Articles de revues sur le sujet « Disease modelling, Systems analysis, epidemiology, Model evaluation »

Introduction. Outbreaks of infectious diseases and the COVID-19 pandemic in particular pose a serious public health challenge. The other side of the challenge is always opportunity, and today such opportunities are information technology, decision making systems, best practices of proactive management and control based on modern methods of data analysis (data driven decision making) and modeling. The article reviews the prospects for the use of publicly available software in modeling epidemiological trends. Strengths and weaknesses, main characteristics and possible aspects of application are considered. The purpose of the article is to review publicly available health software. Give situations in which one or another approach will be useful. Segment and determine the effectiveness of the underlying models. Note the prospects of high-performance computing to model the spread of epidemics. Results. Although deterministic models are ready for practical use without specific additional settings, they lose comparing to other groups in terms of their functionality. To obtain evaluation results from stochastic and agentoriented models, you first need to specify the epidemic model, which requires deeper knowledge in the field of epidemiology, a good understanding of the statistical basis and the basic assumptions on which the model is based. Among the considered software, EMOD (Epidemiological MODelling software) from the Institute of Disease Modeling is a leader in functionality. Conclusions. There is a free access to a relatively wide set of software, which was originally developed by antiepidemiological institutions for internal use in decision-making, however was later opened to the public. In general, these programs have been adapted to increase their practical application. Got narrowed focus on potential issues. The possibility of adaptive use was provided. We can note the sufficient informativeness and convenience of using the software of the group of deterministic methods. Also, such models have a rather narrow functional focus. Stochastic models provide more functionality, but lose some of their ease of use. We have the maximum functionality from agentoriented models, although for their most effective use you need to have the appropriate skills to write program code. Keywords: epidemiological software, deterministic modeling, stochastic modeling, agentoriented mode-ling, high performance computing, decision making systems.

Pertussis is an infectious respiratory disease for which mass vaccination is an effective preventive strategy. In many developed countries, where high vaccination coverage has been maintained for approximately 50 years, re-emergence of the disease has been observed in all age groups. In the municipality of Rio de Janeiro (RJ), where vaccination started in the 1980s, surveillance data show no sign of disease re-emergence. We developed a mathematical model that incorporates the major demographic aspects of a large urban centre in a developing nation, in addition to the most important epidemiological aspects of disease transmission. Parameter values were estimated based on RJ demographic and vaccine coverage data. Overall, all vaccination strategies determined a major decrease (over 95% decrease when compared to the pre-vaccine era) in the incidence of primary infections (occurring in individuals who have never been immunized through infection or vaccine). On the other hand, the strategies (a) three doses at age 2–11 months, (b) three doses plus booster at age 12–23 months, (c) three doses plus booster at age 4–5 years, and (d) three doses plus both boosters, differently affected the incidence of secondary infections (occurring in previously infected/vaccinated individuals). Given that the immunity against pertussis wanes with time and that the infectious agent has not been eliminated from the population, it is expected that pertussis will continue to be a problem in RJ. Actually, since immunity acquired from vaccine wanes faster than disease-acquired immunity and the possibility of natural boosters has decreased with mass vaccination, an increase in the incidence of secondary infections among older age groups is expected (and predicted by the model). Possible explanations as to why this dynamics is not captured by the RJ surveillance system are discussed. A poorly effective surveillance system and a lack of awareness regarding loss of immunity and the possibility of pertussis infection in older age groups are among them. Finally, we bring attention to the need of (i) field studies for the measurement of pertussis incidence in adolescents and adults; (ii) better understanding of the transmission dynamics currently occurring in RJ, and (iii) re-evaluation of vaccination strategies with the possible introduction of acellular vaccines for the vaccination of older individuals.

A cardinal challenge in epidemiological and ecological modelling is to develop effective and easily deployed tools for model assessment. The availability of such methods would greatly improve understanding, prediction and management of disease and ecosystems. Conventional Bayesian model assessment tools such as Bayes factors and the deviance information criterion (DIC) are natural candidates but suffer from important limitations because of their sensitivity and complexity. Posterior predictive checks, which use summary statistics of the observed process simulated from competing models, can provide a measure of model fit but appropriate statistics can be difficult to identify. Here, we develop a novel approach for diagnosing mis-specifications of a general spatio-temporal transmission model by embedding classical ideas within a Bayesian analysis. Specifically, by proposing suitably designed non-centred parametrization schemes, we construct latent residuals whose sampling properties are known given the model specification and which can be used to measure overall fit and to elicit evidence of the nature of mis-specifications of spatial and temporal processes included in the model. This model assessment approach can readily be implemented as an addendum to standard estimation algorithms for sampling from the posterior distributions, for example Markov chain Monte Carlo. The proposed methodology is first tested using simulated data and subsequently applied to data describing the spread of Heracleum mantegazzianum (giant hogweed) across Great Britain over a 30-year period. The proposed methods are compared with alternative techniques including posterior predictive checking and the DIC. Results show that the proposed diagnostic tools are effective in assessing competing stochastic spatio-temporal transmission models and may offer improvements in power to detect model mis-specifications. Moreover, the latent-residual framework introduced here extends readily to a broad range of ecological and epidemiological models.

Abstract Purpose Three-dimensional (3D) gallbladder (GB) geometrical models are essential to GB motor function evaluation and GB wall biomechanical property identification by employing finite element analysis (FEA) in GB disease diagnosis with ultrasound systems. Methods for establishing such 3D geometrical models based on static two-dimensional (2D) ultrasound images scanned along the long-axis/sagittal and short-axis/transverse cross-sections in routine GB disease diagnosis at the beginning of emptying phase have not been documented in the literature so far. Methods Based on two custom MATLAB codes composed, two images were segmented manually to secure two sets of the scattered points for the long- and short-axis GB cross-section edges; and the points were best fitted with a piecewise cubic spline function, and the short-axis cross-section edges were lofted along the long-axis to yield a 3D geometrical model, then GB volume of the model was figured out. The model was read into SolidWorks for real surface generation and involved in ABAQUS for FEA. Results 3D geometrical models of seven typical GB samples were established. Their GB volumes are with 15.5% and − 4.4% mean errors in comparison with those estimated with the ellipsoid model and sum-of-cylinders method but can be correlated to the latter very well. The maximum first principal in-plane stress in the 3D models is higher than in the ellipsoid model by a factor of 1.76. Conclusions A numerical method was put forward here to create 3D GB geometrical models and can be applied to GB disease diagnosis and GB shape analysis with principal component method potentially in the future.

Abstract Background Antimicrobial resistance (AMR) is a global threat to effective prevention and treatment of an ever-increasing range of infections. Pneumococcal conjugate vaccines (PCV) used in infant national immunization programs have been shown to decrease AMR pneumococci. Cost-effectiveness models evaluating the value for money of PCV programs have not considered the economic impact of reducing antimicrobial prescribing or prolonged infections due to treatment failures. Standardized frameworks are needed for models to address outcomes and impact on health resource utilization related to AMR. Methods We developed a conceptual modeling methodology suitable for a health economic evaluation of an infant PCV program. We considered impact of PCVs on pneumococcal disease (PD) specifically related to clinical management of AMR-PD, including AMR epidemiology, antibiotic prescribing patterns, and healthcare resource utilization. Model inputs were evaluated regarding optimal and available data sources considering the complex nature of AMR at the national, regional, and global level. Results The proposed framework considers impact of PCVs on antimicrobial prescribing due to invasive pneumococcal disease (IPD), community acquired pneumonia (CAP), and acute otitis media (AOM) across 3 pathways (Figure 1). The population and pathogen-level pathway describe epidemiology and vaccine impact. The care level pathway describes clinical disease management. The health outcomes pathway characterizes resistant or successfully treated PD costs and quality of life. Conceptual Economic Model Methodology Conclusion We present a generalizable methodology to quantify impact of PCVs on cases and outcomes of PD related to AMR. Modelling vaccine-preventable burden of AMR-PD requires data extrapolations and assumptions due to the myriad of interconnected pathways (i.e. microbiology, epidemiology, environment, health systems). Further work is needed to validate assumptions and linkages across incomplete data sources. Disclosures Raymond Farkouh, PhD, Pfizer (Employee) Arianna Nevo, MPH, Pfizer, Inc. (Other Financial or Material Support, I am an employee of IQVIA. IQVIA received funding from Pfizer to carry out the project.) Jennifer Uyei, PhD, MPH, Pfizer, Inc. (Other Financial or Material Support, I am an employee of IQVIA. IQVIA received funding from Pfizer to carry out the project.) Cassandra Hall-Murray, PharmD, Pfizer, Inc. (Employee) Joseph Lewnard, PhD, Pfizer, Inc. (Consultant, Grant/Research Support, Advisor or Review Panel member) Matthew Wasserman, MSc., Pfizer Inc. (Employee)

The safe removal of disease-carrying human waste is the objective of all sanitation systems and the limiting of air pressure transients within the system remains a significant part of current codes and regulations. The water trap seal offers fundamental protection and is the system’s sole barrier between the public sewer network and habitable space inside a building. Modelling water trap seal responses to air pressure fluctuations offers an opportunity to analyse whole system performance, but the quality of the data depends on the accuracy of the modelling technique and that of the defining inputs. AIRNET, a 1D Method of Characteristics based model, enables rapid whole system testing; however, the present boundary condition for the water trap seal within the model is based solely on steady state conditions, ignoring system dynamics. Computational fluid dynamics offers an opportunity to numerically evaluate the flow patterns within the trap seal in response to applied air pressure transients. This research confirms the importance of the rate of rise, and hence frequency of air pressure transients incident on water trap seals and relates this to potential vulnerabilities of different device geometries, particularly the ratio between inner and outer wall length. The research led to the development of a dynamic velocity decrement model encapsulating unsteady friction and separation losses linked to device geometry for the first time. The development of a frequency-dependent internal energy term Δ v, suitable for inclusion in AIRNET provides the capability to predict more realistic water trap response to air pressure transients over a range of air pressure transient frequencies likely to cause problems: 1 Hz to 8 Hz. Practical application: Whole system modelling can greatly improve the ability of design engineers to fully simulate the operation of a building drainage system in a realistic way. The work described in this paper improves the accuracy of whole system models by evaluating water dynamic responses to air pressure transients using a range of techniques including computational fluid dynamics and more traditional 1D finite difference method of characteristics models. The work also paves the way for more robust evaluation of building drainage products through in-depth investigation of the fluid mechanics associated with their operation.

The widespread, and in many countries unprecedented, use of non-pharmaceutical interventions (NPIs) during the COVID-19 pandemic has highlighted the need for mathematical models which can estimate the impact of these measures while accounting for the highly heterogeneous risk profile of COVID-19. Models accounting either for age structure or the household structure necessary to explicitly model many NPIs are commonly used in infectious disease modelling, but models incorporating both levels of structure present substantial computational and mathematical challenges due to their high dimensionality. Here we present a modelling framework for the spread of an epidemic that includes explicit representation of age structure and household structure. Our model is formulated in terms of tractable systems of ordinary differential equations for which we provide an open-source Python implementation. Such tractability leads to significant benefits for model calibration, exhaustive evaluation of possible parameter values, and interpretability of results. We demonstrate the flexibility of our model through four policy case studies, where we quantify the likely benefits of the following measures which were either considered or implemented in the UK during the current COVID-19 pandemic: control of within- and between-household mixing through NPIs; formation of support bubbles during lockdown periods; out-of-household isolation (OOHI); and temporary relaxation of NPIs during holiday periods. Our ordinary differential equation formulation and associated analysis demonstrate that multiple dimensions of risk stratification and social structure can be incorporated into infectious disease models without sacrificing mathematical tractability. This model and its software implementation expand the range of tools available to infectious disease policy analysts.

