Toward a risk-based approach to the assessment of the surety of information systems

Traditional approaches to the assessment of information systems have treated system security, system reliability, data integrity, and application functionality as separate disciplines. However, each areas requirements and solutions have a profound impact on the successful implementation of the other areas. A better approach is to assess the ``surety`` of an information system, which is defined as ensuring the ``correct`` operation of an information system by incorporating appropriate levels of safety, functionality, confidentiality, availability, and integrity. Information surety examines the combined impact of design alternatives on all of these areas. We propose a modelling approach that combines aspects of fault trees and influence diagrams for assessing information surety requirements under a risk assessment framework. This approach allows tradeoffs to be based on quantitative importance measures such as risk reduction while maintaining the modelling flexibility of the influence diagram paradigm. This paper presents an overview of the modelling method and a sample application problem

Searching for Programme theories for a realist evaluation: a case study comparing an academic database search and a simple Google search

Background: Realist methodologies are increasingly being used to evaluate complex interventions in health and social care. Programme theory (ideas and assumptions of how a particular intervention works) development is the first step in a realist evaluation or a realist synthesis, with literature reviews providing important evidence to support this. Deciding how to search for programme theories is challenging and there is limited guidance available. Using an example of identifying programme theories for a realist evaluation of Pressure Ulcer Risk Assessment Instruments in clinical practice, the authors explore and compare several different approaches to literature searching and highlight important methodological considerations for those embarking on a programme theory review. Methods: We compared the performance of an academic database search with a simple Google search and developed an optimised search strategy for the identification primary references (i.e. documents providing the clearest examples of programme theories) associated with the use of Pressure Ulcer Risk Assessment Instruments (PU-RAIs). We identified the number of primary references and the total number of references retrieved per source. We then calculated the number needed to read (NNR) expressed as the total number of titles and abstracts screened to identify one relevant reference from each source. Results: The academic database search (comprising CINAHL, The Cochrane Library, EMBASE, HMIC, Medline) identified 2 /10 primary references with a NNR of 1395.The Google search identified 7/10 primary references with a NNR of 10.1. The combined NNR was 286.3. The optimised search combining Google and CINAHL identified 10/10 primary references with a NNR of 40.2. Conclusion: The striking difference between the efficiency of the review’s academic database and Google searches in finding relevant references prompted an in-depth comparison of the two types of search. The findings indicate the importance of including grey literature sources such as Google in this particular programme theory search, while acknowledging the need for transparency of methods. Further research is needed to facilitate improved guidance for programme theory searches to enhance practice in the realist field and to save researcher time and therefore resource

Development of a National Pain Management Competency Profile to Guide Entry-Level Physiotherapy Education in Canada

Background National strategies from North America call for substantive improvements in entry-level pain management education to help reduce the burden of chronic pain. Past work has generated a valuable set of interprofessional pain management competencies to guide the education of future health professionals. However, there has been very limited work that has explored the development of such competencies for individual professions in different regions. Developing profession-specific competencies tailored to the local context is a necessary first step to integrate them within local regulatory systems. Our group is working toward this goal within the context of entry-level physiotherapy (PT) programs across Canada. Aims This study aimed to create a consensus-based competency profile for pain management, specific to the Canadian PT context. Methods A modified Delphi design was used to achieve consensus across Canadian university-based and clinical pain educators. Results Representatives from 14 entry-level PT programs (93% of Canadian programs) and six clinical educators were recruited. After two rounds, a total of 15 competencies reached the predetermined endorsement threshold (75%). Most participants (85%) reported being “very satisfied” with the process. Conclusions This process achieved consensus on a novel pain management competency profile specific to the Canadian PT context. The resulting profile delineates the necessary abilities required by physiotherapists to manage pain upon entry to practice. Participants were very satisfied with the process. This study also contributes to the emerging literature on integrated research in pain management by profiling research methodology that can be used to inform related work in other health professions and regions

Lineage-specific distribution of high levels of genomic 5-hydroxymethylcytosine in mammalian development

Methylation of cytosine is a DNA modification associated with gene repression. Recently, a novel cytosine modification, 5-hydroxymethylcytosine (5-hmC) has been discovered. Here we examine 5-hmC distribution during mammalian development and in cellular systems, and show that the developmental dynamics of 5-hmC are different from those of 5-methylcytosine (5-mC); in particular 5-hmC is enriched in embryonic contexts compared to adult tissues. A detectable 5-hmC signal appears in pre-implantation development starting at the zygote stage, where the paternal genome is subjected to a genome-wide hydroxylation of 5-mC, which precisely coincides with the loss of the 5-mC signal in the paternal pronucleus. Levels of 5-hmC are high in cells of the inner cell mass in blastocysts, and the modification colocalises with nestin-expressing cell populations in mouse post-implantation embryos. Compared to other adult mammalian organs, 5-hmC is strongly enriched in bone marrow and brain, wherein high 5-hmC content is a feature of both neuronal progenitors and post-mitotic neurons. We show that high levels of 5-hmC are not only present in mouse and human embryonic stem cells (ESCs) and lost during differentiation, as has been reported previously, but also reappear during the generation of induced pluripotent stem cells; thus 5-hmC enrichment correlates with a pluripotent cell state. Our findings suggest that apart from the cells of neuronal lineages, high levels of genomic 5-hmC are an epigenetic feature of embryonic cell populations and cellular pluri- and multi-lineage potency. To our knowledge, 5-hmC represents the first epigenetic modification of DNA discovered whose enrichment is so cell-type specific

