Cancer Incidence and Mortality in a Cohort of US Blood Donors: A 20-Year Study

Blood donors are considered one of the healthiest populations. This study describes the epidemiology of cancer in a cohort of blood donors up to 20 years after blood donation. Records from donors who participated in the Retroviral Epidemiology Donor Study (REDS, 1991–2002) at Blood Centers of the Pacific (BCP), San Francisco, were linked to the California Cancer Registry (CCR, 1991–2010). Standardized incidence ratios (SIR) were estimated using standard US 2000 population, and survival analysis used to compare all-cause mortality among donors and a random sample of nondonors with cancer from CCR. Of 55,158 eligible allogeneic blood donors followed-up for 863,902 person-years, 4,236 (7.7%) primary malignant cancers were diagnosed. SIR in donors was 1.59 (95% CI = 1.54,1.64). Donors had significantly lower mortality (adjusted HR = 0.70, 95% CI = 0.66–0.74) compared with nondonor cancer patients, except for respiratory system cancers (adjusted HR = 0.93, 95% CI = 0.82–1.05). Elevated cancer incidence among blood donors may reflect higher diagnosis rates due to health seeking behavior and cancer screening in donors. A “healthy donor effect” on mortality following cancer diagnosis was demonstrated. This population-based database and sample repository of blood donors with long-term monitoring of cancer incidence provides the opportunity for future analyses of genetic and other biomarkers of cancer

Association between HLA Class I and Class II Alleles and the Outcome of West Nile Virus Infection: An Exploratory Study

BACKGROUND: West Nile virus (WNV) infection is asymptomatic in most individuals, with a minority developing symptoms ranging from WNV fever to serious neuroinvasive disease. This study investigated the impact of host HLA on the outcome of WNV disease. METHODS: A cohort of 210 non-Hispanic mostly white WNV(+) subjects from Canada and the U.S. were typed for HLA-A, B, C, DP, DQ, and DR. The study subjects were divided into three WNV infection outcome groups: asymptomatic (AS), symptomatic (S), and neuroinvasive disease (ND). Allele frequency distribution was compared pair-wise between the AS, S, and ND groups using χ2 and Fisher's exact tests and P values were corrected for multiple comparisons (Pc). Allele frequencies were compared between the groups and the North American population (NA) used as a control group. Logistic regression analysis was used to evaluate the potential synergistic effect of age and HLA allele phenotype on disease outcome. RESULTS: The alleles HLA-A*68, C*08 and DQB*05 were more frequently associated with severe outcomes (ND vs. AS, P(A*68) = 0.013/Pc = 0.26, P(C*08) = 0.0075/Pc = 0.064, and P(DQB1*05) = 0.029/Pc = 0.68), However the apparent DQB1*05 association was driven by age. The alleles HLA-B*40 and C*03 were more frequently associated with asymptomatic outcome (AS vs. S, P(B*40) = 0.021/Pc = 0.58 and AS vs. ND P(C*03) = 0.039/Pc = 0.64) and their frequencies were lower within WNV(+) subjects with neuroinvasive disease than within the North American population (NA vs. S, P(B*40) = 0.029 and NA vs. ND, P(C*03) = 0.032). CONCLUSIONS: Host HLA may be associated with the outcome of WNV disease; HLA-A*68 and C*08 might function as "susceptible" alleles, whereas HLA-B*40 and C*03 might function as "protective" alleles

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

A Benefit-Risk Assessment Framework for Development of Clinical Guidelines in Diagnostic Radiology