4596 Background: Small bowel adenocarcinoma is a rare malignancy and is often associated with poor outcome. The impact that the number of positive and negative lymph nodes (LN) have upon survival following curative resection has not been studied. Methods: Patients aged 18–90 with adenocarcinoma of the small intestine diagnosed between 1988 and 2005 were identified from SEER data (ver. 2008). Disease-specific survival (DSS) outcomes were determined through 12/2005. Cox proportional hazards regression analyses were performed after adjusting for age, sex, race, T stage, grade, and primary site. Stage I-II cases were categorized by total LN examined (1–8, 9–12, and >12). Stage III cases were evaluated using cut-point analysis to determine the number of positive LN that predicted outcomes. This result was then compared to the predictive value of the ratio of positive to total LN (LNR) using the chi-square statistic. Results: 1,991 patients were identified in the SEER database. Survival among stage I/II patients (n=1,216) was dependent upon the total number of LN assessed. 5-year DSS for stage II patients was 66%, 82% (HR 0.52 95% CI .33-.84), and 88% (HR 0.38, 95% CI .23-.61) for 1–8, 9–12, >12 LN, respectively. The optimal cutpoint of positive LN for stage III disease (n=775) was <3 compard to ≥3 with 5 year DSS of 58% vs. 37% (HR 1.49, 95% CI 1.15–1.92, P=0.002), respectively. Among stage III patients, the LNR was even more predictive of survival than stratification by the number of positive lymph nodes as demonstrated by an improved chi-square statistic for the multivariate model (78.8 vs 63.1, P=0.0005). Conclusions: As noted in colon cancer, the total number of LN assessed has considerable influence upon survival in stage I, II and III small bowel adenocarcinoma. Stratifying stage III small bowel adenocarcinoma into those with <3 and ≥3 positive lymph nodes significantly improves prognostication for these patients and future staging systems should incorporate the number of positive nodes into nodal staging. The use of LNR may provide additional prognostic information. No significant financial relationships to disclose.

Objectives Sub-Saharan Africa faces a shortage of skilled epidemiologists to prevent, detect, and respond to health threats. Tanzania has implemented one of the first Centers for Disease Control and Prevention Field Epidemiology Training Program (FETP) Intermediate courses in Africa. This course aims to strengthen health workforce capacity in surveillance system assessment, outbreak investigation, and evaluation, prioritizing HIV control. We conducted an outcome evaluation of this new course. Methods We used a pre/post evaluation design using data from 4 cohorts of trainees who took the FETP Intermediate course from 2017 to 2020. We conducted knowledge assessments before and after each cohort and combined those results. Outcomes included knowledge and self-rated competency and trends in integrated disease surveillance and response (IDSR) data. We collected data through tests, field assignments, exit interviews, and data audits. We compared the mean change in pre-/posttest scores using linear regression and 95% CIs. We used content analysis to summarize exit interviews. Results Fifty-three FETP trainees from 10 regions enrolled in the FETP Intermediate course, and 52 (99.0%) completed the course. We found substantial increases in mean knowledge (44.0 to 68.0 points) and self-rated competency (4.14 to 4.43) scores before and after the course. Trainees evaluated 52 surveillance systems and 52 district HIV care programs, and 39 (75.0%) trainees participated in outbreak investigations. From before to after cohort 1, timeliness and completeness of IDSR reports increased from 4.2% to 52.1% and from 27.4% to 76.5%, respectively. Course strengths were quality of instruction, individualized mentoring, and practical skills gained. Challenges were mentor availability, limited time for data analysis practice, and balancing work and field assignments. Conclusions The Tanzania FETP Intermediate course substantially improved trainee knowledge and helped to improve local data quality and reporting. This course is a promising model to strengthen subnational capacity to prevent, detect, and respond to public health threats in Africa.

Bluetongue (BT) is among the World Animal Health Organization (OIE) listed diseases due to its potential for rapid spread and serious economic impact on livestock. Because of its epidemiology, in Europe, only Southern countries were affected by the disease in the past. However in the latter half of 2006, an unprecedented outbreak of bluetongue virus (BTV) serotype 8 occurred in North-Western European countries. To define potential regions that are at risk for BT epidemics it is essential to study vector distribution and abundance. This study focused on BT vector spread, mostly in Austria. The objective was to produce risk maps with the more likely areas for vector occurrence and thus to support BT prevention and control. The introductory review gives an overview of the epidemiology of the disease with a focus on the vectors, the recent outbreaks in North-Western Europe, and the importance of statistical model­ling and geographical information systems (GIS) in predicting, preventing and controlling BT. The statistical analysis was mainly based on data from the Austrian entomological surveillance system, weather stations and topo­graphical information. A multiple linear regression model was fitted to the data to predict the occurrence of BTV vectors and subsequently to create risk maps for the whole country. Despite the fact that the limited nature of the data does not allow precise estimation, in general the models indicated that vectors occurred in preferential areas where they could be very abundant. A more detailed analysis should be carried out with a multidisciplinary team including epidemiologists, biologists, meteorologists, ento­mologists, and statisticians, so that the complexity of BT epide­miology may be better understood, and a more efficient process of prevention and control of the disease may be set up.

Spatial analysis has become an increasingly used analytic approach to describe and analyze spatial characteristics of disease burden, but the depth and coverage of its usage for health surveys data in Sub-Saharan Africa are not well known. The objective of this scoping review was to conduct an evaluation of studies using spatial statistics approaches for national health survey data in the SSA region. An organized literature search for studies related to spatial statistics and national health surveys was conducted through PMC, PubMed/Medline, Scopus, NLM Catalog, and Science Direct electronic databases. Of the 4,193 unique articles identified, 153 were included in the final review. Spatial smoothing and prediction methods were predominant (n = 108), followed by spatial description aggregation (n = 25), and spatial autocorrelation and clustering (n = 19). Bayesian statistics methods and lattice data modelling were predominant (n = 108). Most studies focused on malaria and fever (n = 47) followed by health services coverage (n = 38). Only fifteen studies employed nonstandard spatial analyses (e.g., spatial model assessment, joint spatial modelling, accounting for survey design). We recommend that for future spatial analysis using health survey data in the SSA region, there must be an improve recognition and awareness of the potential dangers of a naïve application of spatial statistical methods. We also recommend a wide range of applications using big health data and the future of data science for health systems to monitor and evaluate impacts that are not well understood at local levels.

Background Local authorities in England commission the NHS Health Check programme to invite everyone aged 40–74 years without pre-existing conditions for risk assessment and eventual intervention, if needed. However, the programme’s effectiveness, cost-effectiveness and equity impact remain uncertain. Aim To develop a validated open-access flexible web-based model that enables local commissioners to quantify the cost-effectiveness and potential for equitable population health gain of the NHS Health Check programme. Objectives The objectives were as follows: (1) co-produce with stakeholders the desirable features of the user-friendly model; (2) update the evidence base to support model and scenario development; (3) further develop our computational model to allow for developments and changes to the NHS Health Check programme and the diseases it addresses; (4) assess the effectiveness, cost-effectiveness and equity of alternative strategies for implementation to illustrate the use of the tool; and (5) propose a sustainability and implementation plan to deploy our user-friendly computational model at the local level. Design Co-production workshops surveying the best-performing local authorities and a systematic literature review of strategies to increase uptake of screening programmes informed model use and development. We then co-produced the workHORSE (working Health Outcomes Research Simulation Environment) model to estimate the health, economic and equity impact of different NHS Health Check programme implementations, using illustrative-use cases. Setting Local authorities in England. Participants Stakeholders from local authorities, Public Health England, the NHS, the British Heart Foundation, academia and other organisations participated in the workshops. For the local authorities survey, we invited 16 of the best-performing local authorities in England. Interventions The user interface allows users to vary key parameters that represent programme activities (i.e. invitation, uptake, prescriptions and referrals). Scenarios can be compared with each other. Main outcome measures Disease cases and case-years prevented or postponed, incremental cost-effectiveness ratios, net monetary benefit and change in slope index of inequality. Results The survey of best-performing local authorities revealed a diversity of effective approaches to maximise the coverage and uptake of NHS Health Check programme, with no distinct ‘best buy’. The umbrella literature review identified a range of effective single interventions. However, these generally need to be combined to maximally improve uptake and health gains. A validated dynamic, stochastic microsimulation model, built on robust epidemiology, enabled service options analysis. Analyses of three contrasting illustrative cases estimated the health, economic and equity impact of optimising the Health Checks, and the added value of obtaining detailed local data. Optimising the programme in Liverpool can become cost-effective and equitable, but simply changing the invitation method will require other programme changes to improve its performance. Detailed data inputs can benefit local analysis. Limitations Although the approach is extremely flexible, it is complex and requires substantial amounts of data, alongside expertise to both maintain and run. Conclusions Our project showed that the workHORSE model could be used to estimate the health, economic and equity impact comprehensively at local authority level. It has the potential for further development as a commissioning tool and to stimulate broader discussions on the role of these tools in real-world decision-making. Future work Future work should focus on improving user interactions with the model, modelling simulation standards, and adapting workHORSE for evaluation, design and implementation support. Study registration This study is registered as PROSPERO CRD42019132087. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 35. See the NIHR Journals Library website for further project information.

Background Vascular services is changing rapidly, having emerged as a new specialty with its own training and specialised techniques. This has resulted in the need for reconfiguration of services to provide adequate specialist provision and accessible and equitable services. Objectives To identify the effects of service configuration on practice, resource use and outcomes. To model potential changes in configuration. To identify and/or develop electronic data collection tools for collecting patient-reported outcome measures and other clinical information. To evaluate patient preferences for aspects of services other than health-related quality of life. Design This was a multiple methods study comprising multiple systematic literature reviews; the development of a new outcome measure for users of vascular services (the electronic Personal Assessment Questionnaire – Vascular) based on the reviews, qualitative studies and psychometric evaluation; a trade-off exercise to measure process utilities; Hospital Episode Statistics analysis; and the development of individual disease models and a metamodel of service configuration. Setting Specialist vascular inpatient services in England. Data sources Modelling and Hospital Episode Statistics analysis for all vascular inpatients in England from 2006 to 2018. Qualitative studies and electronic Personal Assessment Questionnaire – Vascular evaluation with vascular patients from the Sheffield area. The trade-off studies were based on a societal sample from across England. Interventions The data analysis, preference studies and modelling explored the effect of different potential arrangements for service provision on the resource use, workload and outcomes for all interventions in the three main areas of inpatient vascular treatment: peripheral arterial disease, abdominal aortic aneurysm and carotid artery disease. The electronic Personal Assessment Questionnaire – Vascular was evaluated as a potential tool for clinical data collection and outcome monitoring. Main outcome measures Systematic reviews assessed quality and psychometric properties of published outcome measures for vascular disease and the relationship between volume and outcome in vascular services. The electronic Personal Assessment Questionnaire – Vascular development considered face and construct validity, test–retest reliability and responsiveness. Models were validated using case studies from previous reconfigurations and comparisons with Hospital Episode Statistics data. Preference studies resulted in estimates of process utilities for aneurysm treatment and for travelling distances to access services. Results Systematic reviews provided evidence of an association between increasing volume of activity and improved outcomes for peripheral arterial disease, abdominal aortic aneurysm and carotid artery disease. Reviews of existing patient-reported outcome measures did not identify suitable condition-specific tools for incorporation in the electronic Personal Assessment Questionnaire – Vascular. Reviews of qualitative evidence, primary qualitative studies and a Delphi exercise identified the issues to be incorporated into the electronic Personal Assessment Questionnaire – Vascular, resulting in a questionnaire with one generic and three disease-specific domains. After initial item reduction, the final version has 55 items in eight scales and has acceptable psychometric properties. The preference studies showed strong preference for endovascular abdominal aortic aneurysm treatment (willingness to trade up to 0.135 quality-adjusted life-years) and for local services (up to 0.631 quality-adjusted life-years). A simulation model with a web-based interface was developed, incorporating disease-specific models for abdominal aortic aneurysm, peripheral arterial disease and carotid artery disease. This predicts the effects of specified reconfigurations on workload, resource use, outcomes and cost-effectiveness. Initial exploration suggested that further reconfiguration of services in England to accomplish high-volume centres would result in improved outcomes, within the bounds of cost-effectiveness usually considered acceptable in the NHS. Limitations The major source of evidence to populate the models was Hospital Episode Statistics data, which have limitations owing to the complexity of the data, deficiencies in the coding systems and variations in coding practice. The studies were not able to address all of the potential barriers to change where vascular services are not compliant with current NHS recommendations. Conclusions There is evidence of potential for improvement in the clinical effectiveness and cost-effectiveness of vascular services through further centralisation of sites where major vascular procedures are undertaken. Preferences for local services are strong, and this may be addressed through more integrated services, with a range of services being provided more locally. The use of a web-based tool for the collection of clinical data and patient-reported outcome measures is feasible and can provide outcome data for clinical use and service evaluation. Future work Further evaluation of the economic models in real-world situations where local vascular service reconfiguration is under consideration and of the barriers to change where vascular services do not meet NHS recommendations for service configuration is needed. Further work on the electronic Personal Assessment Questionnaire – Vascular is required to assess its acceptability and usefulness in clinical practice and to develop appropriate report formats for clinical use and service evaluation. Further studies to assess the implications of including non-health-related preferences for care processes, and location of services, in calculations of cost-effectiveness are required. Study registration This study is registered as PROSPERO CRD42016042570, CRD42016042573, CRD42016042574, CRD42016042576, CRD42016042575, CRD42014014850, CRD42015023877 and CRD42015024820. Funding This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 9, No. 5. See the NIHR Journals Library website for further project information.

