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OBJECTIVES: Decision-aids (DAs) may facilitate shared decision-making for patients and caregivers, by providing evidence-based information to assist healthcare professionals, patients, and caregivers in making choices about aspects of care, and/or highlighting decision factors to discuss with the potential of altering the treatment decision. These decision factors may not be well integrated in DAs. METHODS: A systematic literature review was conducted in the field of multiple myeloma (MM) on peer-reviewed publications, extended with a gray literature search. Data on whether and how patient and caregiver experience elements, other than survival and physical quality of life, were mentioned as decision factors in the identified MM DAs were extracted and analyzed qualitatively. RESULTS: Seventy MM DAs were found and analyzed; 51% of DAs mentioned any patient non-routinely assessed experience decision factors and only 17% mentioned any caregiver-related information. One hundred and forty potential decision factors were extracted, deduplicated and categorized into the following categories: 1) financial, 2) mode of administration / transportation issues, 3) personal beliefs and values, 4) emotional and social quality of life, 5) other medical information, 6) availability of social support, 7) caregiver burden. None of the DAs presented a comprehensive framework on all seven categories of decision factors being consider when mapping patient and caregiver experience value elements in MM. CONCLUSIONS: Based on available DAs, we recommend a set of patient and caregiver experience decision factors that have the potential to affect treatment choices of patients with MM, which should be included in DAs, including MM clinical guidelines.

AIMS: The goal of this study was to review the economic evaluations of health technologies in multiple myeloma (MM) and provide guidance and recommendations for future health economic analyses. MATERIALS AND METHODS: A systemic literature review (SLR) was conducted on original economic assessment studies and structured review papers focusing on the studies in MM. The search was limited to English language papers published from 1 January 2000 onwards. Publications not applying any type of modelling methodology to describe disease progression and patient pathways over a specific time horizon were excluded. RESULTS: A total of 2,643 publications were initially identified, of which 148 were eligible to be included in the full-text review phase. From these, 49 publications were included in the final analysis. Most published health economic analyses supported by models came from high-income countries. Evaluations from middle-income countries were rarely published. Diagnostic technologies were rarely modelled and integrated care had not been modelled. Very few models investigated MM treatments from a societal perspective and there was a relative lack of evaluations regarding minimal residual disease (MRD). LIMITATIONS: Limitations of the publications included differences between trial populations and modelled populations, justification of methods, lack of confounder analyses, and small trial populations. Limitations of our study included the infeasibility of comparing MM economic evaluations due to the significant variance in modelled therapeutic lines and indications, and the relative scarcity of published economic evaluations from non-high-income countries. CONCLUSIONS: As published economic models lacked many of the elements of the complex and heterogeneous patient pathways in MM and they focused on single decision problems, a thorough, open-source economic whole disease modelling framework is needed to assess the economic value of a wide range of technologies across countries with various income levels with a more detailed view on MM, by including patient-centric and societal aspects.

AIM: The goal of this research was to quantify and qualify all the costs associated with multiple myeloma (MM) from a healthcare and societal perspective and to highlight certain costs that are often underestimated. MATERIALS AND METHODS: The study used a mixed methods approach that consisted of three phases: a systemic literature review (SLR), a virtual roundtable discussion based on the results of the SLR, and an online survey. RESULTS: In total, 4321 records were identified by literature and snowball searches. After applying the eligibility criteria, 49 articles were included in the narrative summary. As combination treatments have become the mainstay of MM treatment, drug costs have become the most important component of the total healthcare costs. Collected evidence suggests that optimizing treatment pathways, besides prolonging patient survival and maintaining quality of life, has the potential to generate cost savings for all stakeholders (payers and patients). Improved patient access to new therapies that can improve outcomes may reduce the "financial toxicity" of MM by decreasing patients' and caregivers' productivity loss due to better prognosis and it also has the potential of reducing patients' direct health care payments. LIMITATIONS: Heterogeneity of research objectives of included studies, costing methods, and applied measurement units limited the comparability of cost data between studies. Data for more than half of the world's population, including China, Russia, the Middle East, and Africa were not investigated. CONCLUSION: While treatment costs are burdensome for healthcare systems, it is only one of several items that make up the True Cost of MM. Understanding these burdens is one way to argue for optimized treatment pathways and improve patient outcomes by tearing down access barriers.