Thesis (Ph.D.)--University of Washington, 2015-12Background The body of this dissertation focuses on benefit-risk assessment in diagnostic radiology guideline development. We look specifically at structuring and making more transparent the role of expert consensus in evidence-based practice guidelines like those developed by the American College of Radiology (ACR). While several frameworks for structured benefit-risk assessment for pharmaceutical products are available, their applicability in guiding guideline development of diagnostic imaging is not well characterized.2 The most prominent are the (BRAT) Benefit-Risk Action Team and ProACT-URL (Problem, Outcomes, Alternatives, Consequence and Tradeoffs Uncertainty Risk and Linked decisions) frameworks. The six steps of the BRAT framework include, (1) defining the decision context (selecting stakeholder perspective and time horizon); (2) identifying benefit and risk outcomes visually with use of a value tree (one branch exploding all benefits and the other, all harms); (3) identifying data sources and creating a data source table; (4) tuning or customizing the framework, i.e. aligning outcomes in value tree criteria with outcomes for which data are available; (5) assessing the importance or weight of each outcome under consideration; (6) and displaying or communicating the metrics using visual and tabular formats. Likewise, the PrOACT-URL decision-making framework comprises five core elements (Problem, Outcomes, Alternatives, Consequences and Tradeoffs) and three elements relevant to evolving or volatile settings: Uncertainty, Risk attitude, and Linked decisions.3 The ACR expert panels follow a structured process in developing appropriateness criteria (AC) but do not employ a benefit-risk framework.4-7 In many cases benefit-risk assessment is limited to comparing the diagnostic accuracy of a test against test procedural risks (e.g., exposure to radiation, invasiveness). Unlike endpoints of pharmaceutical product trials, the endpoint of diagnostic accuracy does not easily fit within the benefit-risk framework and needs to be translated into other endpoints. Endpoints that are easily identified as benefits or risks — effects of test information on the provider, on patient management, and on the patient — are rarely known. It is for this reason that the ACR AC are developed using a combined approach, relying in part on the body of evidence, and in part on expert consensus.8 However, the ACR AC lack key framework elements that ensure the transparent contribution of expert consensus: making explicit relevant benefits and risks, their prioritization and respective data sources or lack thereof. Independently, several frameworks for assessing the value of diagnostic imaging are available.9-12 These frameworks are of limited value in this setting as few new studies are conducted specifically to inform clinical guideline development. At the same time, there are calls for expanding the way imaging tests are valued.13 Lee et al. proposed a three dimensional value framework (medical, psychic, and planning) for health technology assessment, proposing that the value of diagnostic tests may be underestimated in cost-effectiveness analyses that limit the scope to medical impacts.9 Staub et al. promote inclusion of patient management measures as proxies for patient health outcomes.14,15 Otero et al. discuss the lack of inclusion in cost-utility analyses of intrinsic value elements (non-clinical impacts of test information), similar to the Lee et al. psychic and planning dimensions but incorporating both provider and patient intrinsic value.16 Bossuyt and McCaffery present a framework incorporating dimensions independent of clinical outcome (emotional, social, cognition, behavior) with incomplete overlap with Otero’s and Lee’s.17 Chapter 1. Toward a Framework for Benefit Risk Assessment in Diagnostic Imaging: Identifying Scenario-Specific Criteria In the first paper, we work toward creating a unified framework incorporating elements of structured benefit-risk and elements of diagnostic imaging frameworks. To address the question of clearly defined criteria, we abstract from the literature measures of diagnostic imaging value and translate these into benefit-risk criteria (BRC). To further refine the BRC, we cross-reference our literature findings by surveying radiologist and non-radiologist perceptions of the benefits and risks in diagnostic radiology. Within the survey, we operationalize the initial broad list of BRC across four clinical use case scenarios. For each use case, we compare BRC selections between radiologists and non-radiologists. We arrive at thirty six criteria, organized into three domains: 1) those that account for differences among tests, attributable only to the test or device (n=17); 2) those that account for clinical management and provider experience effects (n=12); and 3) and those that measure distant, less direct effects of imaging tests on patients (n=7). Our results suggest that radiologist considerations do not dramatically differ from those of non-radiologists but the addition of non-radiologist selections may help guideline developers reach the goal of a broader set of priorities. These results can inform future hypotheses and studies of effects of increased clinical diversity on guideline quality and adoption. Chapter 2. A Proposed Approach for Quantitative Benefit-Risk Assessment in Diagnostic Radiology Guideline Development: The American College of Radiology Appropriateness Criteria Example In the second paper, we continue building a framework for benefit-risk assessment with a critical appraisal of quantitative benefit-risk assessment (QBRA) methodology. As there is only limited guidance on method selection and it is not clear whether these methods are well suited to the clinical guideline development process, further exploration of the potential for benefit-risk methodology to meet the needs of the ACR AC process is warranted.18-20 Thus, we review the benefit-risk methodology literature and propose several steps for selection of comparators and criteria. These steps include investigation of weak evidence and disagreement. We identify a set of benefit-risk methods addressing one or more of these needs and build a decision aid for selecting among these methods. Our results suggest there is opportunity to use multi-criteria decision analysis and incremental net health benefit methods for some decision problems the ACR faces when creating AC ratings. The process leading to the decision aid facilitates transparent contribution of expert opinion to ratings. Since the structure of the decision aid is based on clinicians’ input but also requires the skills of methods experts, the decision aid represents a key component to uniting clinical experts and methodologists. Chapter 3. Analytic Hierarchy Process for Prioritizing Imaging Tests in Diagnosis of Suspected Appendicitis In the third paper, to complement inclusion of QBRA in the framework, we evaluate empirically one of the QBRA methods for use in guideline development. There is prevailing skepticism that regulatory approval and clinical guideline decision-making is far too complicated, and too multi-dimensional for quantitative methods.21 To investigate this position further, we compare the results of a multi-criteria decision analysis approach, analytic hierarchy process, evaluating computed tomography against magnetic resonance imaging and ultrasound for classic presentation of suspected appendicitis, to the ACR AC ratings. We ask those who participated whether the process is manageable, transparent, and improves shared-understanding of the decision problem. This is, to our knowledge, the first study to show that a quantitative method produces comparable results to ratings of ACR AC guidelines and that this QBRA was found, among study participants, to facilitate shared understanding and transparency. Conclusions Structured benefit-risk assessment promises to improve the transparency of the contribution of expert consensus to clinical guideline development in diagnostic radiology. In this body of work, we propose a step-wise process resembling existing benefit-risk frameworks, but tailored to the unique needs of diagnostic radiology and demonstrate the feasibility of these recommendations. Specifically, we provide a systematic approach to selection of benefits and risks in evaluating the value of diagnostic imaging. We show that diversity of participants in selection of BRC expands the decision problem and suggests that a comprehensive definition of value is best accomplished using a multi-disciplinary perspective. Likewise, we reduce the number of QBRA for ACR to consider and provide guidance for when and how to use QBRA. Lastly, we demonstrate that MCDA can add transparency to a process like the ACR AC guideline development. Future work will entail field testing the BRC, the decision aid for QBRA selection as well as the QBRA in a setting like the ACR AC

