Examining the knowledge work of person-centred care: Towards epistemic reciprocity.

OBJECTIVE: It is increasingly recognised that when healthcare staff fails to give adequate credence to patients' illness-related knowledge work, this epistemic injustice undermines person-centred care. Therefore, we set out to examine the experiences of people with long-term conditions with knowledge work in healthcare settings to identify changes needed to strengthen person-centred primary care. METHODS: We designed a qualitative study and recruited people with long-term conditions in the UK. We conducted individual interviews (analysed using interpretive phenomenological analysis) and focus groups (analysed using thematic analysis), then integrated findings from both methods through an approach focused on their complementarity. RESULTS: Participants described how successful person-centred consultations were characterised by a negotiation between patient and doctor and moments of broad exploration, reflexive listening, and reciprocal enquiry, which allowed for epistemic reciprocity. CONCLUSIONS: Epistemic reciprocity is a core component of person-centred clinical consultations, fostering the co-creation of new knowledge of patient experience and need through the interactive knowledge work of patient and doctor. PRACTICE IMPLICATIONS: Medical education could benefit from initiatives that develop knowledge use and integration skills across primary care professionals. Accommodating for patient's and doctor's knowledge work during clinical practice requires redesigning the consultation process, including timing, headspace, pre-consultation, and post-consultation work.

Effects of preoperative physiotherapy on signs and symptoms of pulmonary collapse and infection after major abdominal surgery: secondary analysis of the LIPPSMAck-POP multicentre randomised controlled trial.

BACKGROUND: Preoperative education and breathing exercise training by a physiotherapist minimises pulmonary complications after abdominal surgery. Effects on specific clinical outcomes such as antibiotic prescriptions, chest imaging, sputum cultures, oxygen requirements, and diagnostic coding are unknown. METHODS: This post hoc analysis of prospectively collected data within a double-blinded, multicentre, randomised controlled trial involving 432 participants having major abdominal surgery explored effects of preoperative education and breathing exercise training with a physiotherapist on postoperative antibiotic prescriptions, hypoxemia, sputum cultures, chest imaging, auscultation, leukocytosis, pyrexia, oxygen therapy, and diagnostic coding, compared to a control group who received a booklet alone. All participants received standardised postoperative early ambulation. Outcomes were assessed daily for 14 postoperative days. Analyses were intention-to-treat using adjusted generalised multivariate linear regression. RESULTS: Preoperative physiotherapy was associated with fewer antibiotic prescriptions specific for a respiratory infection (RR 0.52; 95% CI 0.31 to 0.85, p = 0.01), less purulent sputum on the third and fourth postoperative days (RR 0.50; 95% CI 0.34 to 0.73, p = 0.01), fewer positive sputum cultures from the third to fifth postoperative day (RR 0.17; 95% CI 0.04 to 0.77, p = 0.01), and less oxygen therapy requirements (RR 0.49; 95% CI 0.31 to 0.78, p = 0.002). Treatment effects were specific to respiratory clinical coding domains. CONCLUSIONS: Preoperative physiotherapy prevents postoperative pulmonary complications and is associated with the minimisation of signs and symptoms of pulmonary collapse/consolidation and airway infection and specifically results in reduced oxygen therapy requirements and antibiotic prescriptions. TRIAL REGISTRATION: ANZCTR 12613000664741 ; 19/06/2013.

Cognitive profile of young children with Williams syndrome.

BACKGROUND: There is very little research on the cognitive profile of young children with Williams syndrome (WS). METHOD: The present study utilised the Differential Ability Scales - Second Edition to examine the early cognitive abilities of 22 young children with WS (aged 3.98 to 7.70 years, 10 male and 12 female participants). RESULTS: Overall, IQ ranged from 38 (severely impaired) to 81.00 (low average). Consistent with Mervis et al. who looked at an older sample, over half (59.08%) of our young WS sample showed a significant and abnormal weakness in spatial ability relative to verbal ability. Moreover, 81.82% showed a significant and clinically unusual weakness in spatial ability relative to nonverbal reasoning ability. At the subtest level, only 4.55% of our sample showed a significant strength in naming vocabulary compared with verbal comprehension, while 13.64% showed a significant weakness in naming vocabulary relative to verbal comprehension. CONCLUSIONS: The results of the present study show cognitive heterogeneity, consistent with the literature on older children and adults with WS. There were variable levels of intellect and variable patterns of cognitive strength and weakness across both index and subtest scores. Findings highlight the need for individual assessment and management of young children with WS but also indicate that for the majority of WS individuals spatial skills are indeed an area of significant and abnormal weakness and should be a focus for early intervention.

Real Time Central Assessment of Kidney Transplant Indication Biopsies by Microarrays: The INTERCOMEX Study.

The authors conducted a prospective trial to assess the feasibility of real time central molecular assessment of kidney transplant biopsy samples from 10 North American or European centers. Biopsy samples taken 1 day to 34 years posttransplantation were stabilized in RNAlater, sent via courier overnight at ambient temperature to the central laboratory, and processed (29 h workflow) using microarrays to assess T cell- and antibody-mediated rejection (TCMR and ABMR, respectively). Of 538 biopsy samples submitted, 519 (96%) were sufficient for microarray analysis (average length, 3 mm). Automated reports were generated without knowledge of histology and HLA antibody, with diagnoses assigned based on Molecular Microscope Diagnostic System (MMDx) classifier algorithms and signed out by one observer. Agreement between MMDx and histology (balanced accuracy) was 77% for TCMR, 77% for ABMR, and 76% for no rejection. A classification tree derived to provide automated sign-outs predicted the observer sign-outs with >90% accuracy. In 451 biopsy samples where feedback was obtained, clinicians indicated that MMDx more frequently agreed with clinical judgment (87%) than did histology (80%) (p = 0.0042). In 81% of feedback forms, clinicians reported that MMDx increased confidence in management compared with conventional assessment alone. The authors conclude that real time central molecular assessment is feasible and offers a useful new dimension in biopsy interpretation. ClinicalTrials.gov NCT#01299168.

Navigating physical activity engagement following a diagnosis of cancer: A qualitative exploration.

This qualitative descriptive study explored cancer survivors' experiences of barriers and facilitators to undertaking physical activity to inform how services and professionals might offer better support. Purposive and theoretical sampling was used to recruit 25 people who were up to 5 years post-cancer diagnosis. Participants took part in face to face, semi-structured interviews, and transcripts were analysed using thematic analysis. The analysis identified five interrelated themes which represented cancer survivors' views: 1) You're on your own-a sense of abandonment post-treatment, and lack of sufficient and tailored information; 2) Dis-ease-disruption to self and identity, and a heightened awareness of physical self and fragility; 3) Becoming acclimatised-physical activity in the face of treatment-related side effects and residual impairment; 4) Importance of others-encouragement and support from health professionals, family and friends, and cancer-specific exercise groups; 5) Meanings people ascribed to physical activity-these were central and could help or hinder engagement. Our findings suggest being able to live well and re-engage in meaningful activities following a diagnosis of cancer is both complex and challenging. There appear to be gaps in current service provision in supporting the broader health and well-being of cancer survivors.

Hyalinosis Lesions in Renal Transplant Biopsies: Time-Dependent Complexity of Interpretation.

Because calcineurin inhibitor (CNI) immunosuppressive drugs induce arteriolar hyalinosis (ah) in kidney transplants, ah lesions can potentially provide information about drug exposure. We studied the relationship of ah lesions to findings and outcomes in 562 indication biopsies taken 3 days to 35 years after transplant. Prevalence of ah lesions increased with time of biopsy after transplant (TxBx). The ah scores correlated with arterial intimal thickening and atrophy-fibrosis but, unlike atrophy-fibrosis, did not increase until after 500 days because of a background of ah1 lesions in early biopsies reflecting donor aging. Correlation of ah scores with other features varied with TxBx-in early biopsies, donor age and related changes, and in very late biopsies, chronic antibody-mediated rejection and glomerulonephritis and associated lesions. After correction for TxBx, ah0 in intermediate time periods was associated with increased risk of T cell-mediated rejection and graft loss, probably because of underimmunosuppression and nonadherence. Thus, ah lesions in indication biopsies have multiple associations: donor age (early, usually ah1), chronic glomerular diseases (late, often ah2/3), and adequate exposure to CNIs at intermediate times. This threefold TxBx-dependent complexity must be considered when interpreting indication biopsies: ah lesions often indicate adequate CNI exposure, not toxicity, and unexpected ah0 should increase vigilance for nonadherence and underimmunosuppression.

