Staff shortages among nurses have been severely felt in most countries around the world for many years. In Poland, this problem is particularly visible due to the lowest nursing employment rate per 1000 inhabitants among 28 EU states and the high rate of leaving the profession. The average age of Polish nurses has been constantly growing for several years—in 2016 it was 50.79, while in 2008 it was 44.19. These data confirm that young nurses are the first to leave the profession. Diagnosis of the working conditions and psychosocial burden level among nurses should be subject to detailed analysis, so that leaving the profession will not additionally deepen the difficult staffing situation in health care.  The aim of the study was to identify factors affecting the assessment of work arduousness levels among nursing personnel.  The study was conducted among 573 nurses working on surgical, medical treatment, and emergency wards. A standardized job evaluation questionnaire was used to conduct the survey. p=0.0165). In the medical treatment wards, there was a similar age-to-stress ratio for the area of organizational uncertainty (p=0.0063). With age, employees of the emergency ward became more indifferent to stress related to unpleasant working conditions (p=0.0009), while stress related to organizational uncertainty increased (p=0.0495). (3) Nurses working in managerial positions assessed the overall stress related to their job higher than other nurses. They were particularly at risk for burdens related to haste, responsibility, and organizational uncertainty. The average overall assessment of work arduousness for this group was 44.6 points, while for surgical nurses it was 37.2 points. Correlations between the performed function and stress levels were found for almost all of the studied work characteristics (except for hazards). (4) Education had a statistically significant impact on the perception of working conditions in several dimensions. The people with the lowest education evaluated working conditions the best. The difference between people with a higher and those with a secondary education with a specialization was definitely smaller and often nonexistent. Education differentiated the work arduousness assessment depending on the ward. The most statistically significant correlations were obtained in surgical wards, and the least in medical treatment wards.  (1) Stress levels depended on the ward in which the surveyed person worked. Nurses working in the emergency ward assessed their conditions the best, with the lowest stress. The average general result in this group was 38.1 points versus 46 and 45.7 points in the surgical and medical treatment wards, respectively. (2) At the level of the whole studied group, both the nurses' age and work experience did not differ statistically significantly in the total assessment of working conditions. Differences in the assessment of work arduousness in different age categories occurred at the level of individual wards. In the surgical ward, younger employees were characterized by higher stress levels, especially in the area of arduousness ( (1) The study results indicate the need to diagnose problems related to work conditions in the context of occupational stress within individual hospital wards. To limit employee turnover, nursing staff managers should approach the issue of improving working conditions individually for each ward, due to differences in the nature of the work and level of stressogenicity. (2) In each hospital ward, employees at different stages of their career are sensitive to the psychosocial burden resulting from different work characteristics. These areas should be thoroughly diagnosed and the burden minimized to prevent departures from the profession—at early stages of the professional career as well as among experienced personnel. (3) Nurses working in managerial positions should receive the necessary substantive support, due to the higher stress burden associated with greater responsibility. Staff shortages among nurses have been severely felt in most countries around the world for many years. In Poland, this problem is particularly visible due to the lowest nursing employment rate per 1000 inhabitants among 28 EU states, which in 2015 was merely 5.2. In comparison, in Denmark, it was 16.7, in Germany 13.3, and in France 9.9, while the average for 35 OECD member countries was 9.0 [Research by the Supreme Council of Nurses and Midwives indicates that the shortage of nurses in Poland is much higher than the available studies show. This is due to the fact that the established minimum employment standards are based on the basis of registered health services, taking into account the number of beds, the specificity of the ward, and not the actual needs of the medical facility. The result is one nurse working the night shift or less personnel on Sundays and holidays. This translates into a greater workload due to the increased number of responsibilities per person .Another unfavorable phenomenon observed in this professional group in Poland is the gradual increase in the average age of registered nurses. In 2008, it was 44.19, while in 2016 it was 50.79, which means a rise by 6.6 years in only 8 years. The majority of registered nurses were in the 41–60 age group (66.51%), while nurses in the youngest age group from 21 to 35 constituted only 5.53% of all registered nurses [The successive increase in the average age of nurses and the declining percentage of nurses in the youngest age group may indicate several phenomena, including lack of employment of new nurses in the profession despite obtained qualifications, financially motivated emigration after graduation, as well as leaving the profession early in the career and retraining to work in another profession. The scientific literature has identified a number of factors that are the most frequent reasons for nurses leaving the profession –8. They Psychosocial burden, in the case of nurses, concerns, among others, overloading with physical work, fears of infection with diseases, work complexity, the ambiguity of the role played in the organization, unpleasant working conditions, conflicts, employment insecurity, and negative family relations resulting from a work-home conflict. Excessive workload is compounded by the fact that in Poland, as in many other countries in the world, this profession is strongly feminized. As a result, there is no possibility that particularly physically burdensome work, such as lifting patients, for example, can be performed by physically stronger men. In addition, nursing aids, who could perform nursing activities around the patient, are not employed in Poland. Therefore, in addition to providing medical care, nurses perform a number of activities, such as patient hygiene and washing, change of bed linens, transporting patients for tests, and other activities . The higThe complexity of work in the case of nurses is first and foremost the necessity to perform many activities requiring attention and accuracy, such as administering the right doses of medicines, carrying out measurements , handling medical devices that are interlaced with hard physical work. A significant source of stress is conflict at the workplace, which include conflicts with other nurses and superiors, including frequent cases of bullying , 13.The health problems of nurses often originate in psychosocial burdens at the workplace. This is confirmed by numerous scientific studies on the general impact of stress on the physical and mental health of employees as well as in detailed research, e.g., confirming the unequivocally negative impact of bullying on psychoemotional aspects of a nurse's health, and indirectly as one of the factors causing burnout on the general health condition of nurses .In this study, we attempted to identify the most arduous and most frequently occurring burdens at the workplace of nursing personnel. Using statistical analysis, we diagnosed the effect of particular factors, such as age, duration of professional experience, and position held, on the intensity of psychosocial burden perception and compared the differences in the work arduousness assessment depending on the respondent's place of work, that is, the ward where he/she worked.The study was conducted from September 2017 to December 2017 in Poland in the Podlaskie Voivodeship. It included 573 people working as nurses at inpatient health care facilities. Participation in the study was voluntary and anonymous. Participants could quit the survey at any level. All procedures were prepared according to the ethics standard approved by the Local Bioethics Committee of the Medical University of Bialystok (ref. no R-I 002/296/2017).The study was conducted by a group of experts composed of representatives of nurses and teachers in the nursing profession. These people understood the purpose of the study and knew the specificity of working as a unit nurse at inpatient health care facilities. The study was conducted using a standardized Work Features Assessment Questionnaire developed by Dudek et al. . The queThe selection of respondents to the research group was based on the register of nurses associated with the District Chamber of Nurses and Midwives in Białystok. The criterion was employment based on a contract of employment at a hospital in medical treatment, surgical, or emergency units. 10% of randomly selected persons meeting the selection criterion were invited to the study.A standardized Work Features Assessment Questionnaire for objective assessment of work stressfulness was used as a research tool . The queBased on the statements of the questionnaire, 10 specific measures were determined: unpleasant working conditions, work complexity, hazards, conflicts, uncertainty resulting from the organization of work, arduousness, haste, responsibility, physical effort, competition, and one overall measure of work arduousness. The higher the score, the higher the work arduousness in a given aspect. The results for the individual measures are not comparable with each other, because each individual measure  has a different number of component statements. To allow for comparison between work arduousness estimations in different categories, raw values of the individual measures were normalized to a range of 0–100, with 0 indicating the absence of work arduousness and 100 indicating the maximum work arduousness.Based on the standards set out in the questionnaire, individuals with high stress levels due to work arduousness in the different areas were distinguished. In the case of the overall scale of work arduousness, three categories were distinguished: low, medium, and high.Statistical analysis was performed using the appropriate statistical tests, by means of which the statistical significance of the considered dependencies was verified. In the case of studying the effect of a nominal factor (such as the ward) on work arduousness numerical values, descriptive statistics were determined in the compared groups and differences in the distribution of the measures between the groups were assessed using the Mann–Whitney test (for two groups) or the Kruskal–Wallis test (for three or more compared groups). When studying the effect of a numerical feature  on work arduousness numerical values, Spearman's rank correlation analysis was used. The percentage of people with a high level of work arduousness in particular professional areas relative to the grouping factor was compared using the chi-square test.The study included 573 respondents working as nurses. The vast majority of the respondents were women (97%). The average age for the studied group was 38.5 years, with a slightly higher median equal to 39 years. The youngest employee was 21 years old and the oldest was 61. Over half of the respondents had completed nursing studies, one-fourth had a secondary education with a specialization, and one-fifth had secondary education. The average duration of work experience was 15 years, with a slightly lower median of 14 years. Work experience ranged from one to 41 years. The majority (3/4 of the respondents) worked as a unit nurse. Every tenth nurse was employed as a surgical nurse, and every twentieth held a managerial position. The percentage distribution of employees between wards  was almost even.On the basis of the obtained results, a ranking of work arduousness measures, presented in Next, based on the standards set out in the questionnaire , individIn the case of the overall scale of work arduousness, three categories were distinguished: low, medium, and high. According to such a classification, more than two-thirds of the respondents considered their work to be very arduous, and only one in twenty to be easy.The work arduousness values were compared in terms of the ward on which the respondents worked. The results of the comparison lead to an unambiguous conclusion about the significant impact of this factor on work assessment. For all areas in which work arduousness was assessed, the differences between wards were statistically significant. Considering the total work arduousness levels, the emergency ward stood out . Detailed data are presented in th, as well as the 10th and 90th centile of work arduousness measures for the overall result and the hazards measure (selected as an example from the other measures).The relationship between the ward and work arduousness occurrence was also compared in terms of the incidence of people who felt high burden levels in individual areas. In this analytical approach, we also found highly statistically significant differences between the wards for almost all the considered areas (with the exception of the work complexity category). Analyzing the results in Analysis of the variation of work arduousness assessments in terms of the wards ends with a list of adjective distribution of the arduousness scale in the compared groups, listed in The effect of age on the assessment of stress levels at work in particular areas and on the overall result was examined. The analysis consisted of determining the Spearman's rank correlation coefficients between age and the numerical measures of stressful situation occurrence, determined on the basis of a standardized questionnaire. The analysis was carried out both at the level of the entire population and when controlling for the ward type, because this factor may affect the occurrence of dependence .At the level of the entire surveyed population, very weak correlations with age were found only in two areas: haste and physical effort. The stressfulness of haste accompanying work increased with age and the stress associated with physical effort decreased with age. However, both of these correlations had negligible strength , which mAn alternative form of analysis was also conducted. We divided the respondents into four age groups, presenting the descriptive statistics values in these groups and assessing the differences between them using the Kruskal–Wallis test. This analysis ignored age differences within the created groups, which may lead to different results than the conducted correlation analysis. As shown in Analysis of work stressfulness in relation to age groups led to distinguishing one highly significant result; namely, age differentiates the assessment of stress resulting from physical effort. The stress levels associated with this were much higher among employees aged up to 39 years (median 50 points) compared with other people (median 37.5 points). Other burdens were not correlated with age in any way .A similar correlation analysis was performed for each ward. It turned out that this was the right approach, because we found that there were more statistically significant relationships within individual wards. These were also dependencies of slightly greater strength than the two correlations found at the level of the entire population. The analysis results are presented in R = 0.94), so it could be expected that the duration of work experience would affect the work stress assessment in a similar way as age. The results in Work experience was very strongly correlated with age  on only two areas: organizational uncertainty and physical effort, whereas, among emergency ward employees, longer work experience increased stress levels caused by conflicts, organizational uncertainty, work arduousness, and haste and decreased the stress associated with unpleasant working conditions and physical effort .The relationship between the held position and the assessment of work arduousness was analyzed. Due to the fact that ward type was a factor strongly differentiating assessment of working conditions, analysis