Abstract Background: Multiple myeloma remains an incurable disease, placing a significant burden on patients (pts), families, and healthcare systems. Bortezomib (BORT) and IMiDs® immunomodulatory agents (thalidomide and lenalidomide [LEN]) have improved progression-free survival (PFS), time to progression, and overall survival (OS). However, over time, nearly all pts become refractory which greatly impacts prognosis (median OS, 3-9 mos). In the absence of approved treatments, guidelines recommend clinical trials or retreatment with agents that were previously effective, but published data in the appropriate pt population for current care (CC) options are limited to those from small, observational, early-phase studies. There is a need for newer effective treatments; however, access is increasingly being determined by the demonstration of both clinical and economic value. POM + LoDEX demonstrated a significant OS benefit vs. high-dose dexamethasone (HiDEX) in the pivotal phase 3 MM-003 study (San Miguel, Lancet Oncol, 2013). POM + LoDEX has EU approval in RRMM pts in whom BORT and LEN failed. Objective: Explore the cost-effectiveness of POM + LoDEX vs. CC from a UK and Ireland healthcare payer perspective. Methods: A de novo pharmacoeconomic evaluation was conducted to compare costs and outcomes of POM + LoDEX to CC in the UK and Ireland. CC included BORT retreatment (intravenous [IV] or subcutaneous), LEN (oral), and bendamustine (IV) regimens. Efficacy data were sourced from MM-003 and 2 observational studies: a dataset for CC (Gooding, 2013; n = 30 pts primarily treated with BORT, bendamustine, or LEN; 100% received prior BORT and LEN) and a dataset for BORT + LEN (Jimenez-Zepeda, 2013; n = 30, 80% received prior BORT, 73% prior LEN). Validation of the approach and all model assumptions was achieved through extensive clinical and health economic expert consultation and by comparing comparator arm outcomes from observational data to the MM-003 (HiDEX) control arm data. The health economic model used a partitioned survival structure with OS and PFS parametric curves fitted to the datasets to estimate the number of pts at each time point expected to be preprogression, postprogression, or dead. Time to treatment failure curves were estimated to allow treatment discontinuation modelling. EQ-5D data, collected as part of MM-003, were used to inform quality of life (QOL) weights. A utility regression equation was developed to account for important covariates and allow utility to vary over time. The economic evaluation included the cost of treatment, administration, monitoring, tests, adverse events (AEs), blood transfusions, concomitant medication, and terminal care. Costs are presented in US dollars using an exchange rate of 0.74 per € and 0.58 per £. Costs and outcomes were modeled to estimate cost per life year (LY) and cost per quality-adjusted life year (QALY) gained over a lifetime horizon. Results: In the base-case analysis, POM + LoDEX was associated with a total incremental cost of $59,250 per pt over a lifetime horizon compared with CC (Table 1). Pts who receive POM + LoDEX are predicted to live for a mean of 2.2 years, compared with 1.2 years with CC. This represents an additional 0.6 QALYs. The model predicts a deterministic incremental cost-effectiveness ratio (ICER) of $100,920/QALY compared with CC, while the probabilistic ICER obtained through 1000 probabilistic model runs was consistent at $101,947/QALY. Table 1 : Base-Case Cost-Effectiveness Results Model Results POM + LoDEX CC Difference Clinical outcomes Median OS, mos 12.7 5.5 7.2 Mean predicted life-years (over a pt lifetime) 2.2 1.2 1.0 QALYs 1.3 0.7 0.6 Cost outcomes, US dollars Medication and administration $84,698 $29,880 $54,818 Monitoring $8230 $4489 $3741 AE management (outpatient visits and hospitalization) $7135 $6444 $691 Total $100,063 $40,813 $59,250 ICER—Cost/LY $58,112 ICER—Cost/QALY $100,920 Conclusion: There are limited alternative treatment options available in the UK and Ireland for RRMM pts. None have a proven effect on survival leaving pts to face potentially ineffective retreatments. End-of-life drugs that significantly improve survival and QOL and address unmet need can be considered to be cost-effective at a higher “willingness to pay” threshold. POM, an oral therapy with significant PFS, survival, and QOL with a known safety profile, is likely to be a cost-effective use of healthcare resources. Disclosures Dhanasiri: Celgene Corp: Employment, Equity Ownership. Lee:Celgene Corp: Consultancy. Sternas:Celgene Corp: Employment, Equity Ownership. Yu:Celgene Corp: Employment, Equity Ownership. Zaki:Celgene Corp: Employment, Equity Ownership. Elvidge:Celgene Corp: Consultancy.

Background The beginning of the coronavirus disease (COVID-19) epidemic dates back to December 31, 2019, when the first cases were reported in the People’s Republic of China. In the Czech Republic, the first three cases of infection with the novel coronavirus were confirmed on March 1, 2020. The joint effort of state authorities and researchers gave rise to a unique team, which combines methodical knowledge of real-world processes with the know-how needed for effective processing, analysis, and online visualization of data. Objective Due to an urgent need for a tool that presents important reports based on valid data sources, a team of government experts and researchers focused on the design and development of a web app intended to provide a regularly updated overview of COVID-19 epidemiology in the Czech Republic to the general population. Methods The cross-industry standard process for data mining model was chosen for the complex solution of analytical processing and visualization of data that provides validated information on the COVID-19 epidemic across the Czech Republic. Great emphasis was put on the understanding and a correct implementation of all six steps (business understanding, data understanding, data preparation, modelling, evaluation, and deployment) needed in the process, including the infrastructure of a nationwide information system; the methodological setting of communication channels between all involved stakeholders; and data collection, processing, analysis, validation, and visualization. Results The web-based overview of the current spread of COVID-19 in the Czech Republic has been developed as an online platform providing a set of outputs in the form of tables, graphs, and maps intended for the general public. On March 12, 2020, the first version of the web portal, containing fourteen overviews divided into five topical sections, was released. The web portal’s primary objective is to publish a well-arranged visualization and clear explanation of basic information consisting of the overall numbers of performed tests, confirmed cases of COVID-19, COVID-19-related deaths, the daily and cumulative overviews of people with a positive COVID-19 case, performed tests, location and country of infection of people with a positive COVID-19 case, hospitalizations of patients with COVID-19, and distribution of personal protective equipment. Conclusions The online interactive overview of the current spread of COVID-19 in the Czech Republic was launched on March 11, 2020, and has immediately become the primary communication channel employed by the health care sector to present the current situation regarding the COVID-19 epidemic. This complex reporting of the COVID-19 epidemic in the Czech Republic also shows an effective way to interconnect knowledge held by various specialists, such as regional and national methodology experts (who report positive cases of the disease on a daily basis), with knowledge held by developers of central registries, analysts, developers of web apps, and leaders in the health care sector.

Abstract Abstract 4755 Introduction: Per the 2008 WHO report on the spectrum of mast cell disease, ASM is a severe and debilitating form that may progress to mast cell leukemia. Very little has been published on the epidemiology and burden of ASM. This study reviewed the epidemiologic, clinical, humanistic and economic literature on ASM in order to estimate the burden of ASM in the US. Methods: A systematic literature review was conducted in PubMed to identify publications regarding ASM published in English from 2000 to 2011. Data relevant to the burden of ASM were abstracted. 181 citations were identified in PubMed. 156 abstracts were screened and 6 articles were abstracted. An Excel model was developed to estimate the population-level burden of ASM in the US. Direct costs of treatment were calculated based on treatment patterns described in publications identified in the literature review. Indirect costs were not included in this analysis. Results: Mastocytosis is a hematopoietic stem cell disorder with pathological mast cell proliferation in tissues. Bone marrow, liver, spleen, gastrointestinal tract, and musculoskeletal systems are most often involved in ASM, and release of various mediators results in symptoms/conditions which can be severe or even debilitating, including anaphylaxis and allergic reactions, osteoporosis, hepatomegaly, splenomegaly, peptic ulcers, ascites, nausea/vomiting, diarrhea, fatigue, and weight loss. Treatment of ASM focuses on symptom reduction with antihistamines, bisphosphonates, glucocorticoids, proton pump inhibitors and mast cell stabilizers. Medications used to control the disease include interferon-alpha, cladribine (2CdA), hydroxyurea, and imatinib or investigational agents in clinical trials. Two studies examining the burden of ASM on patient quality of life or productivity were identified. In one study, (Hermine O et al., PLoS ONE 2008; 3(5): e2266) 82% of systemic mastocytosis (SM) patients stated they suffer from a disability, with 28% reporting it as severe or intolerable. A recently published study (Nowak A et al., JDDG 2011; 9: 525–532) reported 64% of mastocytosis patients commented that the disease moderately to severely restricted their quality of life. No publications were found in the literature search that provided estimates of the annual incidence or prevalence of ASM in the US. The annual prevalence of ASM was calculated using an Orphanet estimate for the global prevalence rate of 0.2 cases per 100,000 individuals multiplied by age- and gender-specific US Census population projections. The annual prevalence of ASM in the US was estimated at 428 patients age ≥20 years in 2010. An annual incidence estimate for the US was calculated by multiplying age- and gender-specific US Census population projections by an assumption of the percentage of SM patients with ASM based on a retrospective cohort study of patients with SM and a published estimate for the incidence rate of SM in the US. Using this method, the annual incidence of ASM was estimated at 77 patients ≥ age 20 in the US in 2010, with an incidence rate of 0.036 cases/100,000 individuals. In a published study of a large cohort of patients with SM, the median age of ASM patients was 65 years vs. 57 years for all SM patients. The median survival for ASM patients was 41 months vs. 63 months for all SM patients. No studies were identified that examined the economic burden of ASM. Direct costs were estimated to be between $5,315 and $8,741 per patient per month. The majority of direct costs were associated with medications; while this is consistent with treatment based on symptom alleviation, it is also due to the fact that the publications used for estimation provided limited information on resource utilization, especially outpatient and ER visits, and as such resource utilization is likely underestimated. Conclusions: These results provide preliminary estimates for the economic burden of ASM in the US. Additional research can assist in further quantifying healthcare resource utilization in ASM, especially ASM-related ER and outpatient visits. Due to the variety of symptoms experienced by ASM patients, the lack of a curative therapy, and shorter survival, it is likely that patients with ASM experience indirect costs (e.g., limitations in functioning or productivity) that may exceed the direct costs of treatment, and further evaluation is warranted. Disclosures: Sotak: Novartis: Research Funding. Marin:Novartis: Research Funding. Coombs:Novartis: Employment. Teitelbaum:Novartis: Research Funding.

Arsenic and Protein Expression: It might help to know the mechanism of As toxicity is described Introduction One of the largest public health problems at present is the drinking of water containing levels of Inorg-As that are known to be carcinogenic. The chronic ingestion of Inorg-As can results in skin cancer, urinary bladder cancer, lungs cancer, kidneys cancer, liver cancer, and cancer of other human organs 1-6. The molecular mechanisms of the carcinogenicity and toxicity of inorganic arsenic are not well understood 7–9. Many mechanisms of arsenic toxicity and carcinogenicity have been suggested 1, 7, 10 including chromosome abnormalities 11, oxidative stress 12, 13, altered growth factors 14, cell proliferation 15, altered DNA repair 16, altered DNA methylation patterns 17, inhibition of several key enzymes 18, gene amplification 19 etc. Some of these mechanisms result in alterations in protein expression. Proteomics is a powerful tool developed to enhance the study of complex biological system 20. This technique has been extensively employed to investigate the proteome response of cells to drugs and other diseases 21, 22. A proteome analysis of the Na-As (III) response in cultured lung cells found in vitro oxidative stress-induced apoptosis 23. In one of the study, hamsters were exposed to sodium arsenite (173 mg As/L) in drinking water for 6 days and several protein spots were over expressed and several were under expressed in the livers and urinary bladders of hamsters (Fig.) 24, 25. Hamsters were exposed to sodium arsenite (173 mg As/L) in drinking water for 6 days. The control hamsters were given tap water. The spot pairs of (A) equally expressed, (B) overexpressed, and (C) under expressed proteins in the liver tissues were shown. The amount of the protein is proportional to the volume of the protein peak. Transgelin was down-regulated, and GST-pi was up-regulated in the urinary bladder tissues of hamsters. In the liver tissues ornithine aminotransferase (OAT) was up-regulated, and senescence marker protein 30 (SMP 30), and fatty acid binding protein (FABP) were down-regulated. Down-regulation of transgelin has been noted in the urinary bladders of rats having bladder outlet obstruction 26. Ras-dependent and Ras-independent mechanisms can cause the down regulation of transgelin in human breast and colon carcinoma cell lines and patient-derived tumor samples 27. The loss of transgelin expression has been found in prostate cancer cells 28 and in human colonic neoplasms 29. It has been suggested that the loss of transgelin expression may be an important early event in tumor progression and a diagnostic marker for cancer development 26-29. Figure. Three-dimentional simulation of over-and under expressed protein spots in the livers of hamsters using Decyder software. Over-expression of GST-pi has been found in colon cancer tissues 30. Strong expression of GST-pi also has been found in gastric cancer 31, malignant melanoma 32, lung cancer 33, breast cancer 34 and a range of other human tumors 35. GST-pi has been up-regulated in transitional cell carcinoma of human urinary bladder 36. OAT has a role in regulating mitotic cell division and it is required for proper spindle assembly in human cancer cell 37. Ornithine amino transferase knockdown in human cervical carcinoma and osteosarcoma cells by RNA interference blocks cell division and causes cell death 37. It has been suggested that ornithine amino transferase has a role in regulating mitotic cell division and it is required for proper spindle assembly in human cancer cells 37. SMP 30 expressed mostly in the liver. By stimulating membrane calcium-pump activity it protects cells against various injuries 38. High levels of saturated, branched chain fatty acids are deleterious to cells and resulting in lipid accumulation and cytotoxicity. FABP expression has protected the cells against branched chain saturated fatty acid 39. Proteomics would be a powerful tool to know the unknown cellular mechanisms of arsenic toxicity in humans. References. NRC (National Research Council). (2001). Arsenic in Drinking Water. Update to the 1999 Arsenic in Drinking Water Report. National Academy Press, Washington, DC. Chen, C. J., Chen, C. , Wu, M. M., Kuo, T. L. (1992). Cancer potential in liver, lung, bladder, and kidney due to ingested inorganic arsenic in drinking water. Br. J. Cancer 66, 888-892. Hopenhayn-Rich, C., M.L. Biggs, A. Fuchs, et al. 1996. Bladder cancer mortality with arsenic in drinking water in Argentina. Epidemiology 7: 117–124. International Agency for Research on Cancer. (1987). In IARC Monograph on the Evaluation of Carcinogenicity Risk to Humans. 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<p><strong>List of abstracts and authors:</strong></p><p><strong>1. Antipsychotics in anxiety disorders</strong></p><p>Christer Allgulander</p><p><strong>2. Anxiety in somatic disorders</strong></p><p>Christer Allgulander</p><p><strong>3. Community rehabilitation of the schizophrenic patient</strong></p><p>Orlando Alonso Betancourt, Maricela Morales Herrera</p><p><strong>4. Dual diagnosis: A theory-driven multidisciplinary approach for integrative care</strong></p><p>David Blackbeard</p><p><strong>5. The emotional language of the gut - when 'psyche' meets 'soma'</strong></p><p>Helen Clark</p><p><strong>6. The Psychotherapy of bipolar disorder</strong></p><p>Franco Colin</p><p><strong>7. The Psychotherapy of bipolar disorder</strong></p><p>Franco Colin</p><p><strong>8. Developing and adopting mental health policies and plans in Africa: Lessons from South Africa, Uganda and Zambia</strong></p><p>Sara Cooper, Sharon Kleintjes, Cynthia Isaacs, Fred Kigozi, Sheila Ndyanabangi, Augustus Kapungwe, John Mayeya, Michelle Funk, Natalie Drew, Crick Lund</p><p><strong>9. The importance of relapse prevention in schizophrenia</strong></p><p>Robin Emsley</p><p><strong>10. Mental Health care act: Fact or fiction?</strong></p><p>Helmut Erlacher, M Nagdee</p><p><strong>11. Does a dedicated 72-hour observation facility in a district hospital reduce the need for involuntary admissions to a psychiatric hospital?</strong></p><p>Lennart Eriksson</p><p><strong>12. The incidence and risk factors for dementia in the Ibadan study of ageing</strong></p><p>Oye Gureje, Lola Kola, Adesola Ogunniyi, Taiwo Abiona</p><p><strong>13. Is depression a disease of inflammation?</strong></p><p><strong></strong>Angelos Halaris</p><p><strong>14. Paediatric bipolar disorder: More heat than light?</strong></p><p>Sue Hawkridge</p><p><strong>15. EBM: Anova Conundrum</strong></p><p>Elizabeth L (Hoepie) Howell</p><p><strong>16. Tracking the legal status of a cohort of inpatients on discharge from a 72-hour assessment unit</strong></p><p>Bernard Janse van Rensburg</p><p><strong>17. Dual diagnosis units in psychiatric facilities: Opportunities and challenges</strong></p><p>Yasmien Jeenah</p><p><strong>18. Alcohol-induced psychotic disorder: A comparative study on the clinical characteristics of patients with alcohol dependence and schizophrenia</strong></p><p>Gerhard Jordaan, D G Nel, R Hewlett, R Emsley</p><p><strong>19. Anxiety disorders: the first evidence for a role in preventive psychiatry</strong></p><p>Andre F Joubert</p><p><strong>20. The end of risk assessment and the beginning of start</strong></p><p>Sean Kaliski</p><p><strong>21. Psychiatric disorders abd psychosocial correlates of high HIV risk sexual behaviour in war-effected Eatern Uganda</strong></p><p>E Kinyada, H A Weiss, M Mungherera, P Onyango Mangen, E Ngabirano, R Kajungu, J Kagugube, W Muhwezi, J Muron, V Patel</p><p><strong>22. One year of Forensic Psychiatric assessment in the Northern Cape: A comparison with an established assessment service in the Eastern Cape</strong></p><p>N K Kirimi, C Visser</p><p><strong>23. Mental Health service user priorities for service delivery in South Africa</strong></p><p>Sharon Kleintjes, Crick Lund, Leslie Swartz, Alan Flisher and MHaPP Research Programme Consortium</p><p><strong>24. The nature and extent of over-the-counter and prescription drug abuse in cape town</strong></p><p>Liezl Kramer</p><p><strong>25. Physical health issues in long-term psychiatric inpatients: An audit of nursing statistics and clinical files at Weskoppies Hospital</strong></p><p>Christa Kruger</p><p><strong>26. Suicide risk in Schizophrenia - 20 Years later, a cohort study</strong></p><p>Gian Lippi, Ean Smit, Joyce Jordaan, Louw Roos</p><p><strong>27.Developing mental health information systems in South Africa: Lessons from pilot projects in Northern Cape and KwaZulu-Natal</strong></p><p>Crick Lund, S Skeen, N Mapena, C Isaacs, T Mirozev and the Mental Health and Poverty Research Programme Consortium Institution</p><p><strong>28. Mental health aspects of South African emigration</strong></p><p>Maria Marchetti-Mercer</p><p><strong>29. What services SADAG can offer your patients</strong></p><p>Elizabeth Matare</p><p><strong>30. Culture and language in psychiatry</strong></p><p>Dan Mkize</p><p><strong>31. Latest psychotic episode</strong></p><p>Povl Munk-Jorgensen</p><p><strong>32. The Forensic profile of female offenders</strong></p><p>Mo Nagdee, Helmut Fletcher</p><p><strong>33. The intra-personal emotional impact of practising psychiatry</strong></p><p>Margaret Nair</p><p><strong>34. Highly sensitive persons (HSPs) and implications for treatment</strong></p><p>Margaret Nair</p><p><strong>35. Task shifting in mental health - The Kenyan experience</strong></p><p>David M Ndetei</p><p><strong>36. Bridging the gap between traditional healers and mental health in todya's modern psychiatry</strong></p><p>David M Ndetei</p><p><strong>37. Integrating to achieve modern psychiatry</strong></p><p>David M Ndetei</p><p><strong>38. Non-medical prescribing: Outcomes from a pharmacist-led post-traumatic stress disorder clinic</strong></p><p>A Parkinson</p><p><strong>39. Is there a causal relationship between alcohol and HIV? Implications for policy, practice and future research</strong></p><p>Charles Parry</p><p><strong>40. Global mental health - A new global health discipline comes of age</strong></p><p>Vikram Patel</p><p><strong>41. Integrating mental health into primary health care: Lessons from pilot District demonstration sites in Uganda and South Africa</strong></p><p>Inge Petersen, Arvin Bhana, K Baillie and MhaPP Research Programme Consortium</p><p><strong>42. Personality disorders -The orphan child in axis I - Axis II Dichotomy</strong></p><p><strong></strong>Willie Pienaar</p><p><strong>43. Case Studies in Psychiatric Ethics</strong></p><p>Willie Pienaar</p><p><strong>44. Coronary artery disease and depression: Insights into pathogenesis and clinical implications</strong></p><p>Janus Pretorius</p><p><strong>45. Impact of the Mental Health Care Act No. 17 of 2002 on designated hospitals in KwaZulu-Natal: Triumphs and trials</strong></p><p>Suvira Ramlall, Jennifer Chipps</p><p><strong>46. Biological basis of addication</strong></p><p>Solomon Rataemane</p><p><strong>47. Genetics of Schizophrenia</strong></p><p>Louw Roos</p><p><strong>48. Management of delirium - Recent advances</strong></p><p>Shaquir Salduker</p><p><strong>49. Social neuroscience: Brain research on social issues</strong></p><p>Manfred Spitzer</p><p><strong>50. Experiments on the unconscious</strong></p><p>Manfred Spitzer</p><p><strong>51. The Psychology and neuroscience of music</strong></p><p>Manfred Spitzer</p><p><strong>52. Mental disorders in DSM-V</strong></p><p>Dan Stein</p><p><strong>53. Personality, trauma exposure, PTSD and depression in a cohort of SA Metro policemen: A longitudinal study</strong></p><p>Ugashvaree Subramaney</p><p><strong>54. Eating disorders: An African perspective</strong></p><p>Christopher Szabo</p><p><strong>55. An evaluation of the WHO African Regional strategy for mental health 2001-2010</strong></p><p>Thandi van Heyningen, M Majavu, C Lund</p><p><strong>56. A unitary model for the motor origin of bipolar mood disorders and schizophrenia</strong></p><p>Jacques J M van Hoof</p><p><strong>57. The origin of mentalisation and the treatment of personality disorders</strong></p><p>Jacques J M Hoof</p><p><strong>58. How to account practically for 'The Cause' in psychiatric diagnostic classification</strong></p><p>C W (Werdie) van Staden</p><p><strong>POSTER PRESENTATIONS</strong></p><p><strong>59. Problem drinking and physical and sexual abuse at WSU Faculty of Health Sciences, Mthatha, 2009</strong></p><p>Orlando Alonso Betancourt, Maricela Morales Herrera, E, N Kwizera, J L Bernal Munoz</p><p><strong>60. Prevalence of alcohol drinking problems and other substances at WSU Faculty of Health Sciences, Mthatha, 2009</strong></p><p>Orlando Alonso Betancourt, Maricela Morales Herrera, E, N Kwizera, J L Bernal Munoz</p><p><strong>61. Lessons learnt from a modified assertive community-based treatment programme in a developing country</strong></p><p>Ulla Botha, Liezl Koen, John Joska, Linda Hering, Piet Ooosthuizen</p><p><strong>62. 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Hamsters were exposed to sodium arsenite (173 mg As/L) in drinking water for 6 days. Equal amounts of proteins from urinary bladder or liver extracts of control and arsenic-treated hamsters were labeled with Cy3 and Cy5 dyes, respectively. After differential in gel electrophoresis and analysis by the DeCyder software, several protein spots were found to be down-regulated and several were up regulated. Our experiments indicated that in the bladder tissues of hamsters exposed to arsenite, transgelin was down-regulated and GST-pi was up-regulated. The loss of transgelin expression has been reported to be an important early event in tumor progression and a diagnostic marker for cancer development [29-32]. Down-regulation of transgelin expression may be associated with the carcinogenicity of inorganic arsenic in the urinary bladder. In the liver of arsenite-treated hamsters, ornithine aminotransferase was up-regulated, and senescence marker protein 30 and fatty acid binding protein were down-regulated. The volume ratio changes of these proteins in the bladder and liver of hamsters exposed to arsenite were significantly different than that of control hamsters. Introduction Chronic exposure to inorganic arsenic can cause cancer of the skin, lungs, urinary bladder, kidneys, and liver [1-6]. The molecular mechanisms of the carcinogenicity and toxicity of inorganic arsenic are not well understood [7-9). Humans chronically exposed to inorganic arsenic excrete MMA(V), DMA(V) and the more toxic +3 oxidation state arsenic biotransformants MMA(III) and DMA (III) in their urine [10, 11], which are carcinogen [12]· After injection of mice with sodium arsenate, the highest concentrations of the very toxic MMA(III) and DMA(III) were in the kidneys and urinary bladder tissue, respectively, as shown by experiments of Chowdhury et al [13]. Many mechanisms of arsenic toxicity and carcinogenicity have been suggested [1, 7, 14] including chromosome abnormalities [15], oxidative stress [16, 17], altered growth factors [18], cell proliferation [19], altered DNA repair [20], altered DNA methylation patterns [21], inhibition of several key enzymes [22], gene amplification [23] etc. Some of these mechanisms result in alterations in protein expression. Methods for analyzing multiple proteins have advanced greatly in the last several years. In particularly, mass spectrometry (MS) and tandem MS (MS/MS) are used to analyze peptides following protein isolation using two-dimensional (2-D) gel electrophoresis and proteolytic digestion [24]. In the present study, Differential In Gel Electrophoresis (DIGE) coupled with Mass Spectrometry (MS) has been used to study some of the proteomic changes in the urinary bladder and liver of hamsters exposed to sodium arsenite in their drinking water. Our results indicated that transgelin was down-regulated and GST-pi was up-regulated in the bladder tissues. In the liver tissues ornithine aminotransferase was up-regulated, and senescence marker protein 30, and fatty acid binding protein were down-regulated. Materials and Methods Chemicals Tris, Urea, IPG strips, IPG buffer, CHAPS, Dry Strip Cover Fluid, Bind Silane, lodoacetamide, Cy3 and Cy5 were from GE Healthcare (formally known as Amersham Biosciences, Uppsala, Sweden). Thiourea, glycerol, SDS, DTT, and APS were from Sigma-Aldrich (St. Louis, MO, USA). Glycine was from USB (Cleveland, OH, USA). Acrylamide Bis 40% was from Bio-Rad (Hercules, CA, USA). All other chemicals and biochemicals used were of analytical grade. All solutions were made with Milli-Q water. Animals Male hamsters (Golden Syrian), 4 weeks of age, were purchased from Harlan Sprague Dawley, USA. Upon arrival, hamsters were acclimated in the University of Arizona animal care facility for at least 1 week and maintained in an environmentally controlled animal facility operating on a 12-h dark/12-h light cycle and at 22-24°C. They were provided with Teklad (Indianapolis, IN) 4% Mouse/Rat Diet # 7001 and water, ad libitum, throughout the acclimation and experimentation periods. Sample preparation and labelling Hamsters were exposed to sodium arsenite (173 mg) in drinking water for 6 days and the control hamsters were given tap water. On the 6th day hamsters were decapitated rapidly by guillotine. Urinary bladder tissues and liver were removed, blotted on tissue papers (Kimtech Science, Precision Wipes), and weighed. Hamster urinary bladder or liver tissues were homogenized in lysis buffer (30mMTris, 2M thiourea, 7M urea, and 4% w/w CHAPS adjusted to pH 8.5 with dilute HCI), at 4°C using a glass homogenizer and a Teflon coated steel pestle; transferred to a 5 ml acid-washed polypropylene tube, placed on ice and sonicated 3 times for 15 seconds. The sonicate was centrifuged at 12,000 rpm for 10 minutes at 4°C. Small aliquots of the supernatants were stored at -80°C until use (generally within one week). Protein concentration was determined by the method of Bradford [25] using bovine serum albumin as a standard. Fifty micrograms of lysate protein was labeled with 400 pmol of Cy3 Dye (for control homogenate sample) and Cy5 Dye (for arsenic-treated urinary bladder or liver homogenate sample). The samples containing proteins and dyes were incubated for 30 min on ice in the dark. To stop the labeling reaction, 1uL of 10 mM lysine was added followed by incubation for 10 min on ice in the dark. To each of the appropriate dye-labeled protein samples, an additional 200 ug of urinary bladderor liver unlabeled protein from control hamster sample or arsenic-treated hamster sample was added to the appropriate sample. Differentially labeled samples were combined into a single Microfuge tube (total protein 500 ug); protein was mixed with an equal volume of 2x sample buffer [2M thiourea, 7M urea, pH 3-10 pharmalyte for isoelectric focusing 2% (v/v), DTT 2% (w/v), CHAPS 4% (w/v)]; and was incubated on ice in the dark for 10 min. The combined samples containing 500 ug of total protein were mixed with rehydration buffer [CHAPS 4% (w/v), 8M urea, 13mM DTT, IPG buffer (3-10) 1% (v/v) and trace amount of bromophenol blue]. The 450 ul sample containing rehydration buffer was slowly pipetted into the slot of the ImmobilinedryStripReswelling Tray and any large bubbles were removed. The IPG strip (linear pH 3-10, 24 cm) was placed (gel side down) into the slot, covered with drystrip cover fluid (Fig. 1), and the lid of the Reswelling Tray was closed. The ImmobillineDryStrip was allowed to rehydrate at room temperature for 24 hours. First dimension Isoelectric focusing (IEF) The labeled sample was loaded using the cup loading method on universal strip holder. IEF was then carried out on EttanIPGphor II using multistep protocol (6 hr @ 500 V, 6 hr @ 1000 V, 8 hr @ 8000 V). The focused IPG strip was equilibrated in two steps (reduction and alkylation) by equilibrating the strip for 10 min first in 10 ml of 50mM Tris (pH 8.8), 6M urea, 30% (v/v) glycerol, 2% (w/v) SDS, and 0.5% (w/v) DTT, followed by another 10 min in 10 ml of 50mM Tris (pH 8.8), 6M urea, 30% (v/v) glycerol, 2% (w/v) SDS, and 4.5% (w/v) iodoacetamide to prepare it for the second dimension electrophoresis. Second dimension SDS-PAGE The equilibrated IPG strip was used for protein separation by 2D-gel electrophoresis (DIGE). The strip was sealed at the top of the acrylamide gel for the second dimension (vertical) (12.5% polyacrylamide gel, 20x25 cm x 1.5 mm) with 0.5% (w/v) agarose in SDS running buffer [25 mMTris, 192 mM Glycine, and 0.1% (w/v) SDS]. Electrophoresis was performed in an Ettan DALT six electrophoresis unit (Amersham Biosciences) at 1.5 watts per gel, until the tracking dye reached the anodic end of the gel. Image analysis and post-staining The gel then was imaged directly between glass plates on the Typhoon 9410 variable mode imager (Sunnyvale, CA, USA) using optimal excitation/emission wavelength for each DIGE fluor: Cy3 (532/580 nm) and Cy5 (633/670 nm). The DIGE images were previewed and checked with Image Quant software (GE Healthcare) where all the two separate gel images could be viewed as a single gel image. DeCyde v.5.02 was used to analyze the DIGE images as described in the Ettan DIGE User Manual (GE Healthcare). The appropriate up-/down regulated spots were filtered based on an average volume ratio of ± over 1.2 fold. After image acquisition, the gel was fixed overnight in a solution containing 40% ethanol and 10% acetic acid. The fixed gel was stained with SyproRuby (BioRad) according to the manufacturer protocol (Bio-Rad Labs., 2000 Alfred Nobel Drive, Hercules, CA 94547). Identification of proteins by MS Protein spot picking and digestion Sypro Ruby stained gels were imaged using an Investigator ProPic and HT Analyzer software, both from Genomic Solutions (Ann Arbor, MI). Protein spots of interest that matched those imaged using the DIGE Cy3/Cy5 labels were picked robotically, digested using trypsin as described previously [24] and saved for mass spectrometry identification. Liquid chromatography (LC)- MS/MS analysis LC-MS/MS analyses were carried out using a 3D quadrupole ion trap massspectrometer (ThermoFinnigan LCQ DECA XP PLUS; ThermoFinnigan, San Jose, CA) equipped with a Michrom Paradigm MS4 HPLC (MichromBiosources, Auburn, CA) and a nanospray source, or with a linear quadrupole ion trap mass spectrometer (ThermoFinnigan LTQ), also equipped with a Michrom MS4 HPLC and a nanospray source. Peptides were eluted from a 15 cm pulled tip capillary column (100 um I.D. x 360 um O.D.; 3-5 um tip opening) packed with 7 cm Vydac C18 (Vydac, Hesperia, CA) material (5 µm, 300 Å pore size), using a gradient of 0-65% solvent B (98% methanol/2% water/0.5% formic acid/0.01% triflouroacetic acid) over a 60 min period at a flow rate of 350 nL/min. The ESI positive mode spray voltage was set at 1.6 kV, and the capillary temperature was set at 200°C. Dependent data scanning was performed by the Xcalibur v 1.3 software on the LCQ DECA XP+ or v 1.4 on the LTQ [27], with a default charge of 2, an isolation width of 1.5 amu, an activation amplitude of 35%, activation time of 50 msec, and a minimal signal of 10,000 ion counts (100 ion counts on the LTQ). Global dependent data settings were as follows: reject mass width of 1.5 amu, dynamic exclusion enabled, exclusion mass width of 1.5 amu, repeat count of 1, repeat duration of a min, and exclusion duration of 5 min. Scan event series were included one full scan with mass range of 350-2000 Da, followed by 3 dependent MS/MS scans of the most intense ion. Database searching Tandem MS spectra of peptides were analyzed with Turbo SEQUEST, version 3.1 (ThermoFinnigan), a program that allows the correlation of experimental tandem MS data with theoretical spectra generated from known protein sequences. All spectra were searched against the latest version of the non redundant protein database from the National Center for Biotechnology Information (NCBI 2006; at that time, the database contained 3,783,042 entries). Statistical analysis The means and standard error were calculated. The Student's t-test was used to analyze the significance of the difference between the control and arsenite exposed hamsters. P values less than 0.05 were considered significant. The reproducibility was confirmed in separate experiments. Results Analysis of proteins expression After DIGE (Fig. 1), the gel was scanned by a Typhoon Scanner and the relative amount of protein from sample 1 (treated hamster) as compared to sample 2 (control hamster) was determined (Figs. 2, 3). A green spot indicates that the amount of protein from sodium arsenite-treated hamster sample was less than that of the control sample. A red spot indicates that the amount of protein from the sodium arsenite-treated hamster sample was greater than that of the control sample. A yellow spot indicates sodium arsenite-treated hamster and control hamster each had the same amount of that protein. Several protein spots were up-regulated (red) or down-regulated (green) in the urinary bladder samples of hamsters exposed to sodium arsenite (173 mg As/L) for 6 days as compared with the urinary bladder of controls (Fig. 2). In the case of liver, several protein spots were also over-expressed (red) or under-expressed (green) for hamsters exposed to sodium arsenite (173 mg As/L) in drinking water for 6 days (Fig. 3). The urinary bladder samples were collected from the first and second experiments in which hamsters were exposed to sodium arsenite (173 mg As/L) in drinking water for 6 days and the controls were given tap water. The urinary bladder samples from the 1st and 2nd experiments were run 5 times in DIGE gels on different days. The protein expression is shown in Figure 2 and Table 1. The liver samples from the 1st and 2nd experiments were also run 3 times in DIGE gels on different days. The proteins expression were shown in Figure 3 and Table 2. The volume ratio changed of the protein spots in the urinary bladder and liver of hamsters exposed to arsenite were significantly differences than that of the control hamsters (Table 1 and 2). Protein spots identified by LC-MS/MS Bladder The spots of interest were removed from the gel, digested, and their identities were determined by LC-MS/MS (Fig. 2 and Table 1). The spots 1, 2, & 3 from the gel were analyzed and were repeated for the confirmation of the results (experiments; 173 mg As/L). The proteins for the spots 1, 2, and 3 were identified as transgelin, transgelin, and glutathione S-transferase Pi, respectively (Fig. 2). Liver We also identified some of the proteins in the liver samples of hamsters exposed to sodium arsenite (173 mg As/L) in drinking water for 6 days (Fig. 3). The spots 4, 5, & 6 from the gels were analyzed and were repeated for the confirmation of the results. The proteins for the spots 4, 5, and 6 were identified as ornithine aminotransferase, senescence marker protein 30, and fatty acid binding protein, respectively (Fig. 3) Discussion The identification and functional assignment of proteins is helpful for understanding the molecular events involved in disease. Weexposed hamsters to sodium arsenite in drinking water. Controls were given tap water. DIGE coupled with LC-MS/MS was then used to study the proteomic change in arsenite-exposed hamsters. After electrophoresis DeCyder software indicated that several protein spots were down-regulated (green) and several were up-regulated (red). Our overall results as to changes and functions of the proteins we have studied are summarized in Table 3. Bladder In the case of the urinary bladder tissue of hamsters exposed to sodium arsenite (173 mg As/L) in drinking water for 6 days, transgelin was down-regulated and GST-pi was up-regulated. This is the first evidence that transgelin is down-regulated in the bladders of animals exposed to sodium arsenite. Transgelin, which is identical to SM22 or WS3-10, is an actin cross linking/gelling protein found in fibroblasts and smooth muscle [28, 29]. It has been suggested that the loss of transgelin expression may be an important early event in tumor progression and a diagnostic marker for cancer development [30-33]. It may function as a tumor suppressor via inhibition of ARA54 (co-regulator of androgen receptor)-enhanced AR (androgen receptor) function. Loss of transgelin and its suppressor function in prostate cancer might contribute to the progression of prostate cancer [30]. Down-regulation of transgelin occurs in the urinary bladders of rats having bladder outlet obstruction [32]. Ras-dependent and Ras-independent mechanisms can cause the down regulation of transgelin in human breast and colon carcinoma cell lines and patient-derived tumorsamples [33]. Transgelin plays a role in contractility, possibly by affecting the actin content of filaments [34]. In our experiments loss of transgelin expression may be associated or preliminary to bladder cancer due to arsenic exposure. Arsenite is a carcinogen [1]. In our experiments, LC-MS/MS analysis showed that two spots (1 and 2) represent transgelin (Fig. 2 and Table 1). In human colonic neoplasms there is a loss of transgelin expression and the appearance of transgelin isoforms (31). GST-pi protein was up-regulated in the bladders of the hamsters exposed to sodium arsenite. GSTs are a large family of multifunctional enzymes involved in the phase II detoxification of foreign compounds [35]. The most abundant GSTS are the classes alpha, mu, and pi classes [36]. They participate in protection against oxidative stress [37]. GST-omega has arsenic reductase activity [38]. Over-expression of GST-pi has been found in colon cancer tissues [39]. Strong expression of GST-pi also has been found in gastric cancer [40], malignant melanoma [41], lung cancer [42], breast cancer [43] and a range of other human tumors [44]. GST-pi has been up-regulated in transitional cell carcinoma of human urinary bladder [45]. Up-regulation of glutathione – related genes and enzyme activities has been found in cultured human cells by sub lethal concentration of inorganic arsenic [46]. There is evidence that arsenic induces DNA damage via the production of ROS (reactive oxygen species) [47]. GST-pi may be over-expressed in the urinary bladder to protect cells against arsenic-induced oxidative stress. Liver In the livers of hamsters exposed to sodium arsenite, ornithine amino transferase was over-expressed, senescence marker protein 30 was under-expressed, and fatty acid binding protein was under-expressed. Ornithine amino transferase has been found in the mitochondria of many different mammalian tissues, especially liver, kidney, and small intestine [48]. Ornithine amino transferase knockdown inhuman cervical carcinoma and osteosarcoma cells by RNA interference blocks cell division and causes cell death [49]. It has been suggested that ornithine amino transferase has a role in regulating mitotic cell division and it is required for proper spindle assembly in human cancer cells [49]. Senescence marker protein-30 (SMP30) is a unique enzyme that hydrolyzes diisopropylphosphorofluoridate. SMP30, which is expressed mostly in the liver, protects cells against various injuries by stimulating membrane calcium-pump activity [50]. SMP30 acts to protect cells from apoptosis [51]. In addition it protects the liver from toxic agents [52]. The livers of SMP30 knockout mice accumulate phosphatidylethanolamine, cardiolipin, phosphatidyl-choline, phosphatidylserine, and sphingomyelin [53]. Liver fatty acid binding protein (L-FABP) also was down- regulated. Decreased liver fatty acid-binding capacity and altered liver lipid distribution hasbeen reported in mice lacking the L-FABP gene [54]. High levels of saturated, branched-chain fatty acids are deleterious to cells and animals, resulting in lipid accumulation and cytotoxicity. The expression of fatty acid binding proteins (including L-FABP) protected cells against branched-chain saturated fatty acid toxicity [55]. Limitations: we preferred to study the pronounced spots seen in DIGE gels. Other spots were visible but not as pronounced. Because of limited funds, we did not identify these others protein spots. In conclusion, urinary bladders of hamsters exposed to sodium arsenite had a decrease in the expression of transgelin and an increase in the expression of GST-pi protein. Under-expression of transgelin has been found in various cancer systems and may be associated with arsenic carcinogenicity [30-33). Inorganic arsenic exposure has resulted in bladder cancer as has been reported in the past [1]. Over-expression of GST-pi may protect cells against oxidative stress caused by arsenite. In the liver OAT was up regulated and SMP-30 and FABP were down regulated. These proteomic results may be of help to investigators studying arsenic carcinogenicity. The Superfund Basic Research Program NIEHS Grant Number ES 04940 from the National Institute of Environmental Health Sciences supported this work. Additional support for the mass spectrometry analyses was provided by grants from NIWHS ES06694, NCI CA023074 and the BIOS Institute of the University of Arizona. Acknowledgement The Author wants to dedicate this paper to the memory of his former supervisor Dr. H. VaskenAposhian who passed away in September 6, 2019. He was an emeritus professor of the Department of Molecular and Cellular Biology at the University of Arizona. 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Abstract Focus of Presentation Health problems are complex due to multiple interactions whose outcomes are not easily predicted with traditional epidemiology methods. The problems themselves require careful evaluation. Predictive models of human behaviour are potentially powerful tools to frame health problems, especially if the models can link the attributes and behaviour of individuals with the dynamics of the social and environmental systems within which they operate. We explore this potential by proposing a framework combining two modelling approaches — social network analysis (SNA) and agent-based modelling (ABM) - with epidemiological methods. We then apply this framework to understand why measles vaccination rates are decreasing across the world. Findings These techniques allowed us to understand the etiologic implications of heterogeneity within the population, social interaction, and environmental influences simultaneously, and to explore mechanistic interactions, feedback loops, and reciprocity between exposures and outcomes. This approach allowed us to frame complex social factors of health and disease in a holistic manner. Conclusions/Implications The proposed framework allows investigators to analyse complex health problems in a holistic manner. However, both SNA and ABM, and other modelling tools, are still too compartmentalised in application, despite the strong methodological and conceptual parallels between their uses in different disciplines. Key messages A fully integrated approach is needed to understanding complex health problems, which combines modelling approaches and the disciplinary insights of epidemiology and public health.