Introduction To mitigate risks related to human leukocyte antigen (HLA) incompatibility, we assessed whether certain structurally defined HLA targets present in donors but absent from recipients, known as eplet mismatches (EMM), are associated with death-censored graft failure (DCGF). Methods We studied a cohort of 118,313 American 0% panel reactive antibodies (PRA) first kidney transplant recipients (2000 to 2015) from the Scientific Registry of Transplant Recipients. Imputed allele-level donor and recipient HLA-A, -B, -C, -DRB1, and -DQB1 genotypes were converted to the repertoire of EMM. We fit survival models for each EMM with significance thresholds corrected for false discovery rate and validated those in an independent PRA > 0% cohort. We conducted network-based analyses to model relationships among EMM and developed models to select the subset of EMM most predictive of DCGF. Results Of 412 EMM observed, 119 class I and 118 class II EMM were associated with DCGF. Network analysis showed that although 210 eplets formed profiles of 2 to 12 simultaneously occurring EMMs, 202 were singleton EMMs that were not involved in any profile. A variable selection procedure identified 55 single HLA class I and II EMMs in 70% of the dataset; of those, 15 EMMs (9 singleton and 6 involved in profiles) were predictive of DCGF in the remaining dataset. Conclusion Our analysis distinguished increasingly smaller subsets of EMMs associated with increased risk of DCGF. Validation of these EMMs as important predictors of transplant outcomes (in contrast to acceptable EMMs) in datasets with measured allele-level genotypes will support their role as immunodominant EMMs worthy of consideration in organ allocation schemes.

Many of the biomarkers in current clinical use have become accepted via debate, consensus, or merely the passage of time. Biomarkers can no longer become accepted in this way, as they would fail to meet the current regulatory standards of modern medicine. Contemporary biomarkers must be tested in highly regulated human clinical trials. This article focuses on various aspects of discovery, development, clinical validation, and translation of biomarkers. Keywords: biomarkers; validation; regulatory guidance

Background and objective East Asians exposed to the urate-lowering drug allopurinol have a predilection for severe cutaneous drug reactions such as drug-induced hypersensitivity syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Screening is recommended in patients of East Asian descent for the presence of HLA-B*58:01 prior to allopurinol initiation to avoid these complications. Utilization rates of the HLA-B*58:01 predictive screening test within the Greater Vancouver area, which has a population composed of 40.1% people of East Asian descent, are unknown. Measures We identified cases of DRESS or SJS/TEN due to allopurinol using the Vancouver General Hospital dermatology consult service database. We next compared the frequency in which the HLA-B*58:01 screening test was ordered since 2012 to the estimated frequency of new prescriptions for allopurinol prescribed for the management of gout among the East Asians. Results We report 5 cases of East Asian patients exposed to allopurinol for management of gout between 2012 and 2016, who developed DRESS (4 patients) or SJS/TEN (1 patient). All were of HLA-B*58:01 genotype, representing preventable cases. The HLA-B*58:01 test was ordered 6 times in 2012, whereas the estimated number of new cases of allopurinol-prescribed gout among patients of East Asian descent during that time period was 13. For 2012, testing was ordered for only 46% of at-risk patients. Conclusion We continue to observe cases of severe cutaneous drug reactions among high-risk individuals due to allopurinol exposure. The HLA-B*58:01 screening test for allopurinol hypersensitivity is underutilized in our geographic area.

Objective: To assess oral antihyperglycemic agents (OAHA) and/or statin treatment initiation in patients with type 2 diabetes (T2D) and time from diagnosis to both types of treatment initiation and intensification. Research design and methods: We reviewed 662 retrospective medical records of patients with T2D diagnosed by 31 general practitioner or specialist sites across Mexico, Argentina, and Brazil. Demographic and clinical information was abstracted from patients’ medical records and summarized using descriptive statistics. Between-group differences were assessed with Student’s t-test for continuous variables and Fisher’s exact test for categorical variables. The starting time of each therapy (OAHA and statins, separately) was assessed using Kaplan-Meier estimates. Results: At diagnosis, patients’ mean age was 53 years; 44% had hypertension, 42% were obese, and 23% had dyslipidemia. During the 2-year follow-up, 95% of patients received OAHAs but only 29% of those eligible for statins received this prescription. Mean ± SD and median (Q1, Q3) time to first OAHA was 59 ± 141 days and 1 (1, 31) day, respectively, and 230 ± 232 days and 132 (30, 406) days, respectively, for a statin. During follow-up, 51–53% of patients with HbA1c/FPG values above target did not intensify hyperglycemia treatment. Conclusion: Dyslipidemia treatment in patients with T2D was delayed despite its known deleterious effect on atherosclerosis development and β-cell mass/function. Anti-hyperglycemic treatment was not intensified when targets were not attained. This prescriptive inertia needs to be corrected because attainment of HbA1c treatment goals becomes more difficult, favoring the development of diabetes complications. Keywords: Type 2 diabetes, Dyslipidemia, Treatment initiation, Clinical inertia, Antihyperglycemic agent, Statin