of the impact of education on working conditions was done separately for each ward type. To assess the significance of the differences between the groups the Kruskal–Wallis test was used.In the group of nurses working in surgical wards, education had a statistically significant impact on the perception of working conditions in several dimensions. The people with the lowest education evaluated working conditions the best. The difference between people with a higher and those with a secondary education with a specialization was definitely smaller, and often assessments of working conditions in these two groups were almost identical .Among people working on medical treatment wards, the impact of education on the assessment of working conditions was not as pronounced. Only the assessment of stressogenicity related to responsibility and physical effort differed in a statistically significant way due to the education level. In this first dimension (responsibility), people with higher education had the highest stress levels. In the second dimension , the differences were not so clear and logically oriented, so it is difficult to interpret these results unambiguously.From the nurses working on the emergency ward, education differentiated the assessment of unpleasant working conditions, work complexity, and uncertainty resulting from the organization of work. In the first two areas, the higher a nurse's education, the worse the assessment of that particular dimension. In terms of organizational uncertainty, the worst assessments were obtained from nurses with a secondary education with a specialization.p=0.0000∗∗∗) and education (p=0.0001∗∗∗); the interaction between them was also significant (p=0.0185∗). The nurses' work experience and age did not differentiate in a statistically significant way the total assessment of working conditions.Finally, a multivariate analysis was done. A regression model was constructed for the overall assessment of work conditions, in which, apart from nominal factors, which were ward and education, the potential impact of age and work experience was also considered. These variables had numerical values, so they were treated as continuous variables. The models also considered the 2nd-degree interactions between all factors. Using the stepwise regression procedure, the optimal model was selected. This model included only nominal factors: ward  and the level of work satisfaction, which was strongly related to stress levels . StudiesKeeping in mind the earlier observation that the youngest nurses most often leave the profession, we examined how age and experience affected the nurses' perception of psychosocial burdens. The obtained results indicate that with age, employees become more immune to certain stressors. On the surgical wards, the most noticeable were arduousness, responsibility, and competition for young employees; on medical treatment wards, uncertainty resulting from the organization of work and physical effort; while on the emergency ward, unpleasant working conditions, hazards, and physical effort. A similar effect was observed in the case of work experience. Employees with the least work experience felt burdens almost identically to the youngest employees, except for the emergency ward, where no correlations were found in the case of hazards, while inverse correlations were found in the case of uncertainty resulting from the organization of work and haste. These two factors in the case of employees of emergency wards increased with experience.This can be explained by the fact that with age, and thus with increased experience, some factors become less and less stressful, probably due to the fact that employees somehow get used to certain working conditions and do not perceive them as negatively as initially. Research conducted at the Medical University of Gdańsk among nurses employed in hospitals , outpatiAn important result of the conducted research is also an indication of the burdens that did not depend on the nurses' age or experience. Regardless of the ward where the nurses worked, work complexity, conflicts, and haste were felt regardless of age, and hazards regardless of experience.Organizational uncertainty, or a feeling of a threat of job loss, is a more stressful factor than the loss of work alone . This faThe psychosocial burden that nurses experience in their daily work may be the cause of their mistakes . This fact was confirmed by research conducted in public hospitals in Tehran, which showed a close correlation between the stress experienced by nurses and the number of mistakes made during treatment . SimilarThe psychosocial burden had an impact on general job satisfaction among nurses, which in turn leads to employees being more likely to start looking for other career opportunities . This isOne of the limitations of the conducted research is that we show a static picture of the psychosocial burdens in the nurses' workplace. An interesting issue seems to be the impact of global economic changes on the dynamics of psychosocial burdens in the workplace. The negative impact of the global crisis on workers' health was confirmed in the results of research carried out in Northern Ireland .Summing up the results of our research, we found that the factors that influence the assessment of the nurses' working conditions were the position and type of ward they were employed in. Age, work experience, and education did not have a statistically significant impact on the assessment of nurses' working conditions if we treated the nurses as a homogeneous group. The results changed radically if we conducted analyses within the ward type. We then found statistically significant dependencies of the assessment of working conditions depending on age, work experience, education, and position held. In all the wards, the youngest employees were the most exposed to stress, but the most stressful was other work features in each ward. In the surgical ward, these were arduousness, responsibility, and competition; in the medical treatment ward: organizational uncertainty and physical effort; and in the emergency ward: unpleasant working conditions, hazards, and physical effort. Little work experience intensifies stress in the surgical wards, especially in terms of arduousness and responsibility; in the medical treatment ward: organizational uncertainty and physical effort; and unpleasant working conditions and physical effort in the emergency ward. Only in the emergency ward, as many as four features—organizational uncertainty, haste, arduousness, and conflicts—were perceived worse by employees with more work experience. Higher education affected a more critical assessment of the working conditions, which, however, differed between the wards. In the surgical ward, people with higher education experienced work complexity, arduousness, and haste as the worst; in the medical treatment ward, it was responsibility and physical effort; and in the emergency ward, unpleasant working conditions and work complexity.In the face of staff shortages among nurses, which are intensifying due to the aging of society, it is necessary to diagnose factors that increase the stressfulness of work, so that effective actions to counteract them can be taken. Particular attention should be paid to young people, with less work experience and better education, as they are the most susceptible to the psychosocial burden and leave the profession the most often.The study results indicate the need to diagnose problems related to work conditions in the context of occupational stress within individual hospital wards. To limit employee turnover, nursing staff managers should approach the issue of improving working conditions individually for each ward, due to differences in the nature of the work and level of stressogenicity.In each hospital ward, employees at different stages of their career are sensitive to the psychosocial burden resulting from different work characteristics. These areas should be thoroughly diagnosed and the burden minimized to prevent departures from the profession—at early stages of the professional career as well as among experienced personnel.Nurses working in managerial positions should receive the necessary substantive support, due to the higher stress burden associated with greater responsibility.


