 871 $ et à 40 234 $. Le modèle s'est révélé plus sensible au coût du traitement par un ARNI. CONCLUSION: La mise en route d'un traitement par un ARNI de novo est attrayante sur le plan financier, et devient de moins en moins intéressante à mesure que le temps passe. Nos résultats indiquent qu'il faudrait instaurer le traitement par un ARNI le plus rapidement possible chez les patients présentant une insuffisance cardiaque et une fraction d'éjection ventriculaire gauche réduite.

Influence of clinical context on interpretation and use of an advance care planning policy: a qualitative study.

BACKGROUND: Advance care planning is a process through which people share their values, goals and preferences regarding future medical treatments with the purpose of aligning care received with patient wishes. The objective of this study was to explore perspectives from patients and clinicians in 4 clinical settings to understand how context influences interpretation and application of advance care planning processes. METHODS: This study used a qualitative interpretive descriptive design. Patient and clinician participants were recruited across 4 clinical outpatient settings (cancer, heart failure, renal failure and supportive living) in Calgary and Edmonton. Data were collected between 2014 and 2015 by means of recorded one-on-one semistructured interviews. We analyzed the data using thematic analysis in 2016-2017. RESULTS: Thirty-four patients and 34 clinicians participated in interviews. Themes common to all 4 contexts were lack of shared understanding between patients and clinicians, and a lack of consistent clinical process related to advance care planning. Advance care planning understanding and process varied substantially between contexts. This variation seemed to be driven by differences in perceptions around disease burden and the nature of the physician-patient relationship. INTERPRETATION: Provision of a system-wide policy and procedural framework alone was not found to be sufficient to form a standardized approach to advance care planning, as considerable variability existed in advance care planning process between and within clinical settings. Quality-improvement methods that consider local processes, gaps and barriers can help in developing a consistent, comprehensive process.

Impact of abnormal longitudinal rotation on the assessment of right ventricular systolic function in patients with severe pulmonary hypertension.

BACKGROUND: Assessment of right ventricular (RV) function plays an important role in patients with cardiopulmonary disease, and current guidelines recommend parameters including tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic excursion velocity (RVS') to assess RV longitudinal function. We assessed the hypothesis that the previously undescribed motion of RV longitudinal rotation (RVLR) is an independent predictor of both TAPSE and RVS'. METHODS: We assessed a series of 100 consecutive patients with pulmonary hypertension (PH) undergoing echocardiography. Patients with left ventricular (LV) dilation and dysfunction were excluded. Standard RV parameters were determined using established guidelines, while RVLR and right ventricular global longitudinal strain (RVGLS) measurements were performed using 2-dimensional (2D) speckle tracking technique. RESULTS: Mean peak RVLR measured -4.2±3.7 degrees. By convention, negative values implied clockwise motion. In a multiple linear regression model, TAPSE could be predicted from a combination of RVLR and RVGLS (R=0.56, P<0.001). A similar relationship was found for RVS' which could also be predicted from a combination of RVLR and RVGLS (R=0.52, P<0.001). While no association was found between RVLR and RV size, estimated RV systolic pressure (RVSP) or the presence of a pericardial effusion, a mild correlation was noted between RVLR and QRS duration (R=0.25, P=0.01). CONCLUSIONS: RVLR is an independent predictor of TAPSE and RVS'. Awareness of this motion should be considered in the interpretation of TAPSE and RVS' values as markers of RV systolic function, as abnormal RVLR may account for exaggerated values, particularly in patients with PH and RV dysfunction.

Assessing the prognoses on Health care in the information society 2013--thirteen years after.

Health care and information technology in health care is advancing at tremendous speed. We analysed whether the prognoses by Haux et al. - first presented in 2000 and published in 2002 - have been fulfilled in 2013 and which might be the reasons for match or mismatch. Twenty international experts in biomedical and health informatics met in May 2013 in a workshop to discuss match or mismatch of each of the 71 prognoses. After this meeting a web-based survey among workshop participants took place. Thirty-three prognoses were assessed matching; they reflect e.g. that there is good progress in storing patient data electronically in health care institutions. Twenty-three prognoses were assessed mismatching; they reflect e.g. that telemedicine and home monitoring as well as electronic exchange of patient data between institutions is not established as widespread as expected. Fifteen prognoses were assessed neither matching nor mismatching. ICT tools have considerably influenced health care in the last decade, but in many cases not as far as it was expected by Haux et al. in 2002. In most cases this is not a matter of the availability of technical solutions but of organizational and ethical issues. We need innovative and modern information system architectures which support multiple use of data for patient care as well as for research and reporting and which are able to integrate data from home monitoring into a patient centered health record. Since innovative technology is available the efficient and wide-spread use in health care has to be enabled by systematic information management.