Using Molecular Phenotyping to Guide Improvements in the Histologic Diagnosis of T Cell-Mediated Rejection.

Recognition that some lesions typical of T cell-mediated rejection (TCMR) also occur in antibody-mediated rejection requires revision of the histologic TCMR definition. To guide this process, we assessed the relative importance of various lesions and the performance of new histology diagnostic algorithms, using molecular TCMR scores as histology-independent estimates of true TCMR. In 703 indication biopsies, random forest analysis and logistic regression indicated that interstitial infiltrate (i-lesions) and tubulitis (t-lesions) were the key histologic predictors of molecular TCMR, with arteritis (v-lesions) having less importance. Histology predicted molecular TCMR more accurately when diagnoses were assigned by strictly applying the Banff rules to the lesion scores and redefining isolated v-lesion TCMR. This improved prediction from area under the curve (AUC) 0.70 with existing rules to AUC 0.80. Further improvements were achieved by introducing more categories to reflect inflammation (AUC 0.84), by summing the lesion scores (AUC 0.85) and by logistic regression (AUC 0.90). We concluded that histologic assessment of TCMR can be improved by placing more emphasis on i- and t-lesions and incorporating new algorithms for diagnosis. Nevertheless, some discrepancies between histologic and molecular diagnoses persist, partially due to the inherent nonspecificity of i- and t-lesions, and molecular methods will be required to help resolve these cases.

Treatment with the ghrelin-O-acyltransferase (GOAT) inhibitor GO-CoA-Tat reduces food intake by reducing meal frequency in rats.

The ghrelin acylating enzyme ghrelin-O-acyltransferase (GOAT) was recently identified and implicated in several biological functions. However, the effects on food intake warrant further investigation. While several genetic GOAT mouse models showed normal food intake, acute blockade using a GOAT inhibitor resulted in reduced food intake. The underlying food intake microstructure remains to be established. In the present study we used an automated feeding monitoring system to assess food intake and the food intake microstructure. First, we validated the basal food intake and feeding behavior in rats using the automated monitoring system. Afterwards, we assessed the food intake microstructure following intraperitoneal injection of the GOAT inhibitor, GO-CoA-Tat (32, 96 and 288 µg/kg) in freely fed male Sprague-Dawley rats. Rats showed a rapid habituation to the automated food intake monitoring system and food intake levels were similar compared to manual monitoring (P = 0.43). Rats housed under these conditions showed a physiological behavioral satiety sequence. Injection of the GOAT inhibitor resulted in a dose-dependent reduction of food intake with a maximum effect observed after 96 mg/kg (-27%, P = 0.03) compared to vehicle. This effect was delayed in onset as the first meal was not altered and lasted for a period of 2 h. Analysis of the food intake microstructure showed that the anorexigenic effect was due to a reduction of meal frequency (-15%, P = 0.04), whereas meal size (P = 0.29) was not altered compared to vehicle. In summary, pharmacological blockade of GOAT reduces dark phase food intake by an increase of satiety while satiation is not affected.

Degradation of oil by fungi isolated from Gulf of Mexico beaches.

Fungi of the Ascomycota phylum were isolated from oil-soaked sand patties collected from beaches following the Deepwater Horizon oil spill. To examine their ability to degrade oil, fungal isolates were grown on oiled quartz at 20°C, 30°C and 40°C. Consistent trends in oil degradation were not related to fungal species or temperature and all isolates degraded variable quantities of oil (32-65%). Fungal isolates preferentially degraded short (

Vertebral Scheuermann's disease in Europe: prevalence, geographic variation and radiological correlates in men and women aged 50 and over.