Orphan medicinal product (OMP) prices are considered by some to be a challenge to the sustainability of healthcare expenditure. These concerns are compounded by the increasing number of OMPs receiving marketing authorisation (MA) annually. The aim of this study was to explore the sustainability of OMP expenditure within the context of total European pharmaceutical expenditure.Using historical IQVIA data, an analysis was conducted on total pharmaceutical and OMP expenditure in eight countries  in the branded, non-branded and overall pharmaceutical market. Country level and aggregated data was considered for EU5 countries, Austria, Belgium and Ireland.The OMP share of total pharmaceutical expenditure was calculated from 2000 to 2017, to assess its evolution over time.The results of this analysis were compared with a 2011 forecast of OMP budget impact.The evolution of the total pharmaceutical market and its different segments  were assessed by estimating the compound annual growth rate (CAGR) and percentage of pharmaceutical expenditure for each market segment from 2010 to 2017.Three key analyses were conducted:Across countries, OMP share of total pharmaceutical expenditure has increased each year since 2000, rising to 7.2% of total pharmaceutical expenditure in 2017. OMP expenditure has increased at a CAGR of 16% since 2010. The number of OMPs receiving MA each year showed a CAGR of 11% since 2001, four percentage points greater than the CAGR for all medicines receiving MA over the same period. OMP share of total pharmaceutical expenditure is higher than forecasted in 2011 due to slower than expected growth in the non-OMP market. OMP growth has been offset by reduced expenditure in the general market and increased use of generics and biosimilars.Relative spending on OMPs has increased over the last 20 years, but this has been largely compensated for within the current allocation of total pharmaceutical spending by flat expenditure for non-OMPs and increased volumes of (lower-priced) generics/biosimilars, reflecting a shift towards expenditure in higher cost, lower volume patient populations and a shift in drug development towards more specialised targeting of diseases. In Justems …” .These concerns are also expressed specifically in the context of orphan medicinal products (OMPs), medicines approved for the treatment of rare diseases , 5–8. BeSuch concerns prompted the European Council to advise the European Commission (EC) to evaluate its OMP regulation (European Union (EU) Orphan Regulation No 141/2000)) . An eval1/2000) .One such analysis, however, can be found in the frequently cited 2011 paper by Schey et al. , who revTo the best of our knowledge, there have been few if any more current attempts to analyse OMP expenditure trends in the EU or their impact on the overall medicines budget. This paper therefore seeks to describe the actual observed expenditure on OMPs in Europe between the introduction of the regulation in 2000 and 2018 , compare this to the previous forecast of OMP expenditure and explore the factors that may be driving any variance with the previous forecast.This analysis further sought to examine total OMP expenditure in the context of trends in total European pharmaceutical expenditure, including all branded and non-branded medicines.. We acknowledge that there are relevant additional questions on the sustainability of total pharmaceutical expenditure, such as whether the distribution of costs and savings due to entry of generics/biosimilars should be different, and where savings could or should be re-allocated. While these questions are relevant and valid, they require separate extensive research and provision of evidence in and of themselves, and are thus beyond the scope of this paper.Ultimately, the main focus of this analysis is on sustainability of OMP expenditure within the current distribution of total pharmaceutical expenditureA recent paper by Espin et al. (2017)  projecteHistorical sales data was acquired from the IQVIA MIDAS database for OMPs and total branded and unbranded pharmaceutical expenditure for Austria, Belgium, France, Germany, Ireland, Italy, Spain and the UK from 2000 to 2018. The MIDAS database covers retail and hospital products and records sales based on list prices, i.e. without discounts applied. Sales data was provided in two forms: value (euro) and volume (standard units). The volume of product sales can be seen as a proxy for volumes of patients treated and was therefore included within the scope of the analysis to help explain underlying trends in the broader market. The OMP dataset was provided at a product level on a quarterly basis, whereas the aggregated pharmaceutical market data was grouped by IQVIA’s innovation classification system and provided on an annual basis. The data was provided on September 25th, 2018, and included current OMPs on the European Medicines Agency (EMA) register, as well as products that had previously lost their orphan designation. The analyses were conducted on aggregated data across the eight European countries mentioned above.For the purposes of this study, “OMP sales” also include sales of products that were once OMPs, but which have since lost orphan designation. Their inclusion is based on the assumption that their sales following designation withdrawal are a result of the position of strength that has been consolidated within the market prior to a product losing its orphan status. Therefore, the rationale behind the chosen approach was to align with the socioeconomic perspective of OMPs and their impact on the pharmaceutical market. Nevertheless, the impact of excluding sales of OMPs following the loss of their orphan designation is also provided when relevant (noting here the impact can be considerable).The OMP data acquired was at a product level, therefore including sales of all licensed indications for a product, including both orphan and non-orphan indications. However, IQVIA does not provide a split of sales per indication (whether orphan-designated or not), so it was decided that all sales for multi-indication medicines (with some indications not being “orphan”) would be included within the study as “OMP sales”. As such, the sales of OMPs in the analysis are likely to be overestimated – although we comment in the discussion section on other issues that might affect whether “OMP sales” over, or under estimate the true OMP expenditure.The OMP share of total pharmaceutical expenditure was calculated from 2000 to 2017, to assess how it has evolved over time.The results of this analysis were compared with the previously forecasted budget impact by Schey et al.  from 201The evolution  of the total pharmaceutical market, and the different segments within it  was assessed.Three key analyses were conducted:Each analysis is discussed in turn.The annual observed OMP expenditure was identified and calculated as a percentage of annual total pharmaceutical expenditure. For each of the eight countries, the total sales for OMPs and total pharmaceutical expenditure were determined and summed to form an aggregated figure. The OMP share of total pharmaceutical expenditure was calculated from 2000 to 2017, to assess how it has evolved over time.The results of the first analysis in this study, from 2010 to 2017, were compared with the previously forecasted budget impact, published by Schey et al. in 2011 [To investigate the impact of total market expenditure growth on the relative share of the OMP market, the forecast overall market growth rate of 6.6% was applied to the total market from 2010 and the OMP share as a percentage of total expenditure was re-calculated.OMP: All branded OMP salesNon-OMP branded: Sales from products classified by IQVIA as ‘innovative branded’Unbranded: Sales from products classified by IQVIA under the following categoriesNon-original brandedAll unbranded OtherUnassignedSales in value and volume for the eight countries were classified into three distinct market segments for analysis