In kidney transplantation, the use of minimally invasive damage biomarkers that are more sensitive and specific than plasma creatinine will be crucial to enable early, actionable detection or exclusion of structural kidney damage due to acute or chronic rejection. Donor-derived cell-free DNA (dd-cfDNA), which can be quantified, for example, through next-generation sequencing, droplet digital PCR and quantitative PCR, is a candidate biomarker with great potential for enabling comprehensive monitoring of allograft injury. dd-cfDNA has a favourable overall diagnostic performance for the detection of rejection and its high negative predictive value might be especially useful for avoiding unnecessary biopsies. Elevated dd-cfDNA levels have been shown to be detectable before graft injury can be clinically identified using current diagnostic methods. Moreover, dd-cfDNA falls rapidly to baseline levels after successful treatment for rejection owing to its short half-life. dd-cfDNA can detect graft injury caused by immune activation owing to insufficient immunosuppression and might therefore also help guide immunosuppression dosing. The fractional abundance of dd-cfDNA can be affected by changes in the recipient cfDNA (for example, due to infection or physical exercise) but the use of absolute quantification of dd-cfDNA overcomes this limitation. Serial dd-cfDNA determinations might therefore facilitate cost-effective personalized clinical management of kidney transplant recipients to reduce premature graft loss.

To observe the effect of an organization-of-care improvement process on the achievement of therapeutic goals for people with type 2 diabetes mellitus (T2DM).This single-arm cohort study analyzed the electronic medical records of patients with T2DM in 5 primary care practices in Ontario, Canada, before and 2 years after implementation of an individualized quality-improvement program. The primary outcome was the change in glycated hemoglobin (A1C) between baseline and follow up, with secondary analyses including change in other metabolic parameters, medication patterns and clinic visits. Prespecified subgroup analysis of patients with baseline values above guideline therapeutic targets was performed.In the overall population of 1,886 patients, A1C improved from 7.1% (baseline) to 7.0% (follow up) (p0.001); low-density lipoprotein-cholesterol (LDL-C) improved from 2.1 to 1.9 mmol/L (p0.001); and diastolic blood pressure (BP) improved from 75 to 74 mmHg (p0.001), with no significant change observed in systolic BP. Of those patients who were above guideline-recommended therapeutic targets at baseline, improvements were observed at follow-up: A1C 8.3±1.3% to 7.8±1.3% (p0.001), LDL-C 2.9±0.7 mmol/L to 2.4±0.9 mmol/L (p0.001), systolic BP 144±11 to 134±16 mmHg (p0.001) and diastolic BP 80±10 to 75±11 mmHg (p0.001), with the percentages of patients achieving target at follow up being 32% for A1C, 40% for LDL-C and 49% for systolic BP. Overall, 22% of patients achieved all 3 targets at baseline compared to 28% at follow up (p0.001).The implementation of an organization-of-care improvement program in primary care was associated with improved metabolic control, which was most pronounced in patients with baseline levels above guideline-recommended therapeutic targets.

Background There is a need to improve personalized immunosuppression in organ transplantation to reduce premature graft loss. More efficient biomarkers are needed to better detect rejection, asymptomatic graft injury, and under-immunosuppression. Assessment of minimal necessary exposure to guide tapering and to prevent immune activation is also important. Donor-derived cell-free DNA (dd-cfDNA) has become available for comprehensive monitoring of allograft integrity. A value proposition concept was applied to assess the potential benefits of dd-cfDNA to stakeholders (patient, transplant physician, laboratory medicine specialist, hospital management, insurance companies) involved in solid organ transplantation care. Content There is robust clinical evidence from more than 48 published studies supporting the role of dd-cfDNA for monitoring graft integrity and detection or exclusion of rejection. The value proposition framework was used to evaluate published key evidence regarding clinical validity, economic implications, and limitations of this approach. It has been shown that dd-cfDNA testing is essential for guiding earlier transplant injury intervention with potential for improved long-term outcome. Summary Monitoring dd-cfDNA offers a rapid and reproducible method to detect graft injuries at an early actionable stage without protocol biopsies and allows for more effective personalized immunosuppression. The appropriate use of dd-cfDNA testing can provide both clinical and economic benefits to all transplantation stakeholders.