Формування технологічних умінь у майбутніх інженерів-педагогів швейного профілю

The results of development of methods of formation of technological abilities at the future engineers-teachers sewing profile аге presents in this article. The concepts of "skill", "professional skills", "technological skills." The model of formation of technological abilities at the future engineers-teachers sewing profile, which contains the following components: motivational, informative, organizational-activity, assessment and performance. The developed model was the basis for the construction of a methods of formation of technological abilities at the future engineers-teachers in the process of sewing profile of the discipline "Technology of garments", the components of which include the goals, objectives, principles (scientific, systematic and consistency, accessibility, communication training with practice activities, clarity, emotional learning, innovation), the content, methods of implementation and evaluation criteria. Content methods presented theoretical and practical parts in a 2 modules: Module 1 "The technology of processing individual parts outerwear", module 2 "Processing Technology clothing costume Coat-range." The basis for implementation of innovative technologies chosen method of learning, such as: "Aquarium" - workshops; "Algorithm-labyrinth" - a method of tasks; Briefing the group - a method of incidents; "A folder with incoming documents" - a method of case studies; group dynamics - brainstorming; Debates - programmed instructions; discussion; Case technology, training, games - a decision highly specialized issues; short rotation - role-playing games. The criteria for evaluation of methods to determine the motivation of educational activity, the level of development of technological skills, the students' ability to self-control and self-esteemВ статье представлены результаты разработки методики формирования технологических умений у будущих инженеров-педагогов швейного профиля. Определены понятия “умение”, “профессиональные умения”, “технологические умения”. Разработана модель формирования технологических умений у будущих инженеров-педагогов швейного профиля, которая содержит следующие компоненты: целемотивационный, содержательный, организационно-деятельностный, оценочно-результативный. Разработанная модель стала основой построения методики формирования технологических умений у будущих инженеров-педагогов швейного профиля в процессе изучения дисциплины “Технология швейных изделий”, к компонентам которой относятся цели, задачи, принципы, содержание, способы реализации и критерии оценки. Основой реализации методики выбраны инновационные технологии обучения: “Аквариум” - мастерские; “Алгоритм-лабиринт” - метод задач; брифинг-группы - метод инцидентов; “Папка с входящими документами” - метод кейсов; групповая динамика - мозговой штурм; дебаты - программируемые инструкции; дискуссия; кейс-технологии, тренинги, игры - решение узкоспециальных вопросов; кратковременные ротации - ролевые игрыУ статті наведено результати розроблення методики формування технологічних умінь у майбутніх інженерів-педагогів швейного профілю. Визначено поняття “уміння”, “професійні уміння”, “технологічні уміння”. Розроблено модель формування технологічних умінь у майбутніх інженерів-педагогів швейного профілю, яка містить такі компоненти: цілемотиваційний, змістовний, організаційно-діяльнісний, оціночно-результативний. Модель стала основою побудови методики формування технологічних умінь у майбутніх інженерів-педагогів швейного профілю в процесі вивчення дисципліни “Технологія швейних виробів”, до компонентів якої належать мета, завдання, принципи, зміст, способи реалізації та критерії оцінювання. Основою реалізації методики обрано інноваційні технології навчання: “Акваріум” ‒ майстерні; “Алгоритм-лабіринт” ‒ метод завдань; брифінг-групи ‒ метод інцидентів; “Папка з вхідними документами” ‒ метод кейсів; групова динаміка ‒ мозковий штурм; дебати ‒ програмовані інструкції; дискусія ‒ розмова; кейс-технології, тренінги, ігри ‒ рішення вузькоспеціальних питань; короткочасні ротації ‒ рольові ігри