alongside the total market:The compound annual growth rate (CAGR) and share of total pharmaceutical expenditure for each segment and the total, in value and volume, over the period 2010–2017 was determined.To derive an analysis of the evolution of the market directly comparable to the previous forecast, the previously identified 6.6% annual growth rate was applied to the non-OMP branded and unbranded segments from 2010. The approach assessed how these areas of pharmaceutical expenditure compared with an estimate of what was forecasted. This assumes the market segments would have been predicted to follow the same level of growth as the total market. An estimate for the annual OMP market value was produced by applying the same 6.6% annual growth to total market expenditure from 2010. The value in euros that corresponded with the forecasted budget impact percentage for that year was then calculated.Results for each of the three analyses undertaken are presented in turn.As expected, given the increasing OMP authorisations, the OMP share of total pharmaceutical expenditure has increased consistently each year since 2000. Figure For the eight countries in total, OMP expenditure experienced a compound annual growth of 16% (2010–2017), ranging between 13 and 25% across individual countries , which has contributed to the higher OMP market share of total expenditure (7.2%). In 2017, the OMP share of total pharmaceutical expenditure was 5.6% of adjusted total expenditure, versus 4.5% in the forecast.If sales are only included for products which maintain their OMP status, the budget impact is reduced to lower than what was forecasted, peaking in 2017 at 4.5%. Excluding all sales following loss of orphan designation, however, likely underestimates OMP expenditure in this approach.Despite the increase in OMP expenditure, this does not appear to be driving  growth in the total market, as this is offset by changes in the broader market. Primarily, the balance between OMP, non-OMP branded and unbranded medicines remains the same, as can be seen in Fig. Figure On the one hand, the growth of the non-OMP branded market has slowed considerably, resulting in a reduction in its market share  both in value and volume terms. On the other hand, the unbranded segment’s share has grown, albeit at a small rate. From 2010 to 2017, OMP volume has grown by 0.02 percentage points, while non-OMP branded has declined by 5 percentage points, and unbranded has increased by 5.7 percentage points  medicines in a total market with a stable volume.Similar trends have been observed in the United States; spending has shifted towards specialty medicines that treat comparatively few people with chronic or rare diseases. Specialty medicine spending in the U.S. has increased from 11% in 1997 to 43% in 2017 [The growth rate of the number of new OMPs authorised is smaller than that of OMP expenditure. This could be because the average price (or cost per patient) for OMPs is higher than for non-OMPs, or because the number of patients treated per OMP might have increased. Further research is required, however, to determine the exact cause for this result.The findings of the second key analysis initially suggested a misalignment between what was forecasted in 2011 by Schey et al. and what was observed in this study. However, once the observed data was adjusted to compensate for the forecast’s overestimation of the total market growth rate, it was much more aligned with the forecast than it originally appeared to be. In the methodology of the Schey et al. analysis, different approaches were used to predict future orphan expenditure and future total market pharmaceutical expenditure. A bottom-up approach was taken to forecast orphan drug expenditure, based on predictions of the number of new orphan drugs. For the forecast of total market pharmaceutical expenditure, a linear extrapolation approach was used, based on the historical annual growth rate of 6.6% mentioned earlier in this paper. Given the findings of our analysis, it appears that the bottom-up approach was more accurate than the linear extrapolation approach, and could therefore be considered for future forecasts.Furthermore, there are three differences in the methodology/data used in the two analyses: (i) the forecast looked only at the orphan indications of medicines, in this analysis both OMP and non-OMP medicine indications were included; (ii) in the forecast, savings from the entry of biosimilars were assumed, and this has not been observed in the market to date; (iii) in the last seven to 10 years there has been an increased use of discounts and rebates for OMPs, and the gap between the list and net price has increased for specialty medicines . This gaThe third key finding highlighted some of the complex dynamics of the pharmaceutical market, and the factors that may enable health systems to increase expenditure on medicines for disease areas with higher unmet need, like OMPs. Many factors will play a role in the changing dynamics and in the significant growth rate of OMPs, but one of them may reflect the response of the pharmaceutical industry to the OMP regulation by investing in researching and developing OMPs. Indeed, it has been estimated that as of 2017, OMP-designated projects represented 13% of all products in clinical development, and that these percentages were even higher for the later stages of development (17 and 22% in Phase III and Regulatory Review respectively) . An addiAnother critical factor underpinning the dynamics of the market is the impact of patent expirations. For non-OMPs in particular, there has also been an increasing volume of use of biosimilars and generics, resulting in a decreasing use of branded medicines  . In manyFor branded OMPs in particular, the potential impact of generics/biosimilars could decrease the economic burden. In the U.S., this impact has been documented: of 503 drugs with orphan designation, 217 have lost their patent protection, and 116 have generic competitors . This raAs data for specific branded OMPs is, however, included in the database, the evolution of sales of one OMP example is presented Fig. . It is iMore generally, the shift in volume from branded to generics has been a stabilising factor in the pharmaceutical market , and theAggregate expenditure on OMPs appears not to be increasing total pharmaceutical expenditure, but questions remain regarding the efficiency and equity of increasing spending on patients with rare diseases. Drummond and Towse  outlinedThe relative value of expenditure on OMPs versus non-orphan branded is critical to understanding the efficiency of the changes in overall expenditure. Perceptions of the value of OMPs may be influenced by the levels and types of evidence of clinical benefit. Evidence development in rare diseases poses specific challenges; small, heterogeneous populations and diseases of which little natural history is known, make it difficult to produce clinical evidence of the standard required for other medicines . At the Four limitations of this study should be acknowledged, which have an impact on whether the estimated share of total pharmaceutical expenditures fully reflects OMP use in practice. First, IQVIA  might not fully capture the use of OMPs in countries, as sometimes such products are accessed via other routes, such as compassionate use. Second, while the focus on the eight countries produces representative results of western European countries, there are of course other European countries with their own processes for OMPs, which were not included in the analysis. The use of OMPs in these other countries may be higher or lower than these eight countries. Third, and as mentioned before, non-OMP indications were included in the analyses , due to not being able to separate out the data . This implies the estimates of OMP sales presented here would be an overestimate. Fourth, the analyses are based on expenditure at list prices, which overestimates the value of the market. However, to our knowledge there is no information available comparing the level of discounting between OMPs and non-OMPs, although confidential discounts have been shown to be greater for medicines used in a hospital setting , 20.Despite these limitations, the findings from these analyses provide insight into current OMP expenditure in the context of broader expenditure trends in the branded and unbranded pharmaceutical market. Both these segments are moving in opposite directions, but ultimately “balancing out” to provide a relatively stable growth rate overall. This study suggests that in recent years the increasing expenditure on OMPs has been offset by slower growth in the wider market. Although it could therefore be argued that the market has been financially sustainable, uncertainty exists as to whether the observed trends will continue to be sustainable not only financially, but also politically.The EU regulation on OMPs has had success in fostering R&D addressing unmet needs for treatments for rare diseases, with approximately 150 OMPs being approved since its introduction. However, despite the success of the regulation in supporting the development of medicines for rare diseases, the findings from this analysis suggest that the resultant impact on OMP expenditure could be deemed sustainable when seen in the context of total pharmaceutical expenditure. The drivers of expenditure shares across the different components of the total market, however, might be changing, which implies different future dynamics relative to past dynamics. There are signs that the market is undergoing a shift towards higher cost, lower volume medicines in patient populations with high unmet need, and more specialised targeting of diseases, all of which is compensated by increased volumes of (cheaper) generics and flat expenditure for non-OMP (branded) medicines for diseases in which more treatments exist. Future research should seek to further investigate the impact that the entry of biosimilar/generic products will have on the OMP market and future savings. In addition to in-depth analysis of expenditure trends, it is important to look critically into the detailed processes of incentives, and pricing and reimbursement of OMPs, to work towards ensuring long term stability, while at the same time providing the “right” incentives to (keep) encourage(ing) R&D in this area. Any changes to legislation require a strong understanding of underlying trends. This analysis sought to contribute to that understanding, and findings suggest that when the situation as a whole in terms of market growth and use of biosimilars/generics is taken into account, concerns about OMP market expenditure might be alleviated.


Based on this unconditional value, people require autonomy and care. "Voluntary stopping of eating and drinking" (VSED) represents an alternative to assisted suicide because no one else is involved in the action of death fastening, even though from outside, it might be considered as an extreme form of passive euthanasia. However, there are no data available about the prevalence and frequency of either explicit VSED or the implicit reduction of food and liquid in Switzerland. The responsible and independent ethics committee of the Greater Region of Eastern Switzerland (EKOS 17/083) approved this study.The objectives of the study were to research the prevalence and frequency of different types (implicit and explicit) of VSED in Switzerland; to explore the experiences, attitudes, handling and recommendations made by palliative care experts; to develop a practical recommendation about VSED, which will be validated by experts in Delphi rounds.This protocol describes a convergent mixed-method design to answer the research questions. In the first step, a cross-sectional trilingual survey  will be carried out to obtain a comprehensive representative picture of VSED in Switzerland. In the second step, qualitative research will be carried out by focus group interviews with palliative care experts. The interviews will be recorded, transcribed, and analyzed using generic coding, and embedded in an explorative descriptive qualitative approach. Based on the results of the first two steps, a practical recommendation will be developed. Experts will validate the practical recommendation in Delphi rounds.The enrolment was completed in summer of 2018. Data analysis is currently underway and the first results are expected to be submitted for publication in the end of 2019.The results of this study will provide important information about the prevalence and frequency of VSED as well as the interpretation of palliative care experts about handling VSED in daily work. Furthermore, the practice recommendation will help professionals and institutions to improve the quality of care in patients and their relatives who made the decision to fasten death by VSED.DERR1-10.2196/10358 When asked about a “good death,” studies have shown that people name the following factors: consciously experienced death at home, without pain, in good mental condition, at the end of a long, fulfilled life, and after having arranged “last things”. For many people, “death with dignity” includes autonomy, control, and self-determination -4.Even under comprehensive, high-quality palliative care, suffering during the process of dying is not always avoidable . Facing The wish to prematurely end one´s life seems to be difficult to understand for persons who have not been confronted with unbearable suffering. To induce premature death, persons turn to organizations offering assisted suicide, which is possible in Switzerland for people with terminal diseases whose end of life is imminent . HoweverNext to the phenomenon of VSED as a clearly expressed desire of a person to prematurely end her or his life, there are other forms. If a person refuses to eat and drink but is unable to explain or does not want to talk about it, this is called implicit or unspoken (V)SED , which iThis study aims to investigate the prevalence and frequency of VSED in Switzerland. In detail, the occurrence of implicit (V)SED and explicit VSED as well as the experiences, attitudes, handlings, and recommendations made by palliative care experts deserve study. Based on these results and in addition to previous and updated work, a practice recommendation shall be developed for professionals in specialized palliative care. The practice recommendation will be specified and evaluated by experts in Delphi rounds. For this study, the following research questions are essential.How frequent and prevalent is the implicit (V)SED and explicit VSED in palliative care throughout Switzerland?What kinds of experiences, attitudes, handlings, and recommendations regarding VSED exist when comparing palliative care experts?What is the perception and interpretation of the implicit (V)SED and explicit VSED in Switzerland for experts in palliative care in their daily work?What interpretations do the experts in palliative care drag from the experiences, attitudes handlings, and recommendations in their daily work?What information in the form of a practice recommendation based on the findings in Parts I and II and available international research literature can be gathered regarding VSED?The theoretical framework is based on the SENS-model of Eychmüller . This apThe reason for choosing this mixed-methods design is based on the integrity of the data, which influence each other. Both instruments are going to be developed at the same time. With this approach, quantitative data can be compared and integrated with qualitative data and vice versa. This brings the advantage that possible inaccuracies are reduced by different viewpoints.Subsequently, a practice recommendation will be developed based on the survey results (Part I) and focus group interviews (Part II) as well as the current literature. Furthermore, it will be subsequently validated in expert discussion rounds based on the Delphi method .A standardized