Once touted as the future of hip arthroplasty, metal-on-metal (MoM) bearing surfaces have fallen sharply from favor with the emergence of a strong body of evidence demonstrating unacceptably high premature implant failure rates. The previously unpredictable development of adverse local tissue reactions (ALTRs) has been a substantive contributor to this. Although the underlying pathophysiology of these so-called "pseudotumors" is now well understood, the fundamental predisposing patient risk factors have remained elusive.The aim of this research, as a clinical-genotype correlation analysis, was to identify specific alleles (genes) associated with the development of ALTRs in patients with in situ MoM THAs.A case-control study of patients who received a large-head, primary MoM THA between 2005 and 2008 was performed with a minimum followup of 5 years. Twenty-six patients who had undergone revision of a primary MoM THA secondary to symptomatic ALTRs were recruited. The mean timeframe from primary MoM THA to symptomatic revision was 5.5 years (range, 1-10 years). Twenty-eight control subjects were randomly selected asymptomatic patients with no evidence of ALTRs on protocol-specific screening. Baseline demographics and high-resolution genotype (human leukocyte antigen [HLA] Class II) were collected for all patients. Cohorts were similar with respect to age at the time of primary MoM THA (mean, 54.8 versus 54.9 years, p = 0.95) and serum cobalt (mean, 5.5 versus 8.5 μg/L, p = 0.09) and chromium concentrations (mean, 2.9 versus 4.2 μg/L, p = 0.27). The association between genotype and revision surgery secondary to ALTRs was determined with gender as a covariate.The prevalence of the risk genotype was 30% (16 of 54) among the entire cohort. Adjusting for sex, the odds of revision were 6.1 times greater among patients with the risk genotype present than among patients without (95% confidence interval [CI], 1.5-25.4; p = 0.01). Among females, the specificity of the risk genotype was 1.0 (95% CIexact, 0.5-1.0; pexact = 0.03), and for males, it was 0.8 (95% CIexact, 0.6-0.9; pexact0.01).The findings of this study suggest that, among patients with a primary MoM THA, allelic variation within the HLA Class II loci may be a strong, independent risk factor associated with the need for subsequent revision surgery secondary to pseudotumor formation.Given the hypothesis-generating nature of this novel undertaking, confirmatory prospective clinical studies are required to further elucidate this correlation and to explore the clinical utility of targeted genetic screening in this specific population. This research may, however, represent a key missing piece in the puzzle that is metal ion-induced pseudotumor formation.

There is increasing interest in the use of precision medicine tools and evidence-based outcome measures for donor-recipient matching to optimize transplant outcomes. Although the shift toward greater precision can provide health and resource benefits, it may be perceived as conflicting with both established equity-focused organ allocation norms and the legal and ethical obligations of health care providers and related institutions. With increasing evidence that various forms of human leukocyte antigen (HLA) mismatch and/or prognostic biomarkers can affect outcomes, the tension between maximizing utility and ensuring equity seems likely to intensify. In Canada, health care providers are generally required by law to put the interests of their patient, such as access to an organ, above the needs of the health care system and other patients. In addition, transplantation right of access lawsuits, which have been successful in the past, could affect the implementation of precision approaches. These legal tensions could be further heightened by media representations, which have historically favored strong rights of access. When implementing new precision technologies in organ allocation, there will be a recurrent need for policymakers to revisit the balance of equity and utility and to assess how to craft rules that reflect our society's conception of a fair allocation system.Les outils de la médecine de précision et les mesures de résultats fondées sur des données probantes suscitent de plus en plus d’intérêt pour le couplage donneur-receveur afin d’optimiser le résultat d’une transplantation. Bien qu’une plus grande précision offre des avantages sur la santé et pour les ressources, elle peut être perçue comme entrant en conflit avec les normes d’attribution des organes axées sur l’équité, et avec les obligations éthiques et juridiques des fournisseurs de soins et des établissements auxquels ils sont rattachés. Avec le nombre croissant de preuves indiquant que diverses formes d’incompatibilité HLA ou de biomarqueurs pronostiques peuvent affecter les résultats, le différend opposant l’augmentation de leur utilisation au respect de l’équité risque de s’accentuer. Au Canada, les fournisseurs de soins sont légalement tenus de placer l’intérêt du patient, tel que l’accès à un organe, devant les besoins du système de santé et des autres patients. De plus, la mise en œuvre d’approches de précision est susceptible d’être influencée par les poursuites liées aux droits d’accès à une transplantation qui ont abouti dans le passé. Ces tensions juridiques pourraient être exacerbées par les représentations qu’en donnent les médias, ces derniers ayant historiquement favorisé le droit à l’accès. Ainsi, au moment de mettre en œuvre de nouvelles technologies de précision pour l’attribution des organes, les décideurs devront constamment revoir l’équilibre entre équité et pertinence, de même que la façon d’élaborer des règles reflétant notre conception sociétale d’un système équitable d’attribution des organes.

Background Nine mRNA transcripts associated with acute cellular rejection (ACR) in previous microarray studies were ported to the clinically amenable NanoString nCounter platform. Here we report the diagnostic performance of the resulting blood test to exclude ACR in heart allograft recipients: HEARTBiT. Methods Blood samples for transcriptomic profiling were collected during routine post-transplantation monitoring in 8 Canadian transplant centres participating in the Biomarkers in Transplantation initiative, a large (n = 1622) prospective observational study conducted between 2009 and 2014. All adult cardiac transplant patients were invited to participate (median age = 56 [17 to 71]). The reference standard for rejection status was histopathology grading of tissue from endomyocardial biopsy (EMB). All locally graded ISHLT ≥ 2R rejection samples were selected for analysis (n = 36). ISHLT 1R (n = 38) and 0R (n = 86) samples were randomly selected to create a cohort approximately matched for site, age, sex, and days post-transplantation, with a focus on early time points (median days post-transplant = 42 [7 to 506]). Results ISHLT ≥ 2R rejection was confirmed by EMB in 18 and excluded in 92 samples in the test set. HEARTBiT achieved 47% specificity (95% confidence interval [CI], 36%-57%) given ≥ 90% sensitivity, with a corresponding area under the receiver operating characteristic curve of 0.69 (95% CI, 0.56-0.81). Conclusions HEARTBiT’s diagnostic performance compares favourably to the only currently approved minimally invasive diagnostic test to rule out ACR, AlloMap (CareDx, Brisbane, CA) and may be used to inform care decisions in the first 2 months post-transplantation, when AlloMap is not approved, and most ACR episodes occur.