UNLABELLED: In 27 centres across Europe, the prevalence of deforming spinal Scheuermann's disease in age-stratified population-based samples of over 10,000 men and women aged 50+ averaged 8% in each sex, but was highly variable between centres. Low DXA BMD was un-associated with Scheuermann's, helping the differential diagnosis from osteoporosis. INTRODUCTION: This study aims to assess the prevalence of Scheuermann's disease of the spine across Europe in men and women over 50 years of age, to quantitate its association with bone mineral density (BMD) and to assess its role as a confounder for the radiographic diagnosis of osteoporotic fracture. METHODS: In 27 centres participating in the population-based European Vertebral Osteoporosis Study (EVOS), standardised lateral radiographs of the lumbar and of the thoracic spine from T4 to L4 were assessed in all those of adequate quality. The presence of Scheuermann's disease, a confounder for prevalent fracture in later life, was defined by the presence of at least one Schmorl's node or irregular endplate together with kyphosis (sagittal Cobb angle >40° between T4 and T12) or a wedged-shaped vertebral body. Alternatively, the (rare) Edgren-Vaino sign was taken as diagnostic. The 6-point-per-vertebral-body (13 vertebrae) method was used to assess osteoporotic vertebral shape and fracture caseness. DXA BMD of the L2-L4 and femoral neck regions was measured in subsets. We also assessed the presence of Scheuermann's by alternative published algorithms when these used the radiographic signs we assessed. RESULTS: Vertebral radiographic images from 4486 men and 5655 women passed all quality checks. Prevalence of Scheuermann's varied considerably between centres, and based on random effect modelling, the overall European prevalence using our method was 8% with no significant difference between sexes. The highest prevalences were seen in Germany, Sweden, the UK and France and low prevalences were seen in Hungary, Poland and Slovakia. Centre-level prevalences in men and women were highly correlated. Scheuermann's was not associated with BMD of the spine or hip. CONCLUSIONS: Since most of the variation in population impact of Scheuermann's was unaccounted for by the radiological and anthropometric data, the search for new genetic and environmental determinants of this disease is encouraged.

Incidental detection of haemoglobin (Hb) variants during high performance liquid chromatography (HPLC) analysis of HbA1c: is it time for a standardised approach to reporting?

BACK GROUND: Haemoglobin (Hb) variants are genetic variations in the globin genes that code for an abnormal globin protein structure. The prevalence of Hb variants has increased in Ireland due to the number of emigrants from Africa and Southeast Asia. The rate of incidentally detected Hb variants, in laboratories employing HPLC to measure HbA1c, has increased in parallel. The presence of a Hb variant can compromise HbA1c measurement and interpretation. In such cases, HbA1c cannot be used to diagnose diabetes or to assess concordance with glycaemic targets. AIM: To establish the number of incidentally identified Hb variants during 10 months of routine HbA1c analysis, and the percentage of HbA1c reports alerting the requesting clinician to the presence of a Hb variant. METHODS: The laboratory database was interrogated to extract all records of HbA1c requests and incidentally identified Hb variants from March to December 2012. RESULTS: A total of 32,636 HbA1c analyses were performed during the evaluation period. Seventy-three Hb variants were identified in a total of 46 patients. In 32.6% (15 of 46) the haemoglobinopathy status was known prior to testing and 97% of HbA1c reports communicated the presence of the Hb variant to the requesting clinician. CONCLUSION: Hb variants may invalidate the results of HbA1c analysis and could result in a missed diagnosis or a misdiagnosis of diabetes or mismanagement of a patient with diabetes mellitus. It is, therefore, imperative that a comment alerting the requesting clinician to the presence of the Hb variant is appended to the HbA1c result.

Banff Initiative for Quality Assurance in Transplantation (BIFQUIT): reproducibility of polyomavirus immunohistochemistry in kidney allografts.