Background and Aims: To combat hepatitis C virus (HCV) and achieve its elimination by 2030, the emphasis should be on public health policies. In this study, we investigated the dynamics of epidemiology of HCV in Romanian risk groups that are characterized by higher occurrence densities with the aid of The Let’s End HepC (LEHC) project. Methods: The LEHC project addressed the modelling of HCV epidemiology, being applied in several countries, one of which is Romania. The model comprised an integrated solution of public health policies focused on the disease, using Adaptive Conjoint Analysis and Markov chains systems. This tool allowed the quantitative evaluation of public health policies‘ impact, for every year until 2030, in five population groups: people who inject drugs (PWID), prisoners, individuals who have received blood products, children at risk for vertical transmission, and the remnant population. Results: It appears that Romania was already making great efforts in the context of public policies, allowing the achievement of HCV elimination by 2028 if current policies were maintained. Through additional work and greater efforts in further implementing public policies, the LEHC model estimated the possibility of anticipating this outcome to 2026. Conclusion: The LEHC model estimated an anticipation of the HCV elimination year in Romania to be 2026 if the twenty-four health policies in the study are fully implemented and consistently maintained over the years.

Abstract Health impact simulation models are used to predict how a proposed policy or scenario will affect population health outcomes. These models represent the typically-complex systems that describe how the scenarios affect exposures to risk factors for disease or injury (e.g. air pollution or physical inactivity), and how these risk factors are related to measures of population health (e.g. expected survival). These models are informed by multiple sources of data, and are subject to multiple sources of uncertainty. We want to describe which sources of uncertainty contribute most to uncertainty about the estimate or decision arising from the model. Furthermore, we want to decide where further research should be focused to obtain further data to reduce this uncertainty, and what form that research might take. This article presents a tutorial in the use of Value of Information methods for uncertainty analysis and research prioritisation in health impact simulation models. These methods are based on Bayesian decision-theoretic principles, and quantify the expected benefits from further information of different kinds. The expected value of partial perfect information about a parameter measures sensitivity of a decision or estimate to uncertainty about that parameter. The expected value of sample information represents the expected benefit from a specific proposed study to get better information about the parameter. The methods are applicable both to situations where the model is used to make a decision between alternative policies, and situations where the model is simply used to estimate a quantity (such as expected gains in survival under a scenario). This paper explains how to calculate and interpret the expected value of information in the context of a simple model describing the health impacts of air pollution from motorised transport. We provide a general-purpose R package and full code to reproduce the example analyses.