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Generation of Functional Human Hepatic Endoderm from Human Induced Pluripotent Stem Cells

With the advent of induced pluripotent stem cell (iPSC) technology, it is now feasible to generate iPSCs with a defined genotype or disease state. When coupled with direct differentiation of defined lineage, such as hepatic endoderm (HE). iPSC would revolutionise the way we study human liver biology and generate efficient “off the shelf” models of human liver disease. Here we show the `proof of concept' that iPSC lines representing both male and female sexes and two ethnic origins can be differentiated to HE at efficiencies of between 70–90%, using a method mimicking a physiological condition. iPSC-derived HE exhibited hepatic morphology, and expressed the hepatic markers, Albumin and E-Cadherin as assessed by immuno-histochemistry. They also expressed alpha fetal protein (AFP), HNF4a, and a metabolic marker, Cyp7A1, demonstrating a definitive endodermal lineage differentiation. Furthermore, iPSC-derived hepatocytes produced and secreted the plasma proteins, fibrinogen, fibronectin, transthyretin (TTR) and AFP, an essential feature for functional HE. Additionally iPSC-derived HE supported both CYP1A2 and 3A4 metabolism, which is essential for drug and toxicology testing. CONCLUSION: This work is first to demonstrate the efficient generation of hepatic endodermal lineage from human iPSC that exhibits key attributes of hepatocytes, and the potential application of iPSC-derived HE in studying human liver biology. In particular, iPSC from individuals representing highly polymorphic variants in metabolic genes and different ethnic groups will provide pharmaceutical development and toxicology studies a unique opportunity to revolutionise predictive drug toxicology assays and allow the creation of in vitro hepatic disease models

Tamoxifen for the treatment of myeloproliferative neoplasms: a phase II clinical trial and exploratory analysis

Current therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed tamoxifen’s safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2V617F, CALRins5 or CALRdel52 peripheral blood allele burden ≥20% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study’s A’herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk

Development of a national pain management competency profile to guide entry-level physiotherapy education in Canada

Background National strategies from North America call for substantive improvements in entry-level pain management education to help reduce the burden of chronic pain. Past work has generated a valuable set of interprofessional pain management competencies to guide the education of future health professionals. However, there has been very limited work that has explored the development of such competencies for individual professions in different regions. Developing profession-specific competencies tailored to the local context is a necessary first step to integrate them within local regulatory systems. Our group is working toward this goal within the context of entry-level physiotherapy (PT) programs across Canada. Aims This study aimed to create a consensus-based competency profile for pain management, specific to the Canadian PT context. Methods A modified Delphi design was used to achieve consensus across Canadian university-based and clinical pain educators. Results Representatives from 14 entry-level PT programs (93% of Canadian programs) and six clinical educators were recruited. After two rounds, a total of 15 competencies reached the predetermined endorsement threshold (75%). Most participants (85%) reported being “very satisfied” with the process. Conclusions This process achieved consensus on a novel pain management competency profile specific to the Canadian PT context. The resulting profile delineates the necessary abilities required by physiotherapists to manage pain upon entry to practice. Participants were very satisfied with the process. This study also contributes to the emerging literature on integrated research in pain management by profiling research methodology that can be used to inform related work in other health professions and regions. RÉSUMÉ Contexte: Contexte: Les stratégies nationales nord-américaines préconisent des améliorations sensibles à la formation de base en matiére de prise en charge de la douleur afin de contribuer à la réduction du fardeau de la douleur chronique. Des travaux antérieurs ont généré un ensemble de compétences interprofessionnelles utile en matiére de prise en charge de la douleur afin de guider la formation des futurs professionnels de la santé. Cependant, trés peu de travaux ont porté sur l'acquisition de telles compétences pour des professions individuelles dans différentes régions. L’uisition de compétences spécifiques à une profession adaptées au contexte local est une première étape nécessaire pour leur intégration dans les systèmes réglementaires locaux. Notre groupe travaille à cet objectif dans le cadre de programmes de formation de base en physiothèrapie partout au Canada. Objectifs: Cette étude visait à créer un profil de compétences consensuel pour la prise en charge de la douleur, propre au contexte canadien de la physiothérapie. Méthodes: Un devis Delphi modifié a étè utilisé pour parvenir à un consensus parmi des formateurs en milieu universitaire et clinique en matière de douleur en milieu universitaire et clinique. Résultats: Des représentants de 14 programmes de formation de base en physiothérapie (93 % des programmes canadiens) et de six formateurs en milieu clinique ont été recrutés. Après deux tours, 15 compétences ont atteint le seuil d’approbation prédéterminé (75 %). La plupart des participants (85 %) ont déclaré être « très satisfaits »du processus. Conclusions: Ce processus a permis de dégager un consensus sur un nouveau profil de compétences en matiére de prise en charge de la douleur propre au contexte canadien de la physiothérapie. Ce profil délimite les habiletés requises des physiothérapeutes pour prendre en charge la douleur en début de pratique. Les participants ont été très satisfaits du processus. Cette étude contribue également à la littérature émergente sur la recherche intégrée en matière de prise en charge de la douleur en définissant une méthodologie de recherche qui peut être utilisée pour éclairer des travaux similaires dans d’autres professions de la santé et dans d’autres régions

Rare germline copy number variants (CNVs) and breast cancer risk.

Funder: CIHRGermline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance