Background: In Europe, the most prevalent hantavirus, Puumala virus, is transmitted by bank voles and causes nephropathia epidemica in human. The European spatial distribution of nephropathia epidemica is investigated here for the first time with a rich set of environmental variables.Methods: The influence of variables at the landscape and regional level is studied through multilevel logistic regression, and further information on their effects across the different European ecoregions is obtained by comparing an overall niche model (boosted regression trees) with regressions by ecoregion.Results: The presence of nephropathia epidemica is likely in populated regions with well-connected forests, more intense vegetation activity, low soil water content, mild summers, and cold winters. In these regions, landscapes with a higher proportion of built-up areas in forest ecotones and lower minimum temperature in winter are expected to be more at risk. Climate and forest connectivity have a stronger effect at the regional level. If variables are staying at their current values, the models predict that nephropathia epidemica may know intensification but should not spread .Conclusion: Models indicate that large-scale modeling can lead to a very high predictive power. At large scale, the effect of one variable on disease may follow three response scenarios: the effect may be the same across the entire study area, the effect can change according to the variable value, and the effect can change depending on local specificities. Each of these scenarios impacts large-scale modeling differently. Myodes glareolus) , the most prevalent hantavirus in Western and Northern Europe , is respareolus) . Transmiareolus) . Transmiareolus) –8.ex vivo survival  or by municipality of residence (289 records), and 192 records had no spatial information . In Belgium, NE cases from 2000 to 2010 are reported by municipality of residence (Institut scientifique de Santé publique-Wetenschappelijk Instituut Volksgezondheid). In the Netherlands, official notifications for 2008–2012 are provided by municipality of residence [Rijksinstituut voor Volksgezondheid en Milieu (RIVM)]. This dataset is completed with data from a cross-sectional population serological survey of 2929 persons sampled in 2006 (RIVM) and with the RIVM diagnostic database (RIVM is one of three diagnostic centers) for 2007–2011. In Norway, cases reported from 1989 to 2012 are provided by municipality of residence (Folkehelseinstituttet). In southern Sweden, human infections reported for 1997–2012 are collected by municipality of infection (Smittskyddsinstitutet). In northern Sweden, 212 human infections by coordinates of infection are recorded for 1991–1998 (Smittskyddsinstitutet). In Finland, the National Institute of health and Welfare collects the data that are generally available at hospital district level (province level). The coordinates of the administrative unit center were recorded for 2004–2009 (Metsäntutkimuslaitos). For this research, some high-incidence and low-incidence regions are selected.2 is used as the absence/presence point. Small municipalities (area ≤80 km2) are aggregated in a 10 km resolution grid of points. Larger municipalities (area >150 km2) are represented by points located where the population density is highest . Geographical coordinates are used when available. In Finland, the presence and absence data are aggregated on a 10 km grid of points. In northern Sweden, 300 absences are randomly selected among other dwellings  indicates the presence of bank voles at the landscape level, and the presence and also the abundance of bank voles at the regional level. The proportions of coniferous, broadleaved, and mixed forest  are used. It is assumed that broadleaved forest is preferred over coniferous forest but the effect of forest type may differ between the landscape and regional levels. Indeed, if a region is characterized by a large proportion of coniferous forest, the proportion of broadleaved forest could be significant at the landscape level but not at the regional level as, regionally, coniferous forests are used by default by the bank vole. The contiguity index of forest patches  is used as a proxy to represent contacts between rodents, increasing prevalence in bank voles and so, NE cases presence. At the landscape level, a higher proportion of built-up areas in a buffer of 150 m around forests  would indicate a higher probability of contact between bank voles and humans. At the regional level, high levels of urbanization may nonetheless limit PUUV transmission.The mean enhanced vegetation index (EVI)  and number of green days per year  are included. Green days represent the number of days between the detection of the start of a growth cycle and the end of the cycle, when vegetation greenness decreases. These indices are hypothesized to reflect food availability and the number of litters  at the landscape level, as well as a longer breeding season at the regional level, and should thus increase the disease presence probability at both levels.ex vivo survival at the landscape level. At the regional level, we assume that a higher soil water index gives information about land use  unfavorable for the bank voles.Higher soil water index (SWI) , averaged over 2007–2010, should improve the virus The probability of human NE cases increases with human population density, whether at the landscape or regional level. To reflect the presence of humans, the mean distance weighted population proximity index  is considered. The population proximity index represents the population likely to visit a place, taking into account the population in the surrounding environment .The spatial distribution of NE cases in Europe is first modeled using multilevel logistic regression in order to identify significant environmental variables at the landscape and regional level. The intraclass correlation coefficient, a measure of the proportion of the variance found at the regional level , 33, is Multilevel regressions allow including intercepts varying between regions (random intercept model) and/or slopes varying between regions (random slopes model). Variables at the landscape and regional level are tested in a model with random intercepts and a model with random intercepts and slopes (“lme4” package in R2.12.0). These models are compared with an empty model and with each other using an ANOVA test based on the Akaike information criterion and the Bayesian information criterion. The final model includes the variables significant in regressions with one explanatory variable and the random intercepts and slopes, which have better Akaike and Bayesian information criterion. To avoid collinearity issues, variables with a variance inflation factor >10 are removed. The area under the curve (AUC) is used to evaluate the predictive power of the model . ResultiIn order to better distinguish the effects of environmental variables across Europe, logistic regressions are fitted for each ecoregion using landscape level variables. Seven ecological regions encountered in the study area are compared (European Topic Centre on Nature Protection and Biodiversity) Figure .The effect of environmental factors is not necessarily linear, and may be positive in some regions and negative in some other. Because of the broad range of values covered, this is likely to be encountered in our study area. This type of relationship is poorly addressed by classical regression, and a niche model is thus needed to explore the effect of the landscape level variables across the study area.Boosted regression trees (BRT), which allow to model non-linear response, are used to build an European model including all variables (“gbm” package in R) . The AUCThe intraclass correlation coefficient shows that 57% of the variance is at the regional level. A multilevel model is therefore advised. Following the variance inflation factor analysis, snow cover, green days, and the proportion of forest are removed from further analyses to avoid collinearity issues.In bivariate analyses, all variables at the landscape and regional levels are highly significant, except the maximum temperature in summer and the EVI at the landscape level.The results of the multilevel logistic regression are presented in Table Random slopes are included for the landscape level variables coniferous forest, broadleaved forest, mixed forest, contiguity of forest, built-up areas in forest ecotones, and population proximity index and, at the regional level, minimum temperature in winter and EVI.At the landscape level, the coefficient of the variable built-up areas in forest ecotones is significantly positive at the level of 0.001. The coefficient of the minimum temperature in winter is significantly negative at the level of 0.05. At the regional level, the coefficients of forest contiguity, EVI, and population proximity index are significantly positive at the level of 0.05. Also, the maximum temperature in summer is negatively significant at the level of 0.01, and the minimum temperature in winter and SWI at the level of 0.05.The predicted probabilities and the false presences/absences of the model are mapped in Figure The multilevel regression indicates that the effect of environmental factors varies across regions and random slopes were included for several variables. Logistic regressions are therefore elaborated for each ecoregion Figure . When siThe AUC of the boosted regression trees model is 0.921 ± 0.003. The AUC on cross-validation is 0.893 ± 0.003. These indicate a very good predictive power of the model. The variables with a relative importance over 10 are the minimum temperature in winter, the snow cover, and the maximum temperature in summer.The response curves Figure  of snow The boxplots in Figure The general trend by ecoregions can be compared to the sign of the coefficient from the bivariate logistic regressions Figure . The sigBoth the multilevel and the BRT models have very good predictive powers. The distribution of zoonoses at a large-scale using a single database built from national databases is successfully modeled. However, large-scale models can obscure the local effect of environmental factors or how they may differ from place to place. With these models, the interpretation of the variables may generate misleading conclusion as wide range of conditions cannot be summarized into one explanation. We identify three scenarios of response to a variable that can be encountered in modeling studies at a large-scale Figure . These sThe first easiest scenario implies that a variable has the same effect over the complete study area. These variables can be easily included in a large-scale model. In our study, the built-up areas in forest ecotones are assumed to increase the human exposure. This is reflected both by the ecoregional regressions and the global BRT model.ex vivo virus survival; very extensive snow cover  has a decreasing probability because of the harsh conditions for the bank voles and the increasing pressure due to lower prey diversity. The sign of the ecoregional regression matches these hypotheses as well as the BRT response trend.The second scenario, the most common, is when the variable has a non-linear effect on the probability of the disease. Because of this, the effect of the variable varies from region to region, depending on the value of the variable encountered. For these variables, results and hypotheses from local studies can be used for places with the same variable extent. They can be used in non-linear large-scale models. For example, looking at the snow cover BRT trend, less extensive snow cover (such as in southern Europe) increases the probability as it relates to more contact between the virus/bank voles and humans; a more extensive snow cover increases the probability even more as that implies a larger bank voles population and a better The third scenario, the most difficult to identify, is when the variable does not seem to reply to one hypothesis, whatever the extent of its distributions. Different hypotheses are needed for each region. For these variables, results from local studies cannot be applied and interpolated to other places and their interpretation in large-scale study may lead to misleading conclusion. Taking the coniferous forest as an example, the global BRT trend is negative as it is generally expected, but the sign of the regression coefficient appears significantly positive for the northern temperate Atlantic and the Scandinavian montane birch ecoregions. In the northern temperate Atlantic ecoregion, there are very few forests and it is possible that bank voles are found in coniferous forests, lacking a better habitat. For the Scandinavian montane birch ecoregions, coniferous forests are in valleys while mountains are colonized by birches . Soils oSo far, the distribution of NE cases has not been studied at the European level, and this study helps to answer whether factors impact the distribution in one region or at a multi-country level [see question raised in Ref. ]. Our moBy combining ecoregional regressions and a global BRT model, we identified variables for which it is advised to pay attention when hypothesizing effects (Scenario C): precipitations, coniferous forest, broadleaved forests, and population. For the minimum temperature in winter, the snow cover, green days, the SWI, the proportion of mixed forest, the built-up areas in forest ecotones, and the contiguity of forests, our results suggest that they follow one process that can be non-linear.The predicted probabilities map shows that, according to environmental data, fewer cases should be expected in southern, western, central, and the extreme east of France, northern Belgium, the Netherlands, southern and northern Sweden, and northern Finland. The BRT model yields similar predictions. Also, a lot of false presences are found in areas where the disease is already recorded and false absences are located at the edge of these areas. If variables stay at their current values (this model predicts the current situation and not the future), false presences can be interpreted as suitable places to find the disease and where the disease may appear in the future, while false absences can represent unsuitable environments. It seems that the recorded data already covered the potential distribution of NE cases. A spread of the disease should not occur but intensification is possible.As we learned here, effects can vary between scales and, even if the landscape scale is interesting, a finer scale may bring further details and reflect more particularities. Exact geographical coordinates are rarely known or disclosed, due to privacy rules but also due to the nature of the hantavirus pathogenesis, and the size of the administrative units may be too big to make proper models. NE cases are not reported in the same way everywhere (between and within countries). Cases can, for example, be identified from antibodies from serological surveys or by the identification of clinical symptoms. A bias may probably result from the difference of these reports. Inclusion of a variable accounting for these differences could solve this issue but is particularly challenging as distinction of the way of records is not always known. Cases are most often reported by residence or where the disease is identified, rather than the true infection location. Therefore, some presences are reported in unexpected places, like in southern Sweden where PUUV is reportedly absent. These presences were nevertheless included in the database and were all predicted as absences. However, in this area, some false presences are predicted near these false absences. It could indicate that the recorded presences do indicate local transmission, unless these were indeed false predictions. The models presented here are not designed to predict the future distribution of PUUV. False presences indicate places where the confirmation of the absence or presence of cases must be assessed . In southern and central France, absence of confirmed case will probably result from the fact that places are too far and isolated from the current distribution to imagine that the disease will reach these places. The other false absences places like southern Sweden, the Netherlands, and the Norwegian coast, even if located in lower probability areas, should be carefully considered in the future for monitoring and surveillance.This study successfully models the pan-European NE distribution using a compilation of national disease data source and European level environmental databases. Europe covers diverse landscapes and ecoregions and, even if some variables are recurring in the literature for various areas, the underlying hypotheses can be different. This study highlights that these differences can be the result of local specificities or of the non-linearity of the processes. When the effect of a factor varies locally, its inclusion in a large-scale model is compromised.According to both multilevel logistic and non-linear model, the distribution of PUUV seems limited in space by environmental variables that are identified here. Our model does not predict an important spread of the disease, assuming current conditions, but possibly intensification in places where the disease is already there. Also, some lower probabilities areas such as the South of Sweden, the Netherlands, and the Norwegian inner coast should be further studied.CZ and SV contribute to the conception and design of the work, the analysis and interpretation of data, and the drafting of the work. SQ, HH, OL, OV, J-MR, CR, AS, KV, and MH contribute to the design of the work, the acquisition the data, the critical revision for important intellectual content. All the authors approve the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.The research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.http://journal.frontiersin.org/article/10.3389/fpubh.2015.00054/abstractThe Supplementary Material for this article can be found online at Click here for additional data file.Table with results for each ecoregion of logistic regression in bivariate, complete, and step models.Table with results for each country of logistic regression in bivariate, complete, and step models.Table of random intercepts and slopes added in the multilevel model.One Excel file with three sheets:


It is common for elderly people and those with such chronic disorders as respiratory diseases to suffer severe complications from influenza, a viral infection. The voluntary uptake of vaccination is vital to the effectiveness of influenza prevention efforts. The Health Belief Model (HBM) is the most commonly used framework in the field of vaccination behavior to explain the decision that people make to accept or refuse vaccination. In addition, psychological flexibility is considered helpful in causing people to be open to adopting new practices that are consistent with their values. This study examined the role of psychological flexibility and health beliefs in predicting the uptake of influenza vaccination among people in Hong Kong. Eligible participants were Hong Kong permanent residents aged 18 years or above with a history of chronic respiratory diseases (CRD). A convenience sample of 255 patients was recruited to participate in a cross-sectional survey in which HBM components and factors of psychological flexibility were assessed. The following variables were found to be significant predictors of vaccination: age, smoking status, comorbidity, previous hospitalization, perceived susceptibility, perceived severity, and psychological flexibility. Enhancing psychological flexibility might be a potential new direction for motivating people to accept influenza vaccination. Chronic respiratory diseases (CRD) are defined as chronic diseases of the airways and other structures of the lungs, and include asthma, respiratory allergies, chronic obstructive pulmonary disease (COPD), occupational lung diseases, sleep apnea syndrome, and pulmonary hypertension . They coThe majority of cases of morbidity and mortality associated with CRD are due to acute exacerbations . These mThere may be multiple factors contributing to the acceptance or refusal of vaccination, some known and some unknown. In this regard, an extensive review of the literature was carried out to identify the existing evidence on vaccination behavior. Previous studies have reported that people who are older ,20,21,22In summary, all of the reviewed studies had been conducted in Western countries, and most of them had been carried out in community settings. The variables in these studies had been covered in previous studies, and included socio-demographics, lifestyle, co-morbidities, the utilization of health services, medication use, and health beliefs. Almost all of the factors had been generated by reviewing previous research on seasonal influenza vaccinations and expert consultations. Research on influenza vaccinations has primarily focused on high-risk populations, such as pregnant women and healthcare workers. Only a few recent isolated efforts have addressed the vaccination behavior of people with CRD. A scant few studies have been published on influenza vaccinations among Chinese populations. It should be noted that vaccination rates for people with CRD vary greatly, from 19.9% to 71% ,24,25,28Moreover, a number of conceptual frameworks have been developed in an attempt to explain why individuals choose to be vaccinated against influenza. The most commonly used framework is the Health Belief Model (HBM) , which eAn increasing number of recent studies support the view that there is a relationship between the refusal to be vaccinated and various fears and anxieties. It is possible that such emotions as the fear of catching influenza or concerns about the safety and efficacy of the influenza vaccine play a role in determining whether or not a person decides to get vaccinated. Some researchers have linked the refusal to be vaccinated with trait anxiety, such as concerns about the side effects of the flu vaccination ,36. SomePsychological flexibility (PF) is defined as “the ability to contact the present moment more fully as a conscious human being, and to change or persist in behavior when doing so serves valued ends” . By contFurthermore, PF is one of the core concepts in Acceptance and Commitment Therapy (ACT), which is among the third wave of cognitive and behavioral therapies. ACT has been designed to be applicable to a broad range of psychological problems by combining acceptance and mindfulness methods along with activation and behavioral change methods . ACT hasIn this study, it is hypothesized that people with low levels of psychological flexibility would allow their desire to avoid uncomfortable emotions, such as anxiety about catching infections from influenza vaccination or fear of needles, to influence their decision to accept an influenza vaccination. On the other hand, people with high levels of psychological flexibility would be more accepting and tolerant of anxiety and would not allow such emotions to influence their decision to receive an influenza vaccination. Accordingly, the