Sclerotinia sclerotiorum is a predominant plant pathogen, with host crops of agricultural and economic importance internationally. South African host crops of importance include canola, soybean and sunflower, which contribute significantly to the South African economy. This significance emphasises the importance of effective disease management strategies, including rotation with non-host crops, planting cultivars with a degree of tolerance, and using relevant cultural and chemical practices. The sporadic nature of disease outbreaks caused by Sclerotinia spp. can complicate fungicide application timing as a result of the pathogen’s interaction with the host and environment. The use of prediction modelling for diseases caused by Sclerotinia spp. can contribute to increased fungicide application efficacy and a reduction in the number of unnecessary sprays. Predictive modelling is based upon the collection and statistical analysis of multi-locality and multi-seasonal, pathogen, disease and weather data. Incorporating the complexity of disease initiation and development into such models is dependent on selecting the correct statistical tools to interpret appropriate data, which can be used to develop a model that is accurate, precise and reliable. Internationally, forecasting models for diseases caused by Sclerotinia spp. exist and are applied commercially for multiple Sclerotinia spp. on important agricultural crops. The application of these models in a South African context has been limited but provides promise for effective disease intervention technologies. This review provides a platform to raise awareness of the potential applications of plant disease epidemiology and the use of statistics and mathematical modelling in agricultural systems. Plant disease forecasts are an important part of the future for sustainable and economically viable agronomic decisions.

ObjectiveTo describe the development of an evaluation framework thatallows quantification of surveillance functions and subsequentaggregation towards an overall score for biosurveillance systemperformance.IntroductionEvaluation and strengthening of biosurveillance systems is acomplex process that involves sequential decision steps, numerousstakeholders, and requires accommodating multiple and conflictingobjectives. Biosurveillance evaluation, the initiating step towardsbiosurveillance strengthening, is a multi-dimensional decisionproblem that can be properly addressed via multi-criteria-decisionmodels.Existing evaluation frameworks tend to focus on “hard” technicalattributes (e.g. sensitivity) while ignoring other “soft” criteria(e.g. transparency) of difficult measurement and aggregation. Asa result, biosurveillance value, a multi-dimensional entity, is notproperly defined or assessed. Not addressing the entire range of criterialeads to partial evaluations that may fail to convene sufficient supportacross the stakeholders’ base for biosurveillance improvements.We seek to develop a generic and flexible evaluation frameworkcapable of integrating the multiple and conflicting criteria and valuesof different stakeholders, and which is sufficiently tractable to allowquantification of the value of specific biosurveillance projects towardsthe overall performance of biosurveillance systems.MethodsWe chose a Multi Attribute Value Theory model (MAVT) tosupport the development of the evaluation framework. Developmentof the model was done through online decision conferencing sessionswith expert judgement, an indispensable part of MAVT modelling,provided by surveillance experts recruited from the member pool ofthe International Society for Disease Surveillance.The surveillance functions or quality criteria that were consideredfor the framework were initially gathered from a review of theliterature with specific attention to a subset of public health qualitycriteria (1). Group discussions with the experts led to a final list offunctions, finally reviewed to comply with the properties for goodcriteria in decision models. The eleven functions were: sensitivity;timeliness; positive predictive value (PPV); transparency; versatility;multiple utility; representativeness; sustainability; advancing thefield and innovation; risk reduction; and actionable information.In addition, 24 different scenarios were developed for sensitivity,PPV, and timeliness since their values may differ with the level ofinfectiousness of the condition/event of interest, its severity andthe availability of treatment and/or prevention measures. Four orfive levels of performance were also developed for each criterion.Macbeth (Measuring Attractiveness by a Category-Based EvaluationTechnique) tables were used to elicit values of different levels ofperformance from the experts using qualitative pairwise comparisonsand then convert them into numerical values.ResultsTo date, two criteria, sensitivity and transparency, have beenassessed by more than one expert working on the same scenario.Value functions were generated for each criterion and scenario bycalculating the median of the different values produced by the experts.For both sensitivity and transparency, value functions were mostlylinear, indicating similar preferences between levels of performance.However, for some scenarios, experts allocated greater value toincreases at the higher end of the performance level distribution.ConclusionsAt the time of writing new elicitation sessions are planned toconclude the model. Next, we will apply swing weights to supportthe trade-offs between the different criteria. We will present thebaseline model elicitated from the experts and demonstrate howto apply portfolio decision analysis to assess overall performanceof biosurveillance systems according to the specific needs ofstakeholders and in conjunction with macro-epidemiological models.

Agent-based models provide a flexible framework that is frequently used for modelling many biological systems, including cell migration, molecular dynamics, ecology and epidemiology. Analysis of the model dynamics can be challenging due to their inherent stochasticity and heavy computational requirements. Common approaches to the analysis of agent-based models include extensive Monte Carlo simulation of the model or the derivation of coarse-grained differential equation models to predict the expected or averaged output from the agent-based model. Both of these approaches have limitations, however, as extensive computation of complex agent-based models may be infeasible, and coarse-grained differential equation models can fail to accurately describe model dynamics in certain parameter regimes. We propose that methods from the equation learning field provide a promising, novel and unifying approach for agent-based model analysis. Equation learning is a recent field of research from data science that aims to infer differential equation models directly from data. We use this tutorial to review how methods from equation learning can be used to learn differential equation models from agent-based model simulations. We demonstrate that this framework is easy to use, requires few model simulations, and accurately predicts model dynamics in parameter regions where coarse-grained differential equation models fail to do so. We highlight these advantages through several case studies involving two agent-based models that are broadly applicable to biological phenomena: a birth–death–migration model commonly used to explore cell biology experiments and a susceptible–infected–recovered model of infectious disease spread.

Background and objective: In 2011, critical congenital heart disease (CCHD) was added to the Recommended Uniform Screening Panel for newborns. Most state legislatures have not yet mandated pulse oximetry screening to detect CCHD, and evidence that the screening is cost-effective might be influential in these decisions. This study aimed to estimate the cost-effectiveness of universal newborn pulse oximetry screening for CCHD in the U.S. from the hospital system perspective. Methods: A model was developed to estimate the direct medical costs and health effects of screening all newborns. The health benefits were the number of timely (prior to birth hospital discharge) detected CCHD and life-years saved with the screening compared to existing practice. The analysis focused on ductal-dependent CCHD lesions amenable to pulse oximetry detection. The time horizon was the neonatal period. Costs were not discounted, though future life-years were discounted at 3%. Model inputs related to the epidemiology of CCHD, treatment outcomes, and efficacy of pulse oximetry screening to detect CCHD were derived from published literature. Results: The cost of screening was an estimated $3.83 per newborn, with an incremental cost of $4,693 per life year gained as a result of the screening. Using current U.S. hospital-based births, it was estimated that 248 more cases of CCHD would be identified at birth hospitals and 110 infant deaths averted annually with universal screening. Conclusion: Pulse oximetry screening is a life-saving program and is cost-effective by usual standards of health economic evaluation. The results of this analysis might contribute to policymakers’ decisions on universal pulse oximetry screening and may inform other stakeholders, including health care systems and payers, about likely budget impacts. Further analyses of CCHD hospitalization and screening costs can improve these model estimates.

Introduction: This post-hoc analysis applies a fixed dosing stratification approach to patient-level brolucizumab data from the Phase III HAWK and HARRIER trials to determine the proportion of patients who would have been assigned to fixed dosing regimens with treatment intervals of 8, 12 or 16 weeks (q8w, q12w or q16w) based on the presence/absence of disease activity (DA) following the loading phase. The analysis also simulates central subfield thickness (CSFT) data to estimate the anatomical outcomes if the patients had been thus assigned. Of note, the limitations of this analysis include the post-hoc nature of the work, and the inability to directly compare HAWK and HARRIER with TENAYA and LUCERNE due to the differences in design. Design: Post-hoc modelling analysis of patient-level data. Methods: Using patient-level data from HAWK and HARRIER, patients (n=730) were allocated to a fixed q16w, q12w or q8w regimen based on assessment of DA at Weeks 16 and 20. Two definitions of DA were used: DA 1, based on a Phase II study of faricimab, and DA 2, a definition derived from common clinical consideration including visual acuity and anatomical changes. CSFT simulations were performed using a pharmacokinetic/pharmacodynamic model describing CSFT response to anti-VEGF treatment. Outcome measures were modelled patient allocation to fixed regimens and mean CSFT reduction. Results: Using DA definitions 1 and 2 respectively, 78% and 76% of patients in the brolucizumab arm were allocated to a greater than or equal to q12w regimen, and 56% and 52% were allocated to a q16w regimen. Mean reduction in CSFT was similar between the two study drugs with both DA definition assumptions. Conclusions: This analysis demonstrates the potential durability of action and effectiveness of brolucizumab.

AbstractDosing guidance is often lacking for chronic kidney disease (CKD) due to exclusion of such patients from pivotal clinical trials. Physiologically based pharmacokinetic (PBPK) modelling supports model-informed dosing when clinical data are lacking, but application of these approaches to patients with impaired renal function is not yet at full maturity. In the current study, a ganciclovir PBPK model was developed for patients with normal renal function and extended to CKD population. CKD-related changes in tubular secretion were explored in the mechanistic kidney model and implemented either as proportional or non-proportional decline relative to GFR. Crystalluria risk was evaluated in different clinical settings (old age, severe CKD and low fluid intake) by simulating ganciclovir medullary collecting duct (MCD) concentrations. The ganciclovir PBPK model captured observed changes in systemic pharmacokinetic endpoints in mild-to-severe CKD; these trends were evident irrespective of assumed pathophysiological mechanism of altered active tubular secretion in the model. Minimal difference in simulated ganciclovir MCD concentrations was noted between young adult and geriatric populations with normal renal function and urine flow (1 mL/min), with lower concentrations predicted for severe CKD patients. High crystalluria risk was identified at reduced urine flow (0.1 mL/min) as simulated ganciclovir MCD concentrations exceeded its solubility (2.6–6 mg/mL), irrespective of underlying renal function. The analysis highlighted the importance of appropriate distribution of virtual subjects’ systems data in CKD populations. The ganciclovir PBPK model illustrates the ability of this translational tool to explore individual and combined effects of age, urine flow, and renal impairment on local drug renal exposure. Graphical Abstract