Immunohistochemistry (IHC) is the gold standard for diagnosing (positive vs. negative) polyomavirus BK (BKV) nephropathy and has the potential for disease staging based on staining intensity and quantification of infected cells. This multicenter trial evaluated the reproducibility of BKV IHC among 81 pathologists at 60 institutions. Participants stained tissue microarray slides and scored them for staining intensity and percentage of positive nuclei. Staining protocol details and evaluation scores were collected online. Slides were returned for centralized panel re-evaluation and kappa statistics were calculated. Individual assessment of staining intensity and percentage was more reproducible than combined scoring. Inter-institutional reproducibility was moderate for staining intensity (κ = 0.49) and percentage (κ = 0.42), fair for combined (κ = 0.25) and best for simple positive/negative scoring (κ = 0.78). Inter-observer reproducibility was substantial for intensity (κ = 0.74), percentage (κ = 0.66), positive/negative (κ = 0.78) and moderate for combined scoring (κ = 0.43). Inter-laboratory reproducibility was fair for intensity (κ = 0.37), percentage (κ = 0.40) and combined (κ = 0.24), but substantial for positive/negative scoring (κ = 0.67). BKV RNA copies/cell correlated with staining intensity (r = 0.56) and percentage (r = 0.62). These results indicate that BKV IHC is reproducible between observers but scoring should be simplified to a single-feature schema. Standardization of tissue processing and staining protocols would further improve inter-laboratory reproducibility.

Basal serum cortisol concentration as a screening test for hypoadrenocorticism in dogs.

BACKGROUND: Measurement of basal serum or plasma cortisol concentration is used as a screening test for hypoadrenocorticism in dogs, but is not well characterized. OBJECTIVES: To evaluate the sensitivity and specificity of basal serum cortisol to detect hypoadrenocorticism in a population of dogs with a clinical suspicion of hypoadrenocorticism. ANIMALS: Four hundred and fifty dogs with nonadrenal gland illness and 14 dogs with naturally occurring hypoadrenocorticism were included. METHODS: Retrospective case-control study. The records of all dogs having had an ACTH stimulation test performed between January 2005 and September 2011 at the University of Bristol were reviewed. Dogs were included if the test was performed as a screening for hypoadrenocorticism. The sensitivity and specificity of basal serum cortisol concentration to detect dogs with hypoadrenocorticism were calculated using 2 cut-offs and compared to the gold standard ACTH stimulation test. RESULTS: Using a cut-off of ≤2 µg/dL (≤55 nmol/L), the sensitivity and specificity of basal cortisol to detect hypoadrenocorticism were 100% and 63.3%, respectively, whereas for a cut-off of ≤1 µg/dL (≤28 nmol/L), the sensitivity and specificity were 85.7% and 91.8%, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Measurement of basal serum cortisol is useful as a screening test for hypoadrenocorticism in dogs using a cut-off of ≤2 µg/dL (≤55 nmol/L), and the disease is unlikely with a basal serum cortisol >2 µg/dL (>55 nmol/L). A basal serum cortisol ≤2 µg/dL (≤55 nmol/L) cannot be used to diagnose hypoadrenocorticism, and an ACTH stimulation test should be performed in these cases.

Banff fibrosis study: multicenter visual assessment and computerized analysis of interstitial fibrosis in kidney biopsies.

Increasing interstitial fibrosis (IF) in native and kidney transplant biopsies is associated with functional decline and serves as a clinical trial end point. A Banff 2009 Conference survey revealed a range in IF assessment practices. Observers from multiple centers were asked to assess 30 renal biopsies with a range of IF and quantitate IF using two approaches on trichrome, Periodic acid-Schiff (PAS) and computer-assisted quantification of collagen III immunohistochemistry (C-IHC) slides, as well as assessing percent of cortical tubular atrophy% (TA%) and Banff total cortical inflammation score (ti-score). C-IHC using whole slide scans was performed. C-IHC assessment showed a higher correlation with organ function (r = -0.48) than did visual assessments (r = -0.32--0.42); computerized and visual C-IHC assessment also correlated (r = 0.64-0.66). Visual assessment of trichrome and C-IHC showed better correlations with organ function and C-IHC, than PAS, TA% and ti-score. However, visual assessment of IF, independent of approach, was variable among observers, and differences in correlations with organ function were not statistically significant among C-IHC image analysis and visual assessment methods. C-IHC image analysis correlated among three centers (r > 0.90, p < 0.0001, between all centers). Given the difficulty of visual IF assessment standardization, C-IHC image could potentially accomplish standardized IF assessment in multicenter settings.

Bone marrow levels of 25 hydroxy vitamin D are not depressed in cases of hip fracture compared with controls.

There is little information on tissue as distinct from plasma levels of vitamin D metabolites in cases of hip fracture compared with controls. Femoral neck fractures in the elderly are associated with increased cortical remodelling and endosteal resorption, leading to regional increases in porosity and reduced cortical thickness. Vitamin D metabolites play a central role in the maintenance of normal serum calcium levels and may, through interactions with parathyroid hormone, exert an important influence on bone structure. To investigate whether hip fracture might be associated with tissue vitamin D deficiency, we have measured by radioimmunoassay the levels of 25 hydroxy vitamin D (25 (OH)D) in bone marrow samples extracted from the proximal femurs of 16 female subjects who had suffered fracture (mean age = 82.1 years, standard error (se) 1.9) and nine sex matched post mortem controls (mean age = 83.8 years, se 2.5). Twenty five (OH)D concentrations were significantly greater in the fracture cases (median = 3.7, IQR = 2.5-3.9 ng/g) than in the control group (median = 1.5, IQR = 0.9-2.3 ng/g; P = 0.0007, non-parametric Wilcoxon/Kruskal-Wallis test). It was suggested in the 1970s that bone loss and hip fracture risk in the UK were driven by vitamin D deficiency. Our results suggest that the alterations in femoral neck bone microstructure and remodelling in hip fracture cannot be assigned to the single cause of relative deficiency of vitamin D. Vitamin D deficiency or insufficiency may nevertheless increase remodelling and loss of bone tissue and contribute causally to a minority of hip fractures.

Microarray diagnosis of antibody-mediated rejection in kidney transplant biopsies: an international prospective study (INTERCOM).

In a reference set of 403 kidney transplant biopsies, we recently developed a microarray-based test that diagnoses antibody-mediated rejection (ABMR) by assigning an ABMR score. To validate the ABMR score and assess its potential impact on practice, we performed the present prospective INTERCOM study (clinicaltrials.gov NCT01299168) in 300 new biopsies (264 patients) from six centers: Baltimore, Barcelona, Edmonton, Hannover, Manchester and Minneapolis. We assigned ABMR scores using the classifier created in the reference set and compared it to conventional assessment as documented in the pathology reports. INTERCOM documented uncertainty in conventional assessment: In 41% of biopsies where ABMR features were noted, the recorded diagnoses did not mention ABMR. The ABMR score correlated with ABMR histologic lesions and donor-specific antibodies, but not with T cell-mediated rejection lesions. The agreement between ABMR scores and conventional assessment was identical to that in the reference set (accuracy 85%). The ABMR score was more strongly associated with failure than conventional assessment, and when the ABMR score and conventional assessment disagreed, only the ABMR score was associated with early progression to failure. INTERCOM confirms the need to reduce uncertainty in the diagnosis of ABMR, and demonstrates the potential of the ABMR score to impact practice.

Potential impact of microarray diagnosis of T cell-mediated rejection in kidney transplants: The INTERCOM study.

We previously developed a microarray-based test for T cell-mediated rejection (TCMR) in a reference set of 403 biopsies. To determine the potential impact of this test in clinical practice, we undertook INTERCOM, a prospective international study of 300 indication biopsies from 264 patients (ClinicalTrials.gov NCT01299168). Biopsies from six centers-Baltimore, Barcelona, Edmonton, Hannover, Manchester and Minneapolis-were analyzed by microarrays, assigning TCMR scores by an algorithm developed in the reference set and comparing TCMR scores to local histology assessment. The TCMR score correlated with histologic TCMR lesions-tubulitis and interstitial infiltration. The accuracy for primary histologic diagnoses (0.87) was similar to the reference set (0.89). The TCMR scores reclassified 77/300 biopsies (26%): 16 histologic TCMR were molecularly non-TCMR; 15 histologic non-TCMR were molecularly TCMR, including 6 with polyoma virus nephropathy; and all 46 "borderline" biopsies were reclassified as TCMR (8) or non-TCMR (38). Like the reference set, discrepancies were primarily in situations where histology has known limitations, for example, in biopsies with scarring and inflammation/tubulitis potentially from other diseases. Neither the TCMR score nor histologic TCMR was associated with graft loss. Thus the molecular TCMR score has potential to add new insight, particularly in situations where histology is ambiguous or potentially misleading.

Chronic heart failure guidelines: do they adequately address patient need at the end-of-life?

INTRODUCTION: A number of international guidelines have been developed to support primary care clinicians improve the quality of care for patients with chronic heart failure at the end of life. The objective of this study was to undertake a systematic evaluation of such guidelines in relation to end-of-life care. METHODS: A systematic literature search of research databases and guideline clearing houses was undertaken. The selected guidelines were independently assessed by two researchers using the AGREE II quality criteria. A data-extraction framework was devised based on the holistic needs assessment tool of the Gold Standards Framework. The content of each guideline was then analysed using an approach similar to that used for thematic analysis. RESULTS: A total of 19 guidelines were included. Those guidelines with lower overall AGREE II scores covered fewer domains on the holistic needs assessment. Across all guidelines the lowest scoring domain was applicability and stakeholder involvement. Qualitative assessment showed that some guidelines adopt an unwavering disease orientated approach to assessing patient need. Guidance around continuity of care, out of hours care and after care was particularly poor in several guidelines. There was considerable heterogeneity in the evidence presented even amongst those guidelines that achieved high AGREE II scores. CONCLUSION: Combined quantitative and qualitative assessment demonstrates the importance of rigorous guideline development. Whilst the variation in evidence presented could be a result of methodological heterogeneity in the development of guidelines, it raises important questions about the processes by which evidence, information and knowledge become transformed into clinical guidelines.

Molecular diagnosis of antibody-mediated rejection in human kidney transplants.

Antibody-mediated rejection is the major cause of kidney transplant failure, but the histology-based diagnostic system misses most cases due to its requirement for C4d positivity. We hypothesized that gene expression data could be used to test biopsies for the presence of antibody-mediated rejection. To develop a molecular test, we prospectively assigned diagnoses, including C4d-negative antibody-mediated rejection, to 403 indication biopsies from 315 patients, based on histology (microcirculation lesions) and donor-specific HLA antibody. We then used microarray data to develop classifiers that assigned antibody-mediated rejection scores to each biopsy. The transcripts distinguishing antibody-mediated rejection from other conditions were mostly expressed in endothelial cells or NK cells, or were IFNG-inducible. The scores correlated with the presence of microcirculation lesions and donor-specific antibody. Of 45 biopsies with scores>0.5, 39 had been diagnosed as antibody-mediated rejection on the basis of histology and donor-specific antibody. High scores were also associated with unanimity among pathologists that antibody-mediated rejection was present. The molecular score also strongly predicted future graft loss in Cox regression analysis. We conclude that microarray assessment of gene expression can assign a probability of ABMR to transplant biopsies without knowledge of HLA antibody status, histology, or C4d staining, and predicts future failure.

Precision diagnostics in transplantation: from bench to bedside.

The Canadian and American Societies of Transplantation held a symposium on February 22, 2012 in Quebec City focused on discovery, validation and translation of new diagnostic tools into clinical transplantation. The symposium focused on antibody testing, transplantation pathology, molecular diagnostics and laboratory support for the incompatible patient. There is an unmet need for more precise diagnostic approaches in transplantation. Significant potential for increasing the diagnostic precision in transplantation was recognized through the integration of conventional histopathology, molecular technologies and sensitive antibody testing into one enhanced diagnostic system.