study set out to investigate the unique interplay between a person’s level of psychological flexibility and health perceptions in predicting that person’s decision to receive an influenza vaccination.A quantitative, cross-sectional, and correlational survey was employed as the study design in the present research. The target population comprised completely of people with CRD in Hong Kong. The study was carried out in three respiratory medical wards of one public hospital in Hong Kong. Non-probability convenience sampling was used to recruit the sample from the selected settings, where potential participants were accessible to the investigators. A cross-sectional survey was conducted from January to March 2015. The investigators approached patients and invited them to participate in the study. The subject selection criteria were established to maximize the homogeneity of the study sample. Eligible participants were Hong Kong permanent residents aged 18 years or above with a history of chronic respiratory diseases who were able to complete a set of survey questionnaires.A self-administered questionnaire with an information sheet was distributed to the participants. The participants completed the questionnaire on the spot. One investigator was available to answer any enquiries about the survey raised by the participants. Most of the participants completed the questionnaire in about 20 min.A structured questionnaire was used as a research instrument in this study. The questionnaire consisted of three parts. Part one began with eight categorical items assessing the participants’ socio-demographic status , health status (whether they had been diagnosed with other chronic illnesses), and utilization of healthcare services . These items were then followed by a dichotomous item, “vaccinated” and “unvaccinated”, to determine whether the participants had received an influenza vaccination in the preceding 12 months.Part two consisted of the Acceptance and Action Questionnaire II (AAQ-II) to measure psychological flexibility . The itePart three was made up of a total of 34 statements from the Champion’s Health Belief Model Scale (CHBMS) , organizA statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) software, version 21.0 . Frequencies and percentages were utilized to illustrate all of the information on the socio-demographics, health status, utilization of healthcare services, and vaccination status of the participants. Because the influenza vaccine refers to an annual vaccination in which people are administered a vaccine that is specific to a given year to protect them against the highly variable influenza virus, an individual is considered to have been vaccinated against influenza if the vaccination occurred within 12 months prior to the individual’s participation in the current study. Mean and standard deviation were used to describe the central tendency and variability of the AAQ-II scores.2) test for nominal data was conducted to determine differences between vaccinated and unvaccinated sufferers of chronic respiratory diseases with regard to socio-demographic characteristics, morbidity, utilization of healthcare services, and the intention to receive an influenza vaccination in the next influenza season. Second, an independent sample t-test for interval data was carried out to compare the mean differences in the AAQ-II scores between the vaccinated and unvaccinated groups. Third, because the independent variables involved various measurement scales, a multivariate logistic regression analysis was used to investigate the predictors of the uptake of the influenza vaccine for people with CRD. Because of the modest size of the sample that was included in the analysis, the variables “Number of visits to an out-patient clinic in the past 12 months” and “Number of hospitalizations in the past 12 months” were transformed into binary covariates instead of being stratified into four categories.In order to achieve the research objectives, the following statistical tests were used with the level of significance (α) specified to be 0.05. First, a chi-square , and the Hong Kong East Cluster Ethics Committee of the Hong Kong Hospital Authority . Individual participants received an information sheet and an explanation of the selection criteria, objectives, and procedures of the study. They were assured that participation in the study was voluntary, and that there would be no penalties for choosing not to participate in it. It was specified that no compensation would be offered for participating in this study. The survey was anonymous and participants could withdraw from the study at any time. All of the data that were collected will only be used for the purposes of this study. n = 171) had not. The data for the two groups of participants are shown in 2 = 45.07, degree of freedom (df) = 3), smoking status , the presence of comorbidities , the number of visits to the Specialist Out-patient Department (SOPD) , and the number of hospitalizations  in the preceding 12 months were p < 0.05, indicating that the differences in these variables between the vaccinated and non-vaccinated groups were strong and significant.A total of 255 participants completed the questionnaires. Eighty-four of the participants, (32.9%) had received an influenza vaccination and 67.1% (t-test of the AAQ-II and CHBMS between the two groups are shown in p = 0.000) and in some domains of the HBM, including perceived susceptibility (p = 0.000), perceived severity (p = 0.000), and cues to action (p = 0.005). With regard to the HBM variables, the vaccinated participants and non-vaccinated participants did not differ in perceived benefits or barriers to vaccination.The results of the independent sample p = 0.000), being a non-smoker (p = 0.025), the presence of other chronic illnesses (p = 0.001), the number of hospitalizations in the past 12 months (p = 0.004), psychological flexibility (p = 0.000), perceived susceptibility (p = 0.015), and perceived severity (p = 0.004) were significant predictors of influenza vaccination. The regression model had a high Nagelkerke R2 of 0.707  ,29, but With regard to the association between health perception and vaccination status, in the present study vaccinated people with CRD might have perceived that they were a group at risk of getting influenza because of their advanced age and poor lung condition. In addition, the results showed that there was a significant difference between the vaccinated and unvaccinated groups in their overall perception of the severity of influenza. The vaccinated group may have experienced influenza during hospitalization, making them very sick and adversely affecting their usual activities, or have seen others suffering from influenza ,55. WithThere were no significant differences between the vaccinated and unvaccinated groups of people with regard to their perception of the benefits and barriers to influenza vaccination. Pointing out the benefits of the influenza vaccine is not enough to persuade unvaccinated people to receive the vaccine, because of their perception of the low risk of getting the flu, and their concern about the side effects caused by the vaccine and the pain associated with an injection . The resThe PF of the unvaccinated individuals in this study was found to be 45.9, which is comparable to previous findings for people with anxiety disorder (38.14) , but lowThe regression analysis suggested that the variables of being over 65 years of age, a non-smoker, the presence of comorbidity, the perception of oneself as being more susceptible to influenza than others, the perception of influenza as a severe infection, and higher psychological flexibility were predictors of the acceptance of influenza vaccination. A high level of perceived susceptibility and severity may indicate that people felt anxious about getting infected with the influenza virus, as they perceived themselves to be more susceptible to infections than others. This may have motivated them to avoid the kinds of uncomfortable experiences that they had had in the past, such as frequent hospitalizations and severe infections. Prior research has pointed out that a perceived threat (high susceptibility and/or high severity) is associated with more negative emotions . It is pAs shown in the results of this study, despite the implementation of a multifaceted, evidence-based, locally designed promotion program in Hong Kong, the knowledge and beliefs of psychologically inflexible individuals about the influenza vaccine did not change. A recent study also described similar findings and suggested that providing information concerning influenza vaccination may have little impact on strongly held beliefs, even when the information is highly customized . In thisVaccination programs are becoming a public health priority. The findings have important implications for both policy and practice. Social and psychological factors significantly influence influenza vaccination uptake rates; therefore, the inclusion of psychological aspects in vaccine promotion programs is critical to improving vaccination coverage. We suggest that future research could explore whether the prevalence of influenza vaccination among people with CRD could be increased by enhancing psychological flexibility, such as through using acceptance and commitment therapy.ACT is not only an approach that can be applied at the level of therapy for human cognition, but is also a model of psychopathology that is rooted in pragmatic philosophy  and theory  . This moAs a model of therapy, the main goal of ACT is to increase psychological flexibility as opposed to eliminating negative experiences. The positive techniques put forward in ACT, such as acceptance and cognitive defusion, help individuals come into fuller contact with their negative private experiences while behaving in a way that serves their values, therefore attaining a positive outcome . As mentThe present study has several limitations, and caution must be exercised in generalizing its results. This is because the sample was a convenience sample and was not diverse; moreover, it was obtained from only one local hospital. The use of self-reporting in this study might have resulted in recall bias. In addition, unvaccinated people might have been less willing than vaccinated people to participate in such a research study, as has been reported in previous studies. Both of these factors might have contributed to an overestimation of vaccination in our study. Furthermore, although most of the factors influencing individuals to get vaccinated against influenza were covered, some important ones, such as previous vaccination status, were not captured in the current study. Indeed, as documented in a prior study, previous vaccination status was associated with a future intention to receive influenza vaccination .In conclusion, to our knowledge, this is the first study to take factors of two different models, the HBM and PF, to make comparisons between vaccinated and non-vaccinated people with chronic respiratory diseases. The overall prevalence of influenza vaccination in our sample was 32.9%. Our study showed that among people with CRD, smoking status, hospitalization, perceived susceptibility, and psychological flexibility were critical determinants of the likelihood of getting vaccinated against influenza. For the first time, psychological flexibility among people with CRD was identified as a significant contributing factor in influenza vaccination. Acceptance and Commitment Therapy may be helpful in motivating patients to receive the vaccination.


With the rapid development of WIFI technology, WIFI-based indoor positioning technology has been widely studied for location-based services. To solve the problems related to the signal strength database adopted in the widely used fingerprint positioning technology, we first introduce a new system framework in this paper, which includes a modified AP firmware and some cheap self-made WIFI sensor anchors. The periodically scanned reports regarding the neighboring APs and sensor anchors are sent to the positioning server and serve as the calibration points. Besides the calculation of correlations between the target points and the neighboring calibration points, we take full advantage of the important but easily overlooked feature that the signal attenuation model varies in different regions in the regression algorithm to get more accurate results. Thus, a novel method called RSSI Geography Weighted Regression (RGWR) is proposed to solve the fingerprint database construction problem. The average error of all the calibration points’ self-localization results will help to make the final decision of whether the database is the latest or has to be updated automatically. The effects of anchors on system performance are further researched to conclude that the anchors should be deployed at the locations that stand for the features of RSSI distributions. The proposed system is convenient for the establishment of practical positioning system and extensive experiments have been performed to validate that the proposed method is robust and manpower efficient. Nowadays people are more and more concerned about their precise location information for the wide use of location-based services in daily life. Global Navigation Satellite System (GNSS), as an effective way of outdoor positioning, has become a requisite tool for traveling. Unfortunately, for indoor scenarios, the satellite signal is disrupted or blocked and a person would be located with poor accuracy, or even unable to be located. According to social scientists, indoor positioning is highly desirable since 70% of daily life is indoors. Consequently, several indoor positioning technologies have emerged, such as infrared-based positioning, ultra-wideband (UWB) positioning, radio frequency identification (RFID) positioning, and WIFI positioning, most of which are too costly to be used in large areas.With the development of wireless networks, a large amount of WIFI APs have been installed, which represents a convenient foundation for WIFI positioning methods. In addition to the availability, a unique advantage of WIFI positioning technology is that most kinds of mobile devices are already equipped with WIFI modules. Among the various WIFI positioning systems, the fingerprint technology, in which the user’s location is estimated by matching online received signal strength index (RSSI) with values collected offline, is one of the most feasible approaches ,2.In recent years, the WIFI-based localization systems have shown great promise and researchers have focused on several key challenges in real-time accuracy fingerprint positioning for practical deployment. For example, solutions to deal with the heterogeneity of WIFI devices have been addressed in ,4. SeverHowever, for practical applications, the biggest issue of WIFI indoor positioning is the construction and updating of the radio fingerprint database, which requires professional signal collection, and is both time- and labor-consuming, especially in large urban areas. Due to the fluctuating feature of the WIFI signals, the database should be updated periodically by workers, even for the same scenario. Features of the signal are obviously different between office hours and rush hours, and dramatic positioning errors would be generated if the same fingerprint database is adopted. More seriously, the signal environment may change, and APs may be displaced or upgraded, which could also greatly affect the positioning accuracy. Therefore, the radio map for positioning should be constructed and updated adaptively .It has been stated in  that a rIn , a dynamIn , a novelBesides the training signal path loss models , the intAn autonomous and collaborative RSSI fingerprint collection and localization system based on mobile users is proposed in , who traWhereas the paper  proposedThe traditional WIFI positioning system is based on the client-server model, in which the client periodically collects the RSSI information of surrounding APs. However, the latest research in  introducAlthough research involving the fingerprint radio map concept have achieved some progress, an effective method for constructing and updating the fingerprint database to improve the applicability of WIFI positioning technology is still desirable. Compared with the former papers or systems, our main contributions of this paper lie in the following aspects. Firstly, instead of taking the full function devices as the anchors in former papers, our proposed sensor anchors are designed with a single function to periodically broadcast the standard WIFI beacon frame through uplink to APs, which are very cheap and can work for more than one year with an ordinary battery supply. Secondly, this paper proposes novel regression metrics and algorithms for signal fingerprint database construction. We take full advantage of the important but easily overlooked feature that the signal attenuation model varies in different regions in the regression algorithm to get more accurate results. Thus, a novel method called RSSI Geography Weighted Regression (RGWR) is proposed to solve the fingerprint database construction problem. Furthermore, the average error of all the calibration points’ self-localization results will help to make the final decision of whether the database is latest or to be updated automatically. The proposed system is convenient for the establishment of practical positioning system and extensive experiments have been performed to validate and verify the robustness and effectiveness.The remainder of this paper is organized as follows: the new constructing model together with the algorithms is introduced in We first introduce an improved WLAN positioning structure in Note that the modified AP can be replaced by some wireless monitor equipment together with the traditional APs, and they are used here just for system prototyping and proof of concept. In the commercial implementation, the modified firmware is required to be adopted by an AP manufacturer and the power pattern recordings will be carried through the beacon frames to be received and decoded by any WIFI-enable device .Generally, the user equipment (UE) receives the downlink signal from the APs. Inversely, the proposed WIFI anchor, called “uplink anchor”, can periodically broadcast the standard WIFI beacon frame through uplink to APs. The periodic dormancy mechanism with a designed duration of working and sleeping  is adopted, so that the anchor power consumption is little and can work for more than one year with the ordinary battery supply. By contrast, the anchor points proposed in ,25 have Based on the above-mentioned novel system framework, two fingerprint information tables can be obtained periodically. From the proposed system, the WIFI radio map could be constructed based on n method , the Radn method , the GPRn method  and so on method ,28,29,30➢The RSSIs among neighboring locations always exhibit some level of correlations.➢Signal attenuation models vary in different regions.The traditional path loss models have proven that the attenuation is related to the distance and number of walls. Moreover, the research in  has demoThe first principal is adopted by most weighted regression algorithms. The second one, however, is always neglected.In this paper, the RSSI Geography Weighed Regression (RGWR) method is proposed to construct the WIFI radio map for positioning, considering its characteristics fit our two principles well. The Geography Weighted Regression (GWR) is a special form of the vary-coefficient regression method, which considers that the regression coefficients are not only affected by the known anchors surrounding, but also vary as the distance from anchors and the located regions change . GWR is To apply the RGWR method, available information includes the coordinate of each reference point, both of the AP and WIFI anchors, the distance between each anchor and the AP, and the signal strength received by each AP from The logarithmic-distance path loss model arameter :(1)PL=Ai: ith point and the AP. ith point. The following Equation (2) is the basic relationship, in which , which has been widely used to handle the WIFI The estimator for this model is similar to the weighted least squares (WLS) model except that the weights are conditioned on the location IFI RSSI : (4)wj. It is approximately 55 m by 10 m see . The envTo assess the RSSI estimation accuracy, a total of 52 reference locations are selected in the testing areas  moves around the experiment area along the known waypoints. The AP scans the signal transmitted by the device and sends the RSSI to the positioning server. At the known waypoints, we stopped and recorded the reference location for positioning error calculation purpose.The average positioning errors of 25 tracks in both scenarios are given in We deploy the WIFI anchors in our experiments above based on the basic principle that at least three calibration points, including APs and WIFI anchors should be in the coverage of each AP to execute the RWGR algorithms. In addition, the corners and interesting rooms are the candidate locations. Take the test points on the 12th floor in scenario one for example, the estimated error of the test points in the meeting room increase to 15 dBm when the WIFI anchor in the room is removed. That illustrates the importance of the WIFI anchors in the rooms.As shown in To find out the relationship between the anchor number and the average positioning error, we decrease the number of WIFI anchors one by one in scenario one. The results are shown in The radio map changes caused by time are always a serious problem in WIFI positioning systems. Though several specific radio maps created at different times could be stored in the positioning server, such as 8 a.m., 11 a.m., and 5 p.m., the cost is too large. In addition, most existing algorithms cannot solve the RSSI changes due to the environment.Four mobile phones are placed uniformly in fixed locations on the 12th floor in scenario one. During every hour between 8:00 and 18:00, we can obtain 20 positioning results for each mobile phone using the manual database and the newly developed database with our proposed method, respectively. The manual database is collected at 9:00 and remains unchanged. The average positioning errors are show in To verify the self-updating function of our database, an iron door near the 18th reference points was opened and closed to simulate an environment change see  in scenaTo further evaluate our proposed GWR algorithms, another experiment with a bigger and more complicated environment is performed. The second environment is 25 m by 115 m on the second floor in the Zhong Guan Cun shopping center in Beijing see . There aAs shown in To evaluate our proposed GWR algorithm, the RBF based aggregation algorithm  is also The results in To evaluate the impact of anchors, we deploy the anchors in the four cases shown in As our proposed algorithm can also be used to obtain the full WIFI database if the data of manual sampling are treated as the data from the anchors, the conclusion is also important. Then, only a few manual samples are required as virtual anchors.In this paper, a novel method RGWR for the calibration of WIFI fingerprint databases is proposed. The basic advantage of the proposed method is that it uses the online RSSI information from the new renovated WLAN AP and anchors to dynamically construct a fine radio map that accurately models the signal power distribution over the whole environment without time-consuming offline surveys. The system can also deal with the changes caused by time and environment together with the detection and updating scheme as proposed. The proposed algorithms provide better performance over the RBF algorithm in the average estimated RSSI error, the RSSI discrimination of reference points and the average positioning error. The effects of anchors on system performance are further researched. A conclusion can be drawn that the anchors should be deployed on the locations that stand for the features of RSSI profiles to obtain better performance.The positioning error of our newly constructed system is 2–3 m and 4–5 m for static and walking scenarios, respectively, and it is among the most accurate results currently obtained by systems with little human intervention. The accuracy of our system is acceptable for most indoor applications. What’s more, the proposed system is easy to be established and maintain for wide deployment. If higher accuracy is required, we can place more WIFI anchors or collect some fingerprints manually in sparse grids as additional input to the RGWR algorithm. In the future, we will perform further research and experiments on the deployment of the WIFI anchors, and potential applications for scenarios like airports and markets.


In the field of health technology assessment (HTA), there are several approaches that can be used for ethical analysis. However, there is a scarcity of literature that critically evaluates and compares the strength and weaknesses of these approaches when they are applied in practice. In this paper, we analyse the applicability of some selected approaches for addressing ethical issues in HTA in the field of complex health interventions. Complex health interventions have been the focus of methodological attention in HTA. However, the potential methodological challenges for ethical analysis are as yet unknown.Six of the most frequently described and applied ethical approaches in HTA were critically assessed against a set of five characteristics of complex health interventions: multiple and changing perspectives, indeterminate phenomena, uncertain causality, unpredictable outcomes, and ethical complexity. The assessments are based on literature and the authors’ experiences of developing, applying and assessing the approaches.The Interactive, participatory HTA approach is by its nature and flexibility, applicable across most complexity characteristics. Wide Reflective Equilibrium is also flexible and its openness to different perspectives makes it better suited for complex health interventions than more rigid conventional approaches, such as Principlism and Casuistry. Approaches developed for HTA purposes are fairly applicable for complex health interventions, which one could expect because they include various ethical perspectives, such as the HTA Core Model® and the Socratic approach.This study shows how the applicability for addressing ethical issues in HTA of complex health interventions differs between the selected ethical approaches. Knowledge about these differences may be helpful when choosing and applying an approach for ethical analyses in HTA. We believe that the study contributes to increasing awareness and interest of the ethical aspects of complex health interventions in general. Ethics has been on the health technology assessment (HTA) agenda since the inception of HTA. This is reflected in the definition of HTA: “a multidisciplinary process that summarises information about the medical, social, economic and ethical issues related to the use of a health technology in a systematic, transparent, unbiased, robust manner. Its aim is to inform the formulation of safe, effective, health policies that are patient focused and seek to achieve best value” . Ethics Over the years, a series of methods for ethical analysis in HTA have been developed and suggested . HoweverRecently the methodological challenges associated with complex health interventions(Bio)medical ethics is a multidisciplinary field, i.e. a field that involves a range of disciplinesTo assess the included approaches, we used an established set of characteristics of complexity that have ethical relevance: 1) multiple and changing perspectives, 2) indeterminate phenomena, 3) uncertain causality, 4) unpredictable outcomes, and 5) ethical complexity.7Unfortunately, the literature reporting on ethics analysis of complex interventions is too small for a systematic review and an analysis of how suitable the various ethics approaches are for such interventions. Therefore, we were forced to analyse and discuss the various ethical approaches against a set of complexity characteristics.8In the following text, we briefly present the selected approaches for addressing ethical issues in HTA before analysing and discussing their appropriateness for complex health interventions, according to the characteristics presented in Table specified and balanced . Principlism is a popular approach because it is simple and feasible. Its simplicity lies in the application of a stable set of ethical themes and concepts [The most frequently used form of Principlism  addresses the four basic ethical principles: respect for autonomy, non-maleficence, beneficence and justice . These pconcepts . Howeverconcepts .Principlism is not designed as a participatory approach. It primarily takes into account physicians’ and patients’ perspectives, but tends to leave other stakeholder perspectives out. Society's perspective is taken into account (principle of justice), although in a top-down manner, i.e. according to the perspective of the user of the approach. Therefore, Principlism is only partially suited to address multiple perspectives and goals.The four principles entail taking account of the view of physicians, patients and society. Therefore, the approach may encourage the user to think about normative issues and the implications of interactions/relationship between agents (particularly physician-patient relationships). Issues of control, decision-making and related responsibilities are not addressed in this approach.Respecting the principles of beneficence/non-maleficence requires a strict evaluation of the benefits and risks related to the use of technologies. However, the indeterminacy of the intervention and/or the target condition would make this type of evaluation difficult or even impossible. This means that Principlism is not very useful for identifying moral challenges related to indeterminate phenomena. This has been acknowledged e.g. in the case of nanotechnologies where the toxicological risk assessment for use of nanomaterials is difficult. Therefore, establishing the right balance between benefits for patients and society and risks of harms may be unclear .As mentioned above, Principlism is not suitable for handling uncertainty. The symbolic value of an intervention is not addressed and the impact of context on outcome may be only partially recognized (subject to pure speculation).Principlism does not directly include questions about morally relevant methodological choices in the HTA. Nevertheless, this approach requires data to be available on safety, efficacy/effectiveness  and economic impact (principle of justice) related to the interventions. In this sense, Principlism may influence some choices in the HTA process.Principlism may encourage the user to think about some possible outcomes or consequences of an intervention, particularly benefits and harms , change of patient role (respect for autonomy) and effects on the distribution of health care resources (principle of justice). These issues are always addressed in a top-down manner, therefore they may be subject to pure speculation. Principlism is not suitable for handling uncertainties in outcomes , e.g. if some kind of uncertainty itself may infer harm or challenge autonomy.Principlism may be excellent for identifying possible contradictions . In addition, the “balancing activity” of Principlism may be a useful “tool” for solving possible conflicts and elucidating which moral norms should prevail. Even if identifying and balancing contradictions is apparently simple and feasible, it may not provide incontrovertible solutions to possible conflicts in practice, since there is no unified moral theory from which the four principles are derived. Besides, some contradictions may be overlooked due to the limited scope of the four principles approach.In summary, Principlism does not seem well suited for addressing several aspects of complexity  solutions. The rejection of universal moral norms also fits the need for flexibility in complex interventions. This makes it possible to take into account how socio-cultural, religious etc. circumstances matter in the comparing case, and analyse the similarities with the case under investigation. Moreover, different types of experts may take part in the explication of an ethical problem in Casuistry, which may enable the capturing of possible ethical issues arising from a ‘number of groups or organizational levels targeted by the intervention.’ However, to find cases that join, synthesize, or compromise various perspectives may be challenging. The chosen analogues (paradigmatic cases) instead tend to favour one perspective. E.g., it is difficult to find an analogue to substance abuse that both embraces “victim-of-disease” and “weakness-of-the-will” perspectives. The same challenge occurs when trying to address interconnectedness and interactions between relevant components of health interventions.Analogies may be used to conceptualize vague or indefinite phenomena , 21. HowCasuistry may be well suited to handle uncertainty in cases where the analogues do so as well. However, Casuistry (in HTA) is not suitable to handle or compensate for emerging uncertainties during the implementation and use of a complex intervention. This is because the complex intervention being assessed may develop differently from the paradigm cases. Although the process in Casuistry can address methodological choices in HTA as well as cherish transparency, this may be masked by the chosen analogue. For example, viewing peptic ulcers as a stress related acid imbalance definitely guided treatment and outcome assessment. However, in the view of present knowledge about helicobacter pylori it is clear that the dominant analogue was limited and limiting. Hence, it can be challenging to fulfil the requested justification of choices in Casuistry due to uncertain causal pathways.Some analogues (paradigm cases) may include handling unpredictable outcomes, but whether these are relevant for the given case will inevitably be subject to pure speculations. If one analogy works for handling one outcome that could not be predicted, it is far from clear that it could do the same for another. This means that Casuistry may address unpredictable outcomes, but it may fail as well. Moreover, Casuistry may give the impression that moral problems are always solvable . HoweverCasuistry is excellent for finding solutions to morally challenging problems. However, Casuistry does not provide solutions to genuine paradoxes and aporias. It may find solutions by preferring one perspective or one principle over another, but not by resolving paradoxes. Framing “hearing disability” in the perspective of sign culture does not resolve the tension between the language perspective and the function reduction. Nevertheless, pragmatic (and compromising) solutions in one area may inform potential solutions in other fields.In summary, Casuistry is well suited for addressing several aspects of complexity as shown in Table Wide Reflective Equilibrium (WRE) is a coherentist model of moral argumentation . CoherenWRE is a specific type of formal model of moral argumentation. It can be used by an individual person to develop and justify a judgment of the moral acceptability of a specific  practice or technology. For instance, to develop an argument to challenge or support prenatal testing for autism. What would be characteristic of the argument is that it claims coherence  among the various components , each of which may be scrutinized for its relevance and validity separately. However, WRE may also be employed in the context of a moral deliberation with multiple participants. These could be selected to represent a variety of perspectives, e.g. patient, parent, caregiver, healthcare professional, healthcare insurer, etc. In such cases, WRE may be used to structure the development of a collaborative argument, taking into account multiple perspectives on a healthcare technology and any associated differences in judgment of moral propriety . Some stNot infrequently, different interpretations of particular conditions or interventions lie at the basis of ethical debates. In the case of the CI, for instance, a considerable research effort has been directed at assessing the impact of the technology on outcomes such as hearing and the understanding and production of spoken language . HoweverPerceiving ethical issues that are associated with the use of a healthcare technology implies causal attribution: ethical dilemmas are thought to arise from the use of a healthcare technology. However, things will usually be more complex than this. For instance, whether the use of a healthcare technology results in ethical dilemma may, to a large extent, depend on the social context. For instance, in Sweden, the use of CI in deaf children seems to have been far less contentious than in many other countries. This may be related to the fact that in Sweden, an environment of equal opportunities and inclusive disability policies for its citizens was maintained and that in education, a bilingualism method of Swedish Sign Language and spoken Swedish was used consistently in teaching deaf children . WRE mayIt is impossible to predict how exactly a particular technology will be used over time. For instance, the history of the CI goes back to the 1950s, when an electrode was inserted in the cochlea of a deaf person for the first time . At the Probably one of the key causes of ethical complexity is the commitment to a variety of moral values within a community that seem to be in direct opposition and incompatible in concrete cases. Different schools of ethical thought vary in the way they propose to resolve such dilemmas. The case of the CI for deaf children was complex, not least because there seemed to be a conflict between values such as ‘open future’ and cultural diversity. WRE proposes to resolve such value conflicts by trying to discover whether there is differential support for such ‘narrow equilibria’  from relevant background theories. Clearly, this approach differs substantially from other approaches such as weighing and specification.In summary, WRE allows an evaluator to take into account the complexity of an intervention and its sequelae, since it explicitly addresses how judgments, principles and background theory cohere with each other. However, to this end, it should be used as a method of moral argumentation in the context of public deliberation, allowing stakeholders to provide arguments from different perspectives.Interactive Health Technology Assessment (iHTA) is a specific approach to HTA, involving stakeholders throughout the entire assessment process , i.e. peiHTA is pre-eminently suited to take into account a variety of perspectives on a specific problem and their associated  solutions. It acknowledges that ‘Assessment processes are embedded in different sorts of institutional settings, within which scientists, decision-makers, and advocates communicate to define relevant questions for analysis, mobilize certain kinds of experts and expertise, and interpret findings in particular ways’ . One of One of the key pitfalls in HTA may be to take a  problem, its associated solution and the evaluative framework as given. However, problems do not exist independently of the interpretive frames that are being employed in particular social contexts, nor do their solutions. The nature of the problems that are posed by deafness may differ, depending on whose perspective is taken, and so may their solutions. One of the key threats to the integrity of HTA is to uncritically adopt a dominant way of framing an issue. iHTA can help to prevent this from happening. In iHTA, a technology and its use are not considered as fixed, or given. Indeed, one of the key objectives of the assessment is to discover, collaboratively, what the optimal use of a technology in a particular context might be. In this sense, iHTA is formative, rather than summative . HoweverStakeholders can, and often do, disagree on the likelihood that particular consequences will emerge, following the use of a technology. iHTA can serve as a useful approach to uncover such divergent views, and to critically appraise their empirical and theoretical foundations. The reason for this is that an important element in iHTA is the reconstruction of interpretative frames that stakeholders bring to the inquiry. These include judgments of solutions, problem definition, background theory, and normative preferences. Differences in judgment of solutions  can often be traced back to differences in background theory . Once thAdopting an Interactive approach to HTA (iHTA) will not allow for a more accurate prediction of future outcomes. However, it will usually lead to a wider range of relevant potential outcomes. As indicated above, in the case of the CI for deaf children, there was a strong focus on the impact of the technology on hearing and the understanding and production of spoken language. However, the (hearing) parents of deaf children pointed out that for them, the impact of the technology on the reading proficiency of their child was hugely important . Thus, aOne of the key advantages of an interactive approach to HTA may be that it allows for a better appreciation of the complexity of the ethical issues associated with the (use of) a technology. The reason for this is that the technology is viewed from a range of perspectives, by stakeholders who bring different values to the inquiry. For instance, in the case of the CI, some stakeholders seemed to reason from the open-future argument, while others put more emphasis on the value of cultural diversity. Both represent defensible moral positions, generally. The challenge is to acknowledge such complexity and to devise acceptable solutions in concrete cases. iHTA, of itself, does not provide the tools to normatively assess the validity of ethical arguments. For this, methods of moral argumentation such as Wide Reflective Equilibrium or Casuistry may be used in the context of an iHTA .In summary, iHTA offers a way of systematically involving multiple stakeholders, creating opportunities for mutual learning and improved understanding. iHTA’s emphasis is on procedural justice. Arguably, its main added value will be in cases where quite divergent views exist among stakeholders on the nature of the problem to be solved and the most promising routes for its resolution. This, in itself, may be considered to be an indication of complexity. In principle, the method is never ending.The HTA Core Model 3.0® has been developed in the course of the European network for Health Technology Assessment Joint Action 2 (EUnetHTA JA2) . It consBeyond the ethical domain, the HTA Core Model® introduces ethics as a wider principle and provides a list of ethical issues that should characterize each HTA. These comprise e.g., stakeholder involvement, “morally relevant reasons for performing/not performing a HTA” on specific topics, or the description of the interests of the manufacturer. It acknowledges that the HTA-process itself is characterized by value judgments and that these value judgments should be made explicit. Examples for the ethical analysis guided by the HTA Core Model® are an HTA on Multi-Slice Computed Tomography (MSCT)  an HTA oThe HTA Core Model® assesses the implementation of a health technology from the perspective of the prevailing societal values and it looks at the norms and values that the technology itself constructs. It also assesses the ethical issues related to performing the HTA. Assessment involves explicitly looking at the interests of different stakeholders at various levels; among them patients, relatives, and society. Assessment involves developing a table to synthesize the evidence consequences of implementing or withdrawing the intervention for the patient, family/important others, health care providers, society, and others. The variety of perspectives is also reflected in the iterative process of the analysis, including the involvement of different experts. However, the active involvement of stakeholders, patients and the public seems to be difficult because of time and resource constrains , 46 as wDefining the technology as well as the target group is not directly addressed in the ethical domain of the HTA Core Model®. Both are part of the “Description and technical characteristics of technology” domain. Moral challenges linked with the definition of the intervention would be part of the iterative ethical reflection during the assessment of this domain. The domain asks for a detailed description of the intervention’s components including a glossary and information about the “scientifically proven versus suspected mechanisms of action”. This is used to ensure transparency and clarity about the technology.The HTA Core Model® encourages the user to undertake the ethical analysis throughout the HTA-process rather than seeing it as a “one session” task. Multiple components and difficulties in determining the intervention and target group lead to uncertain causal tracks. The ethics domain contains this up to a certain point, e.g. asking for intended and unintended consequences of the implementation or use of the technology and suggesting the involvement of different stakeholders and the public from the very beginning of the HTA. Furthermore the HTA Core Model® addresses the context and non-technology-specific values such as autonomy, dignity or integrity as well as professional values and traditional roles.Through a set of suggested issues, the approach encourages the user to think about a wide spectrum of possible outcomes and to link these (iteratively) with outcome measures identified in the other domains of the HTA Core Model®. The downside of such an approach is that users might apply it as a finite list of issues ignoring other issues that are not explicitly mentioned. In the HTA Core Model® the assessment questions are chosen at the beginning of the ethical analysis. In the example of the AAA-screening six assessment questions were marked as not relevant. Among them were questions related to challenges of patient autonomy, potential benefits and harms for other stakeholders.One of the issues under the topic “beneficence/non-maleficence” addresses “hidden or unintended consequences of the technology and its applications for different stakeholders”, and the ethical dimension of identifying outcome measures is stressed explicitly through the topic “Ethical consequences of the HTA”. Examples are incidental diagnoses related with the MSCT  or “off-Contradictions between basic ethical principles are not explicitly mentioned in the HTA Core Model®. The approach acknowledges that ethical analysis, although being a separate domain, is closely interrelated with aspects such as safety, clinical effectiveness or cost-effectiveness. Collaboration between ethical experts and stakeholders (e.g. clinicians) is suggested, which could contribute to identify ethical complexity as well as transparency. Stakeholder involvement may reveal fundamental values at stake and possible contradicting principles and values.In summary, the HTA Core Model® offers a structured and transparent method for the ethical assessment of technologies. The HTA Core Model® essentially follows a Principlist approach and the use of tables as a basic structure for analysis might impede the application of approaches reflecting the consistency of ethical arguments and background theories “without prescribing which facts, arguments or principles are prima facie relevant” . A strong focus on the assessment tables could mean that important aspects of a specific technology are overlooked. The HTA Core Model® addresses many of the complexity aspects, although not always in a systematic way. The way methodological approaches are linked with the assessment tables remains open. Depending on the methodological approach chosen the complexity of a health technology will be more or less taken into account.The Socratic approach is axiological as it studies values. The aim is to uncover and highlight the values, norms and ethical challenges that are relevant for the health intervention, the HTA process, as well as for the decision making process. The Socratic approach consists of six steps and seven basic morally relevant questions, which are further specified in thirty-three explanatory and guiding questions . For claThe Socratic approach has been applied in a range of assessments, e.g. of Bariatric surgery , Autologinterests of users (Q19), producers (Q21), persons participating in the HTA (Q28), and autonomy of the professionals (Q20). Revealing the purpose and background for the HTA (step 1) may also provide information on stakeholder interests. Additionally, a reflexive dialogue with stakeholders is recommended.Identifying persons, groups, and stakeholders is a separate preparatory step (2) in this approach. In addition, the stakeholders respective perspectives, interest, values and intention is the focus of many of the questions from the list, e.g. questions about the The question of normative implications of interactions/relationship between agents is indirectly and partly covered by the question of relationship between patients and health care professionals, and within the latter group (Q12). Similarly, the general issue of interactions between numerous (human and non-human) components are briefly addressed (in Q16), but this may not be ethically relevant unless they influence other characteristics of complexity (e.g. outcome uncertainty). Many characteristics of interactions between the intervention as a whole and people/society are covered, e.g. the questions about whether use of the technology will change the patient role (Q3).Issues of control and decision-making and related responsibilities (as part of the technology itself) are not directly addressed in this approach, though it is touched upon in the question about impact of the technology on professional’s autonomy (Q20). The obligations of people doing the HTA are more detailed as indicated in Q23 – 31.Various understandings and interpretations of the interventions can be explored as part of the initial identification of the purpose of the health intervention and background for the HTA (step 1). Additionally, the undefined nature of the complex intervention(s) may be further illuminated by the recommended stakeholder involvement. It seems paradoxical that the scoping process and selection of experts/stakeholders to include (Q26) is ever more important when the concept and understanding of the intervention is wide and unclear. Indeed, at the same time, this vagueness may confine the fraction of experts that it is possible to include. For example, in the case of Welfare technology, which covers a heterogeneous group of technologies , the numThe approach contains questions about moral issues related to the characteristics of the technology (Q14-17), and about the health condition and the target population(s) (Q1 – 4). These may reveal indeterminacy and contradictions, e.g. regarding purpose of the intervention or the status of the disease. Consequently questions about justification of flexibility, tailoring, alternative and unexpected use of the intervention can be addressed.The Socratic approach includes several questions about morally relevant methodological choices in the HTA. For example, it includes, questions about choice of end points, cut-off values and outcome measures (Q23), selection (criteria) of studies to include in the HTA (Q24), the choices in the HTA process from planning  to presenting results (Q26), specific presumptions and methodological choices in the economical part of the assessment (Q27), and timing of the assessment (Q29). Such questions can illuminate how appropriate the HTA is for taking into account the uncertainties in causal pathway between intervention and outcome, and pave the way for improvements. Using the approach in an integrative manner will increase transparency of methodological choices and their justification.The symbolic value of the intervention is addressed (Q15) and the impact of context on outcome of analyses is recognized. However, the relevance of these factors may not be directly linked to their possible impact on causal pathway between intervention and outcome. Symbolic value and context may be ethically relevant for other reasons, e.g. related to prestige and stigmatisation. A systematic review of autologous stem cell transplantation (ASCT) in advanced breast cancer, using the Socratic approach, illustrates how this intervention became loaded with the symbolic value of “dissemination of phase II trial results, coverage without evidence, falsified data, high costs to the public and considerable, unnecessary harm to patients” . In thisEven if the variety of outcomes (and for whom) is not addressed specifically, many moral question about  outcomes or consequences are addressed: e.g. change of patient role (Q3), effects on the distribution of health care (Q7), consequences (benefits and harms) (Q8), moral obligations (Q10), change of relationships (Q12), alteration of professional autonomy (Q20).The uncertainties  in outcomes (type and size) are not addressed as such, e.g. if some kind of uncertainty itself may infer harm, challenge autonomy etc.The aim of the approach is to highlight (underlying) values, viewpoints and arguments regarding an intervention that are important for decision-making. This is achieved by comprehensiveness in the normative issues addressed   , but thiIn summary, the Socratic approach meets the complexity criteria fairly well. The most important points for improving its applicability are: to address questions of decision making and responsibility; to address the moral impact of indeterminacy and uncertain of outcome and finally, to offer some guidance in how to balance conflicting concerns.This study shows how the applicability for addressing ethical issues in HTA of complex health interventions differs between ethical approaches. The approaches are assessed according to a set of five characteristics of complex interventions, which in sum reflect their overall ability to address ethical analysis for these kinds of technologies. In general, processual approaches, such as Interactive, participatory HTA (iHTA), seem to be able to handle most aspects of complexity. The interactive and flexible nature of this approach makes it suitable for handling the unpredictability embedded in complex interventions. The flexibility and openness for different perspectives may also explain why Wide Reflective Equilibrium seems better suited for complex health interventions than more rigid general approaches, such as Principlism and Casuistry. The two latter approaches should be supplemented with additional perspectives and/or applied in a more interactive way, when assessing complex health interventions. The two other HTA specific approaches, The HTA Core Model® and the Socratic approach, also seem fairly applicable for complex health interventions, which should not be surprising as they include various ethical approaches and perspectives.We believe that our work will be helpful when choosing and applying appropriate approaches for ethical analyses in HTA. However, one should be aware of other important factors that may influence the choice and application of an ethical approach, such as local HTA agencies resources, possible locally developed guidelines and whether the aim of the HTA is assessment or appraisal. We also want to emphasise that all ethical approaches have limitations, and challenges associated with conflicting values, interests and consideration should always be expected in ethical analyses. Our study can be helpful in preparing for some ethical assessment challenges embedded in complex interventions, and increases the awareness of ethical aspects of complex health interventions in general.