Abstract Funding Acknowledgements Type of funding sources: None. Background Measurement of vascular inflammation biomarkers is supported for estimation of residual inflammatory risk and cardiovascular risk stratification, but to date there is no systematic assessment of the added value of such biomarkers in predicting cardiovascular events and their comparative performance. Methods We systematically searched in MEDLINE published literature before Apr 14, 2020 for prospective cohort studies assessing the prognostic value of common biomarkers of vascular inflammation in stable patients with or without cardiovascular disease. The primary outcome was the difference in the c-index (Δ[c-index]) of the best clinical model with the use of inflammatory biomarkers for the prediction of the composite endpoint of major adverse cardiovascular events (MACEs) and mortality. The secondary outcome was the Δ[c-index] for MACEs only. We calculated I² to test heterogeneity. We used random-effects modelling for the meta-analyses to assess the primary and secondary outcome. Results We identified 92,507 studies in MEDLINE after duplicates were removed, of which 90,882 (96%) studies were excluded after screening the titles and abstracts, and 1,507 (93%) of the 1,625 remaining studies were excluded after assessment of the full texts. We included 93 (6%) studies in our quantitative evaluation, in which 351,628 individuals participated. The combination of high-risk plaque features and Fat attenuation Index (FAI) by CCTA was associated with the highest prognostic value i.e. Δ[c-index] for the composite endpoint per biomarker type (A). In meta-analysis, both plasma and imaging biomarkers of vascular inflammation offered incremental prognostic value for the primary outcome (pooled estimate for Δ[c-index]% 2.9, 95%CI 2.1-3.6, B) and for MACEs only (pooled estimate for Δ[c-index]% 2.9, 95%CI 2.1-3.8). The prognostic value of imaging biomarkers significantly surpassed that of plasma biomarkers for the primary outcome (Δ[c-index]% 11.3, 95%CI 8.3-14.3 vs. 1.4, 95%CI 0.9-1.8 respectively, p = 1.7x10-10, C). Notably, biomarkers of vascular inflammation offered higher incremental prognostic value in studies with a shorter duration of follow-up (i.e. &lt;5 years), in primary CHD prevention setting and lower cardiovascular risk populations i.e. (studies with &lt;5% cumulative event incidence, D) Conclusions The combination of HRP features and FAI by CCTA imaging had the highest prognostic value for cardiovascular events among plasma or imaging biomarkers of vascular inflammation. CCTA imaging to detect residual inflammatory risk and the vulnerable patient at risk for events is a rational approach to improve risk stratification and prognostication. Abstract Figure.

The importance of temporary housing facilities has been recently highlighted due to the occurrence of migrant flows, agricultural workers, and, more recently, the need for ‘social distancing’ strategies has become crucial to limiting the spread of the coronavirus 2019 (COVID-19) disease. They are built with different shapes, technology, structural and material systems. The structural system is often very simple because the module must be constructed in a short time by a few people. They have guaranteed the safety and well-being of the occupants and have to be designed in accordance with the rules and approved building codes. For these reasons, it is very important to design and verify the structural system with a high level of accuracy using a model and reliable structural analysis methods. Furthermore, it is essential to test the actual behaviour of the structure in use to validate the structural model simulated with the behaviour in situ. In this paper, we have illustrated a simple original test in situ to analyse the behaviour and survey the displacements of the shear wall prototype of a temporary home module in cork and timber loaded with a horizontal force. The comparison between the measured and the calculated displacements by means of finite element model software led to the evaluation of the accuracy of the structural model and the more realistic value of the connection’s metal stiffness. A specific numerical function was obtained using a rational regression interpolation that relates the connections’ stiffness value to the horizontal force. Knowing the actual value of the connection stiffness leads to a more reliable and safe design.

Abstract Background Surveillance efforts are essential to pandemic control, especially where the state is the primary health provider, such as Brazil. When public health testing guidelines limit molecular tests, there are reductions in detection efforts aimed at early recognition, isolation, and treatment of those infected with the virus. This study evaluates the effectiveness of surveillance policies to control the COVID-19 pandemic in São Paulo. Methods We conducted an interrupted time series analysis with a segmented regression model to analyze if changes in the state’s guidelines improved RT-PCR testing outcomes in Brazil’s most affluent and largest state, São Paulo. Anonymized daily data on the RT-PCR tests conducted in public laboratories belonging to the state-wide network from March 1, 2020 to June 5, 2021 were extracted from the Sao Paulo State open-source database, while the data on the genomic sequences were obtained from GISAID. We then aggregated these data for the 17 regional health departments in the state to evaluate regional-level outcomes. Results The public health system restricted RT-PCR testing to hospitalized cases in the first months. Testing was expanded to permit symptomatic testing of non-hospitalized persons only in July 2020, but a statistically significant increase in surveillance efforts was not observed. Case definition was expanded to allow case confirmation based on clinical, laboratory and image data criteria other than an RT-PCR test without increasing the testing effort for asymptomatic suspicious cases in September 2020. There was an increase in the mean volume of testing in each RHD, but the test positivity rate increased due to insufficient testing expansion. Results also show an uneven improvement in testing outcomes following these changes across the state’s regional health departments. Conclusions Evidence suggests that lower RT-PCR testing and genomic surveillance efforts are associated with areas characterized by a higher population concentration and a greater population reliance on the public health system. Our results highlight the need to structure health surveillance and information systems for disease control and prevention in emergency settings considering local demographics and vulnerabilities. In high prevalence settings, efforts at identifying and including vulnerable populations in routine and enhanced surveillance programs during COVID-19 must be significantly improved.

Abstract Focus of Presentation The 10- week internship in 2019 for the pilot cohort of community medicine/ public health resident doctors from various teaching hospitals in Nigeria was an immersion into field epidemiology, rumor surveillance, risk communication, digital tools for surveillance, developing strategic documents, line lists interpretation, weekly presentations and outbreak response coordination alongside working briefly as an incident manager for the Yellow Fever technical working group. Some of the learning points included: meeting coordination, contributions to ongoing research, review of training documents for surveillance officers and the mechanisms of escalating and de-escalating technical working groups in the face of outbreaks and working as an incident manager. Epidemiological concepts from the didactic training in residency and on field experience with the Centre provided numerous opportunities for knowledge integration and translation. This study describes the internship program and the need to sustainably replicate the program across the country and continent in building capacity for epidemiology. Findings The Nigeria Centre for Disease Control (NCDC) was established in 2011 in response to the challenges of public health emergencies and to enhance Nigeria’s preparedness and response to epidemics through prevention, detection and control of communicable and non-communicable diseases. Its core mandate is to detect, investigate, prevent and control diseases of national and international public health importance. The core functions of the NCDC include: to prevent, detect, and control diseases of public health importance, coordinate surveillance systems to collect, analyses and interpret data on diseases of public health importance, support states in responding to small outbreaks, and lead the response to large disease outbreaks, lead Nigeria’s engagement with the international community on diseases of public health relevance and to conduct, collate, synthesize and disseminate public health research to inform policy. The Centre has close to two hundred staff, working across its locations at the Headquarters and the National Reference Laboratory in Abuja, as well as the Central Public Health Laboratory in Lagos State which is a campus of the National Reference Laboratory. The Centre is led by a Director General, the members of staff work in six Directorates. These include: Public Health Laboratory Services, Prevention and Programs Coordination, Emergency Preparedness and Response, Surveillance and Epidemiology, Finance and Accounts; Administration and Human Resources. The internship for resident doctors in community medicine/public health training at various teaching hospitals in Nigeris at the NCDC, which I participated in as a member of the first cohort and pilot program in 2019 intended to provide skills and competencies in various aspects of field epidemiology, providing practical experience, latest knowledge, opportunities for collaboration and hands on experience. A training manual and logbook to guide the posting were available as residents rotated through various departments. The internship commenced with an introductory week in which all the residents were introduced to the various units and their roles in the organization. Following this, we participated in a week long curriculum review for training disease surveillance officers in Nigeria. This was very engaging and was also a crash course in revising many concepts in epidemiology. The orientation, lectures, unit rotations, participation in technical working groups/emergency operation centers and response pillars strengthened capacity, for competencies gained in residency training. It was an enlightening, greatly rewarding, educative and practical experience, integrating the background theoretical knowledge with on field exposure. I had the opportunity to prepare and present slides in different meetings, receive refresher trainings for select medical procedures, write meeting minutes and reports, was deployed to a University Teaching Hospital in the country to assess their suitability for selection as a Congenital Rubella Assessment sentinel site using the National Checklist. Other activities I actively participated in included calling state epidemiologists for priority diseases using the provided templates, data analysis from national line-lists for some priority diseases, budget preparation and interpretation for a grant and field calls at the Connect Centre. I also was involved in proposal writing, drafted a short communication article and a few short articles. Alongside my colleagues in the cohort, we attended and participated in the Lassa Fever Outbreak Response Technical working team. I joined the Risk Communication Pillar for the outbreak response. I completed several online courses to develop competencies on International Health Regulation, Integrated Disease surveillance, antimicrobial resistance which are core thematic areas for the NCDC. Furthermore, I participated in a week-long review of the training curriculum for disease surveillance officers nationwide. I was able to participate in planning for a national training and its logistics and improved on my presentation skills. Thereafter, I participated in the Lassa Fever Response Mid- Review Meeting, learning about case management, the role of partners and risk communication. I learnt first-hand, the huge work in the management of cases, deployments of rapid response teams and the logistics, risk communication, its methods and evaluation and the harmonization of data from the laboratories and cases managed for effective planning. The mid- review meeting assessed international standards, current practices and areas that required subsequent improvement. This also brought to the fore for me, how each response pillar seemingly works on its own, but how also they seamlessly fit into one goal, to reduce the burden of diseases in communities. The importance of goal setting, leadership and coordination, clear reporting lines, engagement with state public health units and proper community engagement and buy-in with the ability to clearly present work done was my major learning from this activity. Subsequently, I followed the processes involved in the escalation of a Technical working group to an emergency operations center and all the workings of an Incident manager for Yellow Fever technical working group in which capacity I served for a week. The role of an Incident Manager in coordination, receiving and synthesizing reports, liasing with partners, collaborating with the various technical pillars and being able to respond promptly to issues of national concern and data reports was a huge learning curve for me. I learnt how national level data is generated and interpreted for public health action. This role positively impacted me by helping me integrate what I had learnt in my residency training program, with the dynamic nature of field epidemiology and enhanced my managerial and technical capabilities under the supervision of the main Incident Manager. One of the numerous highlights was my deployment to a teaching hospital in Northern Nigeria to conduct an assessment of their capacity to host a sentinel surveillance site for Congenital Rubella Syndrome. The trip was my first to Northern Nigeria, alongside an NCDC staff. A checklist was used in assessing the hospital with interviews conducted for the relevant heads of the concerned clinical specialties. The responses were collated from all the centers where the assessments were done including mine and the sites are currently working. This particular experience helped me further appreciate at the national level; the conceptualization of research ideas, the development and deployment of tools and human resources, collaborations with partners, deployment of teams to fields, data analysis and subsequent public health action as a continuum. An important lesson for me was that disease surveillance and response is dynamic and requires collaborations, especially in resource-limited countries like Nigeria. Hopefully, via the feedback given by our cohort, the program will evolve into a better version and create a model that can be replicated on the African continent, between public health institutes and centres for residency training to strengthen the practice of epidemiology. Conclusion Previously uncharted partnerships/collaborations between public health institutes and residency training centers in developing such programs, will enhance the teaching and practice of epidemiology, especially for resource constrained economies, many of which are on the African continent. Key messages There is the need to continue and establish this model of internship to strengthen the capacity of our emerging health workforce and early career researchers in community medicine/ public health residency training to address our public health priorities in Nigeria and possibly Africa, now and for the future.

Indonesian EFL students faced online teaching and learning in such a rapid process. Therefore, this research was carried out to search for EFL students in Indonesia about their responses on teaching and learning online. This research applied the action research method with the paradigm of quantitative descriptive approach. Data for this research was collected via an online questionnaire, distributed to one class size sample consisting of 32 students in the even semester of the 2019/2020 academic year at one of the private colleges in the West Sumatra province of Indonesia. The data were analysed by descriptive statistics, especially the percentage of each item available in the questionnaire. Findings of this research show that the respondents, or the students, had their evaluation toward the online teaching and learning. 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