Cardiovascular disease is more common in patients with chronic kidney disease (CKD), and traditional risk factors do not adequately predict those at risk for cardiovascular (CV) events. Recent evidence suggests elevated trimethylamine N-oxide (TMAO), created by gut microflora from dietary L-carnitine and choline, is associated with CV events. We investigated the relationship of TMAO levels in patients with stages 3b and 4 CKD to ischemic CV events using the CanPREDDICT cohort, a Canada-wide observational study with prospective 3-year follow-up of adjudicated CV events. Baseline samples were obtained for 2529 CKD patients. TMAO, choline, and L-carnitine levels were measured using tandem mass spectrometry. Baseline median TMAO level was high for the whole cohort (20.41 μM; interquartile range [IQR]: 12.82–32.70 μM). TMAO was independently associated with CV events (hazard ratio 1.23; 95% confidence interval: 1.06–1.42 / 1 SD lnTMAO) after adjusting for all potential CV risk factors. Those in the highest TMAO quartile had significantly higher risk of CV events (adjusted hazard ratio 1.59; 95% confidence interval: 1.04–2.43; P = 0.0351) in the analysis of recurring ischemic events. Among those with stage 3b CKD (hazard ratio 1.45; 95% confidence interval: 1.12–1.87 / 1 SD lnTMAO), independent of kidney function, TMAO levels identified those at highest risk for events. Our results suggest that TMAO may represent a new potentially modifiable CV risk factor for CKD patients. Further studies are needed to determine sources of variability and if lowering of TMAO reduces CV risk in CKD.

Transplant glomerulopathy (TG), a morphological lesion associated with confluent mechanisms of endothelial injury of renal allografts, may provide a viable predictor of graft failure. This systematic literature review and meta-analysis were performed according to the PRISMA statement to examine evidence describing the association between TG and graft loss or failure and time to these events. The literature review was conducted using the Scopus, EBSCO, and Cochrane Library search engines. Hazard ratios, median survival times, and 95% confidence intervals (CIs) were estimated to evaluate graft survival in the total population and prespecified subgroups. Meta-regression analysis assessed heterogeneity. Twenty-one publications comprising 6,783 patients were eligible for data extraction and inclusion in the meta-analysis. Studies were highly heterogeneous (I2 = 67.3%). The combined hazard ratio of graft loss or failure from random-effects meta-analysis was 3.11 (95% CI 2.44–3.96) in patients with TG compared with those without. Median graft survival in patients with TG was 3.25 (95% CI 0.94–11.21) years—15 years shorter than in those without TG (18.82 [95% CI 10.03–35.32] years). The effect of time from transplantation to biopsy on graft outcomes did not reach statistical significance (p = 0.116). TG was associated with a threefold increase in the risk of graft loss or failure and a 15-year loss in graft survival, indicating viability as a surrogate measure for both clinical practice and studies designed to prevent or reverse antibody-mediated rejection.

Multi-omics research is a key ingredient of data-intensive life sciences research, permitting measurement of biological molecules at different functional levels in the same individual. For a complete picture at the biological systems level, appropriate statistical techniques must however be developed to integrate different 'omics' data sets (e.g., genomics and proteomics). We report here multivariate projection-based analyses approaches to genomics and proteomics data sets, using the case study of and applications to observations in kidney transplant patients who experienced an acute rejection event (n=20) versus non-rejecting controls (n=20). In this data sets, we show how these novel methodologies might serve as promising tools for dimension reduction and selection of relevant features for different analytical frameworks. Unsupervised analyses highlighted the importance of post transplant time-of-rejection, while supervised analyses identified gene and protein signatures that together predicted rejection status with little time effect. The selected genes are part of biological pathways that are representative of immune responses. Gene enrichment profiles revealed increases in innate immune responses and neutrophil activities and a depletion of T lymphocyte related processes in rejection samples as compared to controls. In all, this article offers candidate biomarkers for future detection and monitoring of acute kidney transplant rejection, as well as ways forward for methodological advances to better harness multi-omics data sets.

Observations of the demands on the work of teachers created by a year long trial implementation of unit standards in secondary schools highlighted an initial tendency for the assessment requirements to dominate teaching and the need for teachers to develop new strategies and systems to combine assessment with teaching, track the achievements of individual students and cope with the practical requirements of re-assessment. Towards the end of the trial some evidence was noted of teachers reducing the quality of the evidence on which assessments were based in order to cope with the demands on their time. The implications of this experience for teacher education, where unit standards are to be applied, are considered. It is argued that the problems noted in secondary schools will need to be addressed but the costs of compliance are likely to be greater because the teacher education unit standards, on which judgements are required, contain more detailed and numerous performance criteria, many of which will need to be assessed in more than one course, often taught by different departments, and during practical teaching. Three ways in which the difficulties might be resolved are proposed.

The development 0/Social Studies in the New Zealand Curriculum over the 1993-1997 period was highly contested. The authors were directly involved in the social studies development over this period, and this paper reflects on some of the major events in the development, from our "insiders" viewpoint. The paper argues that the contest was strongly influenced by two major "dominant voice groups with very different views on luhat a social studies curriculum should be like and by key elements of the political and economic reform agenda of the day. The paper traces the rise and fall in influence of each "dominant voice" group and also examines the way in which the reform agenda changed throughout the development. It argues that in the end the inclusive and liberal-democratic voice ivas dominant over the neo-liberal and educationally conservative one. It also suggests that a return to a more cooperative, negotiated style of curriculum development, rather than a pure "market-contract model" approach, luas needed to bring the development to a satisfactory conclusion.

Background: Identifying non-invasive and reliable blood-derived biomarkers for early detection of acute cellular rejection in heart transplant recipients is of great importance in clinical practice. MicroRNAs are small molecules found to be stable in serum and their expression patterns reflect both physiological and underlying pathological conditions in human. Methods: We compared a group of heart transplant recipients with histologically-verified acute cellular rejection (ACR, n = 26) with a control group of heart transplant recipients without allograft rejection (NR, n = 37) by assessing the levels of a select set of microRNAs in serum specimens. Results: The levels of seven microRNAs, miR-142-3p, miR-101-3p, miR-424-5p, miR-27a-3p, miR-144-3p, miR-339-3p and miR-326 were significantly higher in ACR group compared to the control group and could discriminate between patients with and without allograft rejection. MiR-142-3p and miR-101-3p had the best diagnostic test performance among the microRNAs tested. Serum levels of miR-142-3p and miR-101-3p were independent of calcineurin inhibitor levels, as measured by tacrolimus and cyclosporin; kidney function, as measured by creatinine level, and general inflammation state, as measured by CRP level. Conclusion: This study demonstrated two microRNAs, miR-142-3p and miR-101-3p, that could be relevant as non-invasive diagnostic tools for identifying heart transplant patients with acute cellular rejection.

The Human Proteome Project (HPP) is designed to generate a comprehensive map of the protein-based molecular architecture of the human body, to provide a resource to help elucidate biological and molecular function, and to advance diagnosis and treatment of diseases. Within this framework, the chromosome-based HPP (C-HPP) has allocated responsibility for mapping individual chromosomes by country or region, while the biology/disease HPP (B/D-HPP) coordinates these teams in cross-functional disease-based groups. Chromosome 6 (Ch6) provides an excellent model for integration of these two tasks. This metacentric chromosome has a complement of 1002–1034 genes that code for known, novel or putative proteins. Ch6 is functionally associated with more than 120 major human diseases, many with high population prevalence, devastating clinical impact and profound societal consequences. The unique combination of genomic, proteomic, metabolomic, phenomic and health services data being drawn together within the Ch6 program has enormous potential to advance personalized medicine by promoting robust biomarkers, subunit vaccines and new drug targets. The strong liaison between the clinical and laboratory teams, and the structured framework for technology transfer and health policy decisions within Canada will increase the speed and efficacy of this transition, and the value of this translational research. Biological significance Canada has been selected to play a leading role in the international Human Proteome Project, the global counterpart of the Human Genome Project designed to understand the structure and function of the human proteome in health and disease. Canada will lead an international team focusing on chromosome 6, which is functionally associated with more than 120 major human diseases, including immune and inflammatory disorders affecting the brain, skeletal system, heart and blood vessels, lungs, kidney, liver, gastrointestinal tract and endocrine system. Many of these chronic and persistent diseases have a high population prevalence, devastating clinical impact and profound societal consequences. As a result, they impose a multi-billion dollar economic burden on Canada and on all advanced societies through direct costs of patient care, the loss of health and productivity, and extensive caregiver burden. There is no definitive treatment at the present time for any of these disorders. The manuscript outlines the research which will involve a systematic assessment of all chromosome 6 genes, development of a knowledge base, and development of assays and reagents for all chromosome 6 proteins. We feel that the informatic infrastructure and MRM assays developed will place the chromosome 6 consortium in an excellent position to be a leading player in this major international research initiative. This article is part of a Special Issue: Can Proteomics Fill the Gap Between Genomics and Phenotypes?

Aims Chronic heart failure is a costly epidemic that affects up to 2% of people in developed countries. The purpose of this study was to discover novel blood proteomic biomarker signatures of recovered heart function that could lead to more effective heart failure patient management by both primary care and specialty physicians. Methods and results The discovery cohort included 41 heart transplant patients and 20 healthy individuals. Plasma levels of 138 proteins were detected in at least 75% of these subjects by iTRAQ mass spectrometry. Eighteen proteins were identified that had (i) differential levels between pre-transplant patients with end-stage heart failure and healthy individuals; and (ii) levels that returned to normal by 1 month post-transplant in patients with stable heart function after transplantation. Seventeen of the 18 markers were validated by multiple reaction monitoring mass spectrometry in a cohort of 39 heart failure patients treated with drug therapy, of which 30 had recovered heart function and 9 had not. This 17-protein biomarker panel had 93% sensitivity and 89% specificity, while the RAMP® NT-proBNP assay had the same specificity but 80% sensitivity. Performance further improved when the panel was combined with NT-proBNP, yielding a net reclassification index relative to NT-proBNP of 0.28. Conclusions We have identified potential blood biomarkers of recovered heart function by harnessing data from transplant patients. These biomarkers can lead to the development of an inexpensive protein-based blood test that could be used by physicians to monitor response to therapy in heart failure, resulting in more personalized, front-line heart failure patient management.

Background Coronary angiography remains the most widely used tool for routine screening and diagnosis of cardiac allograft vasculopathy (CAV), a major pathologic process that develops in 50% of cardiac transplant recipients beyond the first year after transplant. Given the invasiveness, expense, discomfort, and risk of complications associated with angiography, a minimally invasive alternative that is sensitive and specific would be highly desirable for monitoring CAV in patients. Methods Plasma proteomic analysis using isobaric tags for relative and absolute quantitationâ€"matrix-assisted laser desorption ionization double time-of-flight mass spectrometry was carried out on samples from 40 cardiac transplant patients (10 CAV, 9 non-significant CAV, 21 possible CAV). Presence of CAV was defined as left anterior descending artery diameter stenosis ≥ 40% by digital angiography and quantitatively measured by blinded expert appraisal. Moderated t- test robust-linear models for microarray data were used to identify biomarkers that are significantly differentially expressed between patient samples with CAV and with non-significant CAV. A proteomic panel for diagnosis of CAV was generated using the Elastic Net classification method. Results We identified an 18-plasma protein biomarker classifier panel that was able to classify and differentiate patients with angiographically significant CAV from those without significant CAV, with an 80% sensitivity and 89% specificity, while providing insight into the possible underlying immune and non-alloimmune contributory mechanisms of CAV. Conclusion Our results support of the potential utility of proteomic biomarker panels as a minimally invasive means to identify patients with significant, angiographically detectable coronary artery stenosis in the cardiac allograft, in the context of post-cardiac transplantation monitoring and screening for CAV. The potential biologic significance of the biomarkers identified may also help improve our understanding of CAV pathophysiology.

Background Acute rejection in cardiac transplant patients remains a contributory factor to limited survival of implanted hearts. Currently, there are no biomarkers in clinical use that can predict, at the time of transplantation, the likelihood of post-transplant acute cellular rejection. Such a development would be of great value in personalizing immunosuppressive treatment. Methods Recipient age, donor age, cold ischemic time, warm ischemic time, panel-reactive antibody, gender mismatch, blood type mismatch and human leukocyte antigens (HLA-A, -B and -DR) mismatch between recipients and donors were tested in 53 heart transplant patients for their power to predict post-transplant acute cellular rejection. Donor transplant biopsy and recipient pre-transplant blood were also examined for the presence of genomic biomarkers in 7 rejection and 11 non-rejection patients, using non-targeted data mining techniques. Results The biomarker based on the 8 clinical variables had an area under the receiver operating characteristic curve (AUC) of 0.53. The pre-transplant recipient blood gene-based panel did not yield better performance, but the donor heart tissue gene-based panel had an AUC=0.78. A combination of 25 probe sets from the transplant donor biopsy and 18 probe sets from the pre-transplant recipient whole blood had an AUC=0.90. Biologic pathways implicated include VEGF- and EGFR-signaling, and MAPK. Conclusions Based on this study, the best predictive biomarker panel contains genes from recipient whole blood and donor myocardial tissue. This panel provides clinically relevant prediction power and, if validated, may personalize immunosuppressive treatment and rejection monitoring.