evidence-based questionnaire is going to be developed, tested, and translated into French, Italian, and additionally into English for reasons of publication. The development of the questionnaire -31 is plA representative sample of palliative care experts, employees in ambulatory care service, Long-Term Care, and general practitioners will be sought for in each case. Access to palliative care experts is first sought through professional association.Outpatient care: The employees are informed about the questionnaire via Associations Spitex priveé Suisse  and SpitThe employees in Long-Term Care should be contacted through CURAVIVA—Association Homes and Institutions Switzerland  via emaiThe physicians should be reached through Foederatio Medicorum Helveticorum, Association of Swiss doctors .Two reminders are scheduled for 3-4 weeks, which are either sent again by the respective professional association or directly by the first author. Members’ mails are obtained through the professional associations’ website. The survey can be started in February and depends on the correspondence and the possible resulting requirements  of the professional associations. The recruitment of all professional associations was planned until June 2018. The survey lasted until the end of August. We expect a return rate of 20% per group. This will be as follows: Associations Spitex priveé Suisse 35 of 175 members; Spitex 85 of 426 members; CURAVIVA 260 of 1302 members; and Foederatio Medicorum Helveticorum 282 of 1411 members.t test and metric variables using analysis of variance.Questback will be used for the survey of the target groups. This is a state-of-the-art software and has a high standard for Web-based surveys ,34. Two In addition to descriptive statistical analyses, methods of inferential statistics will be used ,42. The There is a difference between the 3 target groups, Outpatient Care, Inpatient Long-Term Care, and Family Physicians, and their gender in terms of occurrence, stands, and attitude ,44.There are differences between younger (<50 years) and older (50 years) participants in terms of occurrence, stands, and attitude .There is a difference between participants in terms of levels of competence in palliative care in terms of occurrence, stands, and attitude .There is a difference between participants with short (<20 years) and long (≥20 years) work experience in terms of occurrence, stands, and attitude .There is a difference between attendees with and without personal experience accompanying a person with the VSED in terms of stands and attitudes .Qualitative data will be collected by interviewing experts of palliative care in focus group settings. Because the VSED phenomenon can lead to controversial discussions both inter- and intraprofessionally, utilizing focus groups is particularly suitable for showing the different attitudes. We hope that the participants’ possible different views will allow us to gain deeper insight into understanding their attitude. Therefore, an explorative descriptive qualitative approach ,47 was sThe participants of palliative care congresses and network meetings have been sought out for this purpose. These congresses are well suited to nurses and medical professionals who are often confronted with end-of-life decisions and are expected to include participants with and without experience in caring for a person during VSED. Accordingly, 5-6 groups with up to 10 participants are covered. Each group will discuss 1 of the following topics for about 50 minutes: caring for the person concerned, support of relatives, accompaniment of professionals, how to deal with implicit (V)SED, and the appropriate use of recommendations and communication about VSED.A moderator will perform semistructured interviews that will be digitally recorded ,50. AccoIn this step, the results of Part I and Part II will be integrated and discussed. If possible, quantitative data will be qualified and qualitative data will be quantified. Owing to the very different sample sizes from the survey and focus groups, it is likely that data integration will take an explanatory approach. This means that comparable statements from the quantitative and qualitative studies are listed side by side in a table and will be related to each other; for example, factors (described by the focus groups) can be identified and describe why an item (from the survey) was answered that way .Based on the findings from Part I and Part II and especially the findings of the data integration section of Part I and Part II, a development of a practice recommendation is being considered. The aim is to set strategies for professionals to deal with implicit (V)SED and explicit VSED with patients, relatives, and interdisciplinary team members. As basis for development, international publicized articles will be updated. The developed practice recommendation will then be refined in the project team and in cooperation with the project partners.Approximately 20-30 experts and scholars from various disciplines  will then validate the final practice recommendation in a minimum of 2 and if needed, several Delphi rounds until a consensus is reached. The experts are assigned the task of checking the practice recommendation for intelligibility, comprehensibility, and completeness. The experts will be acquired via the existing network of VSED. The Delphi rounds will be carried out with the survey tool QuestBack and will be conducted in English. The consensus procedure will be carried out personally to ensure the quality of the responses.This investigation is neither a clinical trial nor an observational study with vulnerable groups. Thus, no personal data will be collected. Participation in the study is voluntary, and the participants will be assured irreversible anonymity. Nonparticipation does not entail any disadvantages. With an accompanying letter , the participants will be informed in detail and made aware of the aim and purpose of the study as well as the utilization of the generated data and their personal rights. The participants of the focus group interviews will be informed about the project in advance and asked when the interview starts. The ethical approach is based on the principles of the “Declaration of Helsinki” and “informed consent.” Anonymity and respect for human dignity is guaranteed at all times during the research process. Drawing any conclusions about the respondents will not be possible at any time . The resAfter approval of the Ethics Committee (EKOS 17/083), the Swiss Academy of Medical Sciences provided the first partial funding. As soon as the first results are available and the study phase Part III begins, the second partial funding will be planned. The funding from Ebnet-Foundation and palliacura have each paid their share. The development of the questionnaire (Phase I) started in 2016 and was completed in the spring of 2017. Contacts to the professional associations were successfully established, and the recruitment was completed by the end of August. The focus group interviews have since been completed, and the transcription of the audio files are in progress. The results are forthcoming.In Switzerland, there is a very high willingness to become a member of professional associations. Through the participation and support of the professional associations, we are able to guarantee a Switzerland-wide survey.We recognize that that a trilingual survey, despite the translation process, carries the risk that participants’ statements may be interpreted and answered differently. In addition, the results will subsequently be published in English, which translates the statements further. The participants of the study will be given the summarized results in 3 languages via the professional associations and sent via a newsletter. To ensure that the participants in the study receive the results, the participating professional associations receive the summarized results in 3 languages and make them available for internal use.