The event was organized as a satellite meeting of the 13th European Conference for Computational Biology (ECCB) and took place in Strasbourg, France on September 6 The ISCB Student Council (SC) is the student organization of the International Society for Computational Biology. Its members are typically PhD students in the fields of bioinformatics or computational biology, but include as well scientists in different stages of their career. They come from all around the world and share a passion for bioinformatics and computational biology. The mission of the SC is to support the development of the next generation of computational biologists. This is achieved through the provision of scientific events, networking opportunities, soft-skills training, educational resources and career advice, while attempting to influence policy processes affecting science and education.th anniversary this year [The European Student Council Symposium (ESCS) is one of the activities organized by the SC as a satellite meeting accompanying the European Conference for Computational Biology (ECCB). It is therefore the European spin-off of the Student Council Symposium (SCS), which celebrated its 10rd ESCS took place in Strasbourg, France on September 6th in conjunction with the 13th ECCB conference. The main goal of the meeting was to create opportunities for young researchers to meet and discuss with peers from all over the world, so that ideas could be exchanged and networks built. In addition three highly successful principal investigators were invited to deliver inspiring keynote talks.This year, the 3http://escs2014.iscbsc.org/escs-booklet.We received more than 30 abstract submissions from students who wished to present their work at the symposium. These submissions were peer-reviewed by an independent program committee, and eight abstracts were selected for oral presentations. Another eighteen abstracts were selected to be presented as a poster. Thanks to the generous contributions of our sponsors, we were able to provide four travel fellowships to support student attendance to ESCS. Overall, almost 30 delegates from 13 different countries attended the symposium and the program included three inspiring keynote lectures, eight contributed student presentations, and a lively poster session. The oral presentations were divided into three themed sessions, namely Modeling, Systems Biology, and Networks and Statistics. For the first time in an event organized by the SC, the five delegates with the best posters were given the opportunity to present their work in a flash presentation. This ensured that all attendees had the chance to hear and see the top poster selection unconstrained by the population limits intrinsic to a normal poster presentation. All abstracts of the accepted oral presentations are included in this meeting report. Abstracts of the poster presentations can be found online in the symposium booklet The consistent theme of the ESCS keynotes was the different aspects of dealing and interpreting the massive amounts of biological data that is nowadays available, often publicly and without restrictions of use. In the morning, Dr. Lennart Martens introduced the concept of 'Saprotrophics', a field that many bioinformaticians might be working in without realising it and that has even peaked the interest of the social sciences . The cenThe second keynote, by Dr. Jeroen de Ridder, underlined the critical importance of scale in biological data sets. Depending on the scale used to analyze and interpret data, the features and patterns that emerge can change quite dramatically; this is comparable to the change in perception we have of a landscape when we are flying over it or walking in it. Through an array of working examples Dr. de Ridder guided the audience into understanding that meaningful new insights in molecular data analyses can be achieved by accounting for the importance of scale and using scale-aware analyses tools.Finally, the keynote from Dr. Lars Juhl Jensen concerned the efforts needed to collect and combine data from different sources into a single, biologically meaningful, network. In his talk, Dr. Jensen detailed the efforts and techniques that were necessary to construct the STRING database . This daFrom all abstracts submitted to the symposium, the best eight were selected for oral presentations, which were divided into three sessions.et al. [Information about the DNA replication mechanisms is scarce or absent for many viruses. Kazlauskas et al.  reportedet al. [Conformation alterations are often a critical step for the functionality of a variety of proteins. Narunsky et al.  introducet al. [Proteochemometrics is the modelling of the bioactivity of ligands against different targets. Cortes et al.  demonstret al. [Understanding the manner with which small compounds inhibit protein-protein interactions would greatly help in the design of the next generation of therapeutic compounds. Kuenemann et al.  studied et al. [While rich information sources exist for protein interaction data, their adaptive nature remains poorly understood. Using advanced pattern mining techniques, Naulaerts et al.  discoveret al. [DNA methylation is an important epigenetic marker that has been shown to be involved in gene silencing. Döring et al.  modeled et al. [The identification of critical residues is of great interest for the field of protein engineering. Armenta-Medina et al.  introducet al. [Gene duplications are notoriously hard to correctly position in phylogenetic reconstructions of the genomic evolutionary history. Peres et al.  have devAt ESCS, four awards were given to the best presenters of the day, namely two for oral presentations and two for poster presentations. The attendees determined the winners by scoring the different oral presentations based on presentation style, novelty of the work presented, slide layout and clarity of the message. The best presentation award went to Mélaine Kuenemann, while the runner-up prize went to Isidro Cortes. The best posters were selected during the noon poster session based on preferences expressed by the symposium attendants through stickers. The five top scoring posters were given the chance to give a 5 minutes flash presentation during the main meeting. From these five flash presentations, the award winners were determined by an independent jury. Poster presentation first place went to Jakob Jespersen, and second place to Aurélie Pirayre.As previous editions, the third ESCS was a great success, characterized by talks of high profile and quality, both at the level of keynotes and submitted work. This is confirmed by the results of an online survey that participants were asked to fill in. Most participants agree that the quality of the symposium was high to excellent, and that the equilibrium between keynotes and submitted talks was good. This year, we noted a decrease in the number of participants in comparison to ESCS of two years ago, similarly to what observed in this year's SCS . An infoth SCS and therefore the next ESCS will only take place in 2016. For information on the Student Council and other events we organize for students in computational biology and bioinformatics, please visit our website: http://www.iscbsc.org.Next year the ISMB and ECCB conferences will be co-organised in Dublin, Ireland, in July 10th to 14th. This meeting will serve as the location for the 11


Pharmaceutical research and development aims to design products with ensured safety, quality, and efficacy to treat disease. To make the process more rational, coherent, efficient, and cost-effective, the field of Pharmaceutical Materials Science has emerged as the systematic study of the physicochemical properties and behavior of materials of pharmaceutical interest in relation to product performance. The oral route is the most patient preferred for drug administration. The presence of a mucus layer that covers the entire gastrointestinal tract has been exploited to expand the use of the oral route by developing a mucoadhesive drug delivery system that showed a prolonged residence time. Alginic acid and sodium and potassium alginates have emerged as one of the most extensively explored mucoadhesive biomaterials owing to very good cytocompatibility and biocompatibility, biodegradation, sol-gel transition properties, and chemical versatility that make possible further modifications to tailor their properties. The present review overviews the most relevant applications of alginate microparticles and nanoparticles for drug administration by the oral route and discusses the perspectives of this biomaterial in the future. AL. ALβ-D-m nodosum –26. Mole nodosum , 27, 28  nodosum . In addinetworks , 30. Thinetworks  and it hnetworks , proteinnetworks , 34, gennetworks , 36, andnetworks –40. Anotnetworks .The mechanical and the physical stability of ALG gels depends on the G content, the greater the G content, the more rigid and brittle the matrix. The process can also be reverted in the presence of ion sequestrants such as ethylenediaminetetraacetic acid (EDTA)  or sodiuFrom a regulatory point of view, the U.S. Food and Drug Administration (US-FDA) recognizes ALG as a “Generally Referred As Safe” (GRAS) material, a designation that applies to substances accepted as safe for alimentary use by qualified experts . GRAS exDue to the hydrophilic nature of ALG, the release of encapsulated drug payloads could follow different mechanisms. Water-soluble drugs are mainly released by diffusion, while poorly water soluble drugs by matrix erosion. The release of small molecules is fast due to the fact that swelled ALG matrices display a pore diameter of approximately 5 nm . HoweverALG has been employed for the production of a broad spectrum of drug delivery systems. The present paper will be focused on microparticles and nanoparticles because they represent the most innovative and promising developments .μm) can be produced by different techniques . T. T HelicAiming to develop an oral vaccine against schistosomiasis, a neglected parasitic disease, the Smrho protein was encapsulated within chitosan nanoparticles coated with ALG . Due to Owing to very good biocompatibility and approval by the US-FDA as food additive, ALG has gained a preferential place among pharmaceutical excipients for the development of advanced drug delivery systems for mucosal administration. The greater interest of the scientific community in ALG coincided with the revolution in therapeutics led by nanomedicine. This together with a great versatility to conduct fine chemical modifications and to tailor specific features by combining it with other natural and synthetic polymers have sustained the steady increase of the research at the interface of ALG and microparticles and nanoparticles during the last decade. At the same time, it should be stressed that strict isolation and purification protocols are demanded to ensure low concentrations of endotoxins and immunogenic residues and the interbatch reproducibility. These issues are even more critical to extend the use of ALG to parenteral administration routes. The present spotlight review overviewed the most recent works of ALG as a technology platform to develop microparticles and nanoparticles for oral drug delivery. The most outstanding features are mucoadhesiveness and mucopenetration that increase the passage of drug payloads through the gastrointestinal epithelium. This could be capitalized to enhance local and systemic delivery, increase oral bioavailability, and prolong release. Research on ALG microparticles has been more profuse with a broad spectrum of production methods that range from simple ionotropic gelation to more complex equipment to control size and size distribution and to ensure reproducibility and scale up. Conversely, the research of ALG nanoparticles has been limited to a few payloads, insulin being the most intensively assessed. In any event, ALG bears a great potential and its more extensive implementation in the development of innovative nanodrug delivery systems with translation potential is a matter of time.