AIMS: Exosome-mediated microRNA transfer is a recently discovered mode of cell-to-cell communication, in which microRNAs act as paracrine molecules, exerting their regulatory effects in recipient cells. T cells and endothelial cells are two main players in the mechanism of acute cellular cardiac rejection. The aim of this study was to investigate the role of exosomal microRNAs in the crosstalk between T cells and endothelial cells and its implications for the molecular mechanisms that drive acute cellular rejection in heart transplantation.METHODS AND RESULTS: Exosomes isolated from serum samples of heart transplant patients with and without acute cardiac allograft rejection were profiled and showed enrichment of miR-142-3p, miR-92a-3p, miR-339-3p and miR-21-5p. Treatment of endothelial cells with the respected serum exosomes resulted the increased of miR-142-3p level in endothelial cells. Using T cells isolated from healthy donors and activated with either anti-CD3/CD28 antibody or IL-2/PHA, we could show that miR-142-3p is released from activated cells, is contained in exosomes and can be transferred to human vascular endothelial cells in vitro. Transcriptome analysis of endothelial cells treated with activated T cell supernatant with or without exosomes was used to identify mRNA targets of transferred miR-142-3-p. Overexpression of miR-142-3p in endothelial cells resulted in a significant down-regulation of RAB11FIP2, and interaction of miR-142-3p with its predicted target site was confirmed with a reporter assay. Moreover, treatment of endothelial cells with serum exosomes from heart transplant patients with acute cellular rejection resulted in down-regulation of RAB11FIP2 expression and increase in vascular endothelial permeability.CONCLUSION: We have identified a novel mechanism whereby miR-142-3p, a microRNA enriched in exosomes during acute cellular rejection, is transferred to endothelial cells and compromises endothelial barrier function via down-regulation of RAB11FIP2. This study sheds new light on the interaction between host immune system and cardiac allograft endothelium during acute cellular rejection. (Less)

The introduction of generic immunosuppressant medications may present an opportunity for cost savings in solid organ transplantation if equivalent clinical outcomes to the branded counterparts can be achieved. An interprofessional working group of the Canadian Society of Transplantation was established to develop recommendations on the use of generic immunosuppression in solid organ transplant recipients (SOTR) based on a review of the available data. Under current Health Canada licensing requirements, a demonstration of bioequivalence with the branded formulation in healthy volunteers allows for bridging of clinical data. Cyclosporine, tacrolimus, and sirolimus are designated as "critical dose drugs" and are held to stricter criteria. However, whether this provides sufficient guarantee of therapeutic equivalence in SOTR remains controversial, and failure to maintain an appropriate balance of immunosuppression may have serious consequences, including rejection, graft loss, and death. Published evidence supporting therapeutic equivalence of generic formulations in SOTR is lacking. Moreover, in the setting of multiple generic formulations the potential for uncontrolled product switching is a major concern, since generic preparations are not required to demonstrate bioequivalence with each other. Although close monitoring is recommended with any change in formulation, drug product switches are likely to occur without prescriber knowledge and may pose a significant patient safety risk. The advent of generic immunosuppression will require new practices including more frequent therapeutic drug and clinical monitoring, and increased patient education. The additional workload placed on transplant centers without additional funding will create challenges and could ultimately jeopardize patient outcomes. Until more robust clinical data are available and adequate regulatory safeguards are instituted, caution in the use of generic immunosuppressive drugs in solid organ transplantation is warranted.

Acute cardiac allograft rejection is a serious complication of heart transplantation. Investigating molecular processes in whole blood via microarrays is a promising avenue of research in transplantation, particularly due to the non-invasive nature of blood sampling. However, whole blood is a complex tissue and the consequent heterogeneity in composition amongst samples is ignored in traditional microarray analysis. This complicates the biological interpretation of microarray data. Here we have applied a statistical deconvolution approach, cell-specific significance analysis of microarrays (csSAM), to whole blood samples from subjects either undergoing acute heart allograft rejection (AR) or not (NR). We identified eight differentially expressed probe-sets significantly correlated to monocytes (mapping to 6 genes, all down-regulated in ARs versus NRs) at a false discovery rate (FDR) ≤ 15%. None of the genes identified are present in a biomarker panel of acute heart rejection previously published by our group and discovered in the same data.

This paper is set in the context of Phase One of the Ministry of Education Curriculum Implementation Exploratory Studies (CIES) project. The schools selected for this study were considered early adopters of the revised New Zealand Curriculum (NZC) (Ministry of Education, 2007). The paper provides theoretical insights and research evidence related to the role of professional development and learning in the early stages of implementation of the revised curriculum. A key finding common to most schools was the progressive development of a professional learning culture led by the principal that focused on pedagogy and student achievement prior to the introduction of the curriculum. The establishment of this culture involved processes that were task-oriented, reflective, consultative and collaborative. While there are strong parallels between the experiences of primary and secondary schools in the study, some important differences have also been noted.