Human papillomavirus (HPV) is the most common sexually transmitted infection globally. High-risk HPV types can cause cervical cancer, other anogenital cancer, and oropharyngeal cancer; low-risk HPV types can cause genital warts. Cervical cancer is highly preventable through HPV vaccination and screening; however, a lack of awareness and knowledge of HPV and these preventive strategies represents an important barrier to reducing the burden of the disease. The rapid development and widespread use of mobile technologies in the last few years present an opportunity to overcome this lack of knowledge and create new, effective, and modern health communication strategies.This study aimed to describe the development of a mobile app called FightHPV, a game-based learning tool that educates mobile technology users about HPV, the disease risks associated with HPV infection, and existing preventive methods.The first version of FightHPV was improved in a design-development-evaluation loop, which incorporated feedback from a beta testing study of 40 participants, a first focus group of 6 participants aged between 40 and 50 years and a second focus group of 23 participants aged between 16 and 18 years. Gameplay data from the beta testing study were collected using Google Analytics (Google), whereas feedback from focus groups was evaluated qualitatively. Of the 29 focus group participants, 26 returned self-administered questionnaires. HPV knowledge before and after playing the game was evaluated in the 22 participants from the second focus group who returned a questionnaire.P=.001).FightHPV communicates concepts about HPV, associated diseases and their prevention by representing relationships among 14 characters in 6 episodes of 10 levels each, with each level being represented by a puzzle. Main concepts were reinforced with text explanations. Beta testing revealed that many players either failed or had to retry several times before succeeding at the more difficult levels in the game. It also revealed that players gave up at around level 47 of 60, which prompted the redesign of FightHPV to increase accessibility to all episodes. Focus group discussions led to several improvements in the user experience and dissemination of health information in the game, such as making all episodes available from the beginning of the game and rewriting the information in a more appealing way. Among the 26 focus group participants who returned a questionnaire, all stated that FightHPV is an appealing educational tool, 69% (18/26) reported that they liked the game, and 81% (21/26) stated that the game was challenging. We observed an increase in HPV knowledge after playing the game (FightHPV was easy to access, use, and it increased awareness about HPV infection, its consequences, and preventive measures. FightHPV can be used to educate people to take action against HPV and cervical cancer. Human papillomavirus (HPV) is the most common sexually transmitted virus globally . There aIn almost all countries with a cervical cancer screening program, there is a segment of population (approximately 20%) that does not attend screening, in which a significant proportion of cervical cancers is diagnosed -13. Althmobile apps, represent a very promising, burgeoning market and medium to disseminate interventions aimed at changing health behaviors [Mobile technologies have developed rapidly since 2007 . In the ehaviors . Mobile ehaviors ,23. Mobiehaviors , followeehaviors .Given the popularity of mobile games, the concept of gamification, that is, using the elements of game playing for other purposes, has been launched as a novel and promising tool to improve health communication. The idea is that using game thinking and game mechanics in nongame contexts will help users engage in the learning process and thus facilitate knowledge acquisition, positive health-related attitudes, and positive behavioral changes ,26,27. AIn this paper, we describe the principles and processes preceding the launch of a digital game–based learning tool for mobile devices, FightHPV, which aims to communicate concepts that are relevant to understanding the principles behind the sophisticated technology currently used to prevent HPV-related diseases such as cervical cancer.FightHPV was developed in a stepwise manner, applying an iterative design methodology . We origA multidisciplinary team of software engineers, graphic designers, and medical professionals created a skeleton for gamifying selected story lines or narratives with connected text messages to convey health education. The team included researchers in the field of cancer, HPV infection and the management of the Norwegian Cervical Cancer Screening Program. On the basis of extensive domain knowledge, the team decided on a set of characters, gaming rules, game mechanics, and alternatives for social networking. For the programming, Swift for iOS (Apple Inc) and Java (Oracle) for Android (Google) were used. Crash reporting tools from Fabric (Google) were bundled with FightHPV so that the team could receive information on possible malfunctions during the execution of the program; this allowed us to identify and correct software bugs before public distribution. FightHPV was then evaluated by beta testing and 2 focus groups.The beta testing study included 40 employees of the Cancer Registry of Norway, who were external to the present project but were knowledgeable about cancer. Focus group 1 comprised 6 women aged between 40 and 60 years, who were members of the Norwegian Women’