Long-term costs of introducing hpv-dna post-treatment surveillance to national cervical cancer screening in ireland

Introduction: Co-testing (cytology plus human papillomavirus DNA testing) as part of cervical cancer surveillance in Ireland increases one-time testing costs. Of interest to policy makers was the long-term impact of these costs accompanied by decreases in intensity of recalls for women with no detected abnormalities. Methods: A cost analysis of cytology-only and co-testing strategy was implemented using decision analytic modeling, aggregating testing utilization and costs for each of the two strategies over 12 years. Results: Aggregated incremental costs of the co-testing strategy were positive for the first 3 years but became negative thereafter, generating a cost savings of roughly Euro20 million in favor of the cytology-only strategy over a 12-year period. Results were robust over a range of sensitivity analyses with respect to discount and attrition rates. Discussion: This analysis provided valuable information to policy makers contributing to the introduction of co-testing for post-treatment surveillance (PTS) in Ireland

Long-term costs of introducing hpv-dna post-treatment surveillance to national cervical cancer screening in ireland

Introduction: Co-testing (cytology plus human papillomavirus DNA testing) as part of cervical cancer surveillance in Ireland increases one-time testing costs. Of interest to policy makers was the long-term impact of these costs accompanied by decreases in intensity of recalls for women with no detected abnormalities. Methods: A cost analysis of cytology-only and co-testing strategy was implemented using decision analytic modeling, aggregating testing utilization and costs for each of the two strategies over 12 years. Results: Aggregated incremental costs of the co-testing strategy were positive for the first 3 years but became negative thereafter, generating a cost savings of roughly Euro20 million in favor of the cytology-only strategy over a 12-year period. Results were robust over a range of sensitivity analyses with respect to discount and attrition rates. Discussion: This analysis provided valuable information to policy makers contributing to the introduction of co-testing for post-treatment surveillance (PTS) in Ireland

Scaffolds Based on Silk Fibroin with Decellularized Rat Liver Microparticles: Investigation of the Structure, Biological Properties and Regenerative Potential for Skin Wound Healing

The development of advanced biomaterials and constructs for accelerated recovery of damaged tissues is a key direction in regenerative medicine. Biocompatible scaffolds based on natural biopolymers are widely used for these tasks. Organ decellularization enables obtaining a cell-free extracellular matrix (ECM) with preserved composition and biological activity. The objectives of the present work were combining these two approaches for the development of a composite scaffold based on silk fibroin and ECM microparticles and assessing its structure, biological properties, and regenerative potential. ECM microparticles were obtained by grinding the decellularized matrix of Wistar rat liver in liquid nitrogen. Scaffolds in the form of films were prepared by the casting method. The sinuous and rough topography of the scaffold surface was assessed by the scanning probe nanotomography (SPNT) technique. The inclusion of ECM microparticles in the composition did not affect the elasticity and tensile strength of the scaffolds. The obtained scaffold was non-toxic to cells, maintained high levels of adhesion and proliferation of mouse 3T3 fibroblast and Hep-G2 cells, and showed high regenerative potential, which was studied in the experimental model of full-thickness rat skin wound healing. The wound healing was accelerated by 1.74 times in comparison with the control