Past and next 10 years of medical informatics.

More than 10 years ago Haux et al. tried to answer the question how health care provision will look like in the year 2013. A follow-up workshop was held in Braunschweig, Germany, for 2 days in May, 2013, with 20 invited international experts in biomedical and health informatics. Among other things it had the objectives to discuss the suggested goals and measures of 2002 and how priorities on MI research in this context should be set from the viewpoint of today. The goals from 2002 are now as up-to-date as they were then. The experts stated that the three goals: "patient-centred recording and use of medical data for cooperative care"; "process-integrated decision support through current medical knowledge" and "comprehensive use of patient data for research and health care reporting" have not been reached yet and are still relevant. A new goal for ICT in health care should be the support of patient centred personalized (individual) medicine. MI as an academic discipline carries out research concerning tools that support health care professionals in their work. This research should be carried out without the pressure that it should lead to systems that are immediately and directly accepted in practice.

If we ask, what they might tell: clinical assessment lessons from LGBT military personnel post-DADT.

Following repeal of the Don't Ask Don't Tell Policy, nearly one million lesbian, gay, and bisexual veterans and service members may increasingly seek access to Veterans Affairs services (G. Gates, 2004; G. J. Gates, 2010). Limited data exist regarding lesbian, gay, bisexual, transgender (LGBT) military personnel posing a unique challenge to clinicians and healthcare systems serving veterans with evidence-based and culturally relevant practice. In an effort to fill this information void, participatory program evaluation is used to inform recommendations for LGBT-affirmative health care systems change in a post-DADT world.

Reproducibility of echocardiographic techniques for sequential assessment of left ventricular ejection fraction and volumes: application to patients undergoing cancer chemotherapy.

OBJECTIVES: The aim of this study was to identify the best echocardiographic method for sequential quantification of left ventricular (LV) ejection fraction (EF) and volumes in patients undergoing cancer chemotherapy. BACKGROUND: Decisions regarding cancer therapy are based on temporal changes of EF. However the method for EF measurement with the lowest temporal variability is unknown. METHODS: We selected patients in whom stable function in the face of chemotherapy for breast cancer was defined by stability of global longitudinal strain (GLS) at up to 5 time points (baseline, 3, 6, 9, and 12 months). In this way, changes in EF were considered to reflect temporal variability of measurements rather than cardiotoxicity. A comprehensive echocardiogram consisting of 2-dimensional (2D) and 3-dimensional (3D) acquisitions with and without contrast administration was performed at each time point. Stable LV function was defined as normal GLS (≤-16.0%) at each examination. The EF and volumes were measured with 2D-biplane Simpson's method, 2D-triplane, and 3-dimensional echocardiography (3DE) by 2 investigators blinded to any clinical data. Inter-, intra-, and test-retest variability were assessed in a subgroup. Variability was assessed by analysis of variance and compared with Levene's or t test. RESULTS: Among 56 patients (all female, 54 ± 13 years of age), noncontrast 3D EF, end-diastolic volume, and end-systolic volume had significantly lower temporal variability than all other methods. Contrast only decreased the temporal variability of LV end-diastolic volume measurements by the 2D biplane method. Our data suggest that a temporal variability in EF of 0.06 might occur with noncontrast 3DE due to physiological differences and measurement variability, whereas this might be >0.10 with 2D methods. Overall, 3DE also had the best intra- and inter-observer as well as test-retest variability. CONCLUSIONS: Noncontrast 3DE was the most reproducible technique for LVEF and LV volume measurements over 1 year of follow-up.

Quality assessment of capture-recapture studies in resource-limited countries.

OBJECTIVES: Resource-limited countries often lack robust routine surveillance systems to accurately assess the burden of human attributes and diseases. In these settings capture-recapture analysis can be an alternative tool to obtain prevalence and incidence rates. Performance of capture-recapture analyses in resource-limited countries has not been systematically reviewed. METHODS: Systematic review of the performance of capture-recapture analyses in the categories of human attributes, non-infectious and infectious diseases in resource-limited countries, assessing individual study quality criteria and a minimum quality criterion per category, using PRISMA methodology. RESULTS: A total of 1671 potentially relevant PubMed citations were screened, resulting in 52 eligible publications: 36% in human attributes, i.e. hidden populations, injuries and mortality; 48% in non-infectious and 15% in infectious disease categories. Twenty-one per cent of selected studies were from low income countries, 40% from lower-middle-income countries and 38% from upper-middle-income countries. Thirteen per cent achieved good individual study quality criteria, 25% were intermediate and 19% were poor. Of the good studies, six were performed on human attributes and one on a non-infectious disease. The proportions of publications meeting the minimum quality criterion per category were 42%, 20% and 37%, respectively. CONCLUSIONS: Few capture-recapture studies in resource-limited countries achieved good individual quality criteria and a minority met the minimum quality criterion per category. Capture-recapture techniques in these settings should be carefully considered and implemented rigorously and are not a panacea for strengthening of routine surveillance systems.

Assessment of electronic health information system use and need in US adult congenital heart disease centers.

OBJECTIVES: Efforts to improve care for adult congenital heart disease (ACHD) patients necessitates collection of accurate, detailed, longitudinal data. We sought to document what electronic health record systems are currently available at ACHD centers and to assess national interest in a uniform ACHD-focused system. DESIGN: Directors of ACHD centers in the United States were invited to complete an online questionnaire regarding current health information systems at their institution both for general cardiology and for ACHD. Topics that were surveyed included utility and perceived limitations of currently available systems. The survey also assessed the level of interest in an ACHD-specific system, and its optimal functions. RESULTS: Thirty-four centers responded, representing both pediatric and adult institutions that care for patients with ACHD. Of these, 80% reported using a variety of commercially supported electronic medical record products, whereas only 50% employed an ACHD-specific noncommercial database to supplement their institutional system. Comparison of the two systems revealed that most clinical activities are pursued through the institutional electronic medical record system. Research and tracking of clinical activities were the primary uses of ACHD-specific systems, which have several noted limitations. Strong interest in an integrated ACHD-specific system was found among responders. CONCLUSIONS: There is both an unmet need and a strong interest in an ACHD-oriented electronic health record that could facilitate research, outcome tracking, quality assurance, and inter-institutional collaboration, all functions that are lacking in electronic health systems currently in use.

HER2 assessment on core biopsy specimens using monoclonal antibody CB11 accurately determines HER2 status in breast carcinoma.

AIMS: HER2 status is a prognostic factor in breast carcinoma and predicts response to trastuzumab therapy. Trastuzumab is effective in the neoadjuvant, adjuvant and advanced disease settings. Knowledge of HER2 status early in the diagnostic and therapeutic process is vital for treatment planning. HER2 analysis is usually carried out by immunohistochemistry or fluorescence in situ hybridization (FISH). The aim of this study was to establish whether HER2 immunohistochemistry using monoclonal antibody CB11 and carried out on the initial diagnostic core biopsy specimen accurately predicts HER2 amplification status. METHODS AND RESULTS: This is the largest study to date in which HER2 protein expression has been assessed by CB11 immunohistochemistry on the diagnostic core biopsy specimen and correlated with the result of FISH. Using FISH as the definitive HER2 status, we studied 568 invasive breast cancers using CB11 immunohistochemistry on core biopsy. This analysis had a sensitivity of 99.4%, specificity of 93.9%, false-positive frequency of 3.9% and false-negative frequency of 1.1%. These data are as good as those obtained from analysing resection specimens alone in UK national reference centres. CONCLUSIONS: CB11 immunohistochemistry accurately predicts HER2 amplification status and can be reliably carried out on core biopsy specimens of breast carcinoma.

Assessment of rainwater use and greywater reuse in high-rise buildings in a brownfield site.

This study describes the use of rainwater and greywater (originated from bathroom only) for provision of non-contact indoor and outdoor use in high-rise buildings. A brownfield development site in Box Hill suburb of Melbourne was selected as case study site for this investigation. The performance of alternative servicing options was compared with conventional water supply, stormwater and wastewater servicing. A water balance model UVQ (Urban Volume and Quality) was applied to determine storage capacities and to evaluate the percentage reduction in water supplying, stormwater run-off and wastewater disposal, as well as volumes of rainwater use and greywater reuse. In this study, the impact of variation in collection area (600 m(2) and 900 m(2)) and appliance discharge volumes was examined. A number of demand management options were also investigated. The results of this study indicate greywater reuse is more suited than rainwater use for this development because of the steady, constant supply of greywater compared to the highly fluctuating, storm-event supply of rainwater and the high population density creating comparatively large volumes of greywater.

Integrated obesity care management system -implementation and research protocol.

BACKGROUND: Nearly 50% of Canadians are overweight and their number is increasing rapidly. The majority of obese subjects are treated by primary care physicians (PCPs) who often feel uncomfortable with the management of obesity. The current research proposal is aimed at the development and implementation of an innovative, integrated, interdisciplinary obesity care management system involving both primary and secondary care professionals. METHODS: We will use both action and evaluative research in order to achieve the following specific objectives. The first one is to develop and implement a preceptorship-based continuing medical education (CME) program complemented by a web site for physicians and nurses working in Family Medicine Groups (FMGs). This CME will be based on needs assessment and will be validated by one FMG using questionnaires and semi structured interviews. Also, references and teaching tools will be available for participants on the web site. Our second objective is to establish a collaborative intra and inter-regional interdisciplinary network to enable on-going expertise update and networking for FMG teams. This tool consists of a discussion forum and monthly virtual meetings of all participants. Our third objective is to evaluate the implementation of our program for its ability to train 8 FMGs per year, the access and utilization of electronic tools and the participants' satisfaction. This will be measured with questionnaires, web logging tools and group interviews. Our fourth objective is to determine the impact for the participants regarding knowledge and expertise, attitudes and perceptions, self-efficacy for the management of obesity, and changes in FMG organization for obesity management. Questionnaires and interviews will be used for this purpose. Our fifth objective is to deliver transferable knowledge for health professionals and decision-makers. Strategies and pitfalls of setting up this program will also be identified. CONCLUSION: This project is relevant to health system's decision-makers who are confronted with an important increase in the prevalence of obesity. It is therefore critical to develop strategies allowing the management of obesity in the 1st line setting. Results of this research project could therefore influence health care organization in the field of obesity but also eventually for other chronic diseases.

Exploring students' perceptions on the use of significant event analysis, as part of a portfolio assessment process in general practice, as a tool for learning how to use reflection in learning.

BACKGROUND: Portfolio learning enables students to collect evidence of their learning. Component tasks making up a portfolio can be devised that relate directly to intended learning outcomes. Reflective tasks can stimulate students to recognise their own learning needs. Assessment of portfolios using a rating scale relating to intended learning outcomes offers high content validity. This study evaluated a reflective portfolio used during a final-year attachment in general practice (family medicine). Students were asked to evaluate the portfolio (which used significant event analysis as a basis for reflection) as a learning tool. The validity and reliability of the portfolio as an assessment tool were also measured. METHODS: 81 final-year medical students completed reflective significant event analyses as part of a portfolio created during a three-week attachment (clerkship) in general practice (family medicine). As well as two reflective significant event analyses each portfolio contained an audit and a health needs assessment. Portfolios were marked three times; by the student's GP teacher, the course organiser and by another teacher in the university department of general practice. Inter-rater reliability between pairs of markers was calculated. A questionnaire enabled the students' experience of portfolio learning to be determined. RESULTS: Benefits to learning from reflective learning were limited. Students said that they thought more about the patients they wrote up in significant event analyses but information as to the nature and effect of this was not forthcoming. Moderate inter-rater reliability (Spearman's Rho .65) was found between pairs of departmental raters dealing with larger numbers (20-60) of portfolios. Inter-rater reliability of marking involving GP tutors who only marked 1-3 portfolios was very low. Students rated highly their mentoring relationship with their GP teacher but found the portfolio tasks time-consuming. CONCLUSION: The inter-rater reliability observed in this study should be viewed alongside the high validity afforded by the authenticity of the learning tasks (compared with a sample of a student's learning taken by an exam question). Validity is enhanced by the rating scale which directly connects the grade given with intended learning outcomes. The moderate inter-rater reliability may be increased if a portfolio is completed over a longer period of time and contains more component pieces of work. The questionnaire used in this study only accessed limited information about the effect of reflection on students' learning. Qualitative methods of evaluation would determine the students experience in greater depth. It would be useful to evaluate the effects of reflective learning after students have had more time to get used to this unfamiliar method of learning and to overcome any problems in understanding the task.

When is bioavailable testosterone a redundant test in the diagnosis of hypogonadism in men?

OBJECTIVES: Total testosterone (TT) is frequently prescribed with an SHBG and/or free or bioavailable testosterone measurement. Our objective was to identify a TT range for which subsequent SHBG measurement/calculation adds no additional clinical information. DESIGN AND METHODS: Study data were composed of 3955 sets of TT, SHBG and calculated bioavailable testosterone (cBAT) results from unscreened ambulatory male subjects, aged 18-99. RESULTS: 90% of mismatches between TT and cBAT were observed with TT levels between 6.5 and 13.0 nmol/L, with only slight age variation and no important change with albumin level. SHBG measurement restricted to male patients with TT between 6.5 and 13.0 nmol/L should enable reagent cost savings of over 55%. CONCLUSION: We suggest that a TT level below 6.5 nmol/L or above 13.0 nmol/L provides sufficient useful information for ruling out hypogonadism in ambulatory adult males. This strategy of BAT testing should lead to significant time and cost savings.

Assessment of platelet activation in several different anticoagulants by the Advia 120 Hematology System, fluorescence flow cytometry, and electron microscopy.

In vivo platelet activation results are often confounded by activation induced in vitro during the preparative procedures. We measured ex vivo (basal) and in vitro (thrombin-induced) platelet activation in sodium citrate, ethylenediaminetetraacetic acid (EDTA), and Citrate Theophylline Dipyridamole Adenosine (CTAD) whole blood specimens. Determinations were made by measurements of platelet density (mean platelet component: MPC concentration) on the Advia 120 Hematology System. The MPC has been previously shown to correlate with a fluorescence flow cytometric method, also determined in this study, using the surface expression of CD62P. Moreover, platelet shape and structure changes in EDTA and CTAD anticoagulated whole blood specimens were characterized by transmission electron microscopy (TEM). Observations made using the Advia 120 Hematology System platelet density parameter, MPC, in the absence of thrombin were 25.7 +/- 0.9 g/dl, 27.9 +/- 0.9 g/dl and 24.8 +/- 1.2 g/dl in sodium citrate, EDTA and CTAD whole blood specimens, respectively. Addition of thrombin induced a significant change in platelet MPC for sodium citrate (21.9 +/- 1.9 g/dl; p<0.0001) and EDTA (23.2 +/- 0.9 g/dl; p<0.0001) whole blood specimens. In contrast, thrombin had no effect on MPC measured in whole blood taken into CTAD tubes. In vitro fluorescence flow cytometric platelet activation experiments measuring the percentage of platelets expressing anti-CD62P showed increase in sodium citrate specimens from 9.2 +/- 7.0 to 55.5 +/- 23.1 % (p<0.0001) and in EDTA specimens from 1.9 +/- 1.7 to 64.6 +/- 12.4 % (p<0.0001) after addition of thrombin. However, in blood taken into CTAD tubes, there was no significant change. Studies on platelets isolated from whole blood in CTAD showed activation by thrombin indicating that platelets in CTAD, while protected in its presence remained functional upon its removal. When observed by TEM over time, platelets in EDTA appear more activated and contain fewer granules than platelets in CTAD. We conclude that CTAD demonstrates in vitro platelet activation inhibition and may be useful in stabilizing ex vivo platelet activation. The novel platelet activation parameter, MPC, measured by an automated routine hematology system, using customized proprietary software, may be used in conjunction with CTAD, a stabilizing anticoagulant, to measure the ex vivo platelet activation state in whole blood specimens. TEM studies verify shape modifications and simultaneous retention of intracellular granules at early post-venipuncture time periods in CTAD specimens.

Medicines for sea lice.

Sea louse (Family Caligidae: genera Caligus and Lepeophtheirus) infection of farmed salmonids represents a significant threat to animal welfare and undermines profitability. Lice may also act as vectors for the transmission of viral and bacterial pathogens. Pest-control programmes parallel those deployed in terrestrial livestock farming and include the use of parasiticides. The authorisation process for fish medicines varies widely between salmon farming countries and undue regulatory constraint may place farmers in one country at a competitive disadvantage. In many jurisdictions, fish are a 'minor' species and mounting demands for environmental assessment increase registration costs. A successful integrated louse-management strategy requires free access to a range of effective, chemically unrelated active ingredients deployed according to current best practice. Over-reliance on a limited number of products will lead, inevitably, to resistance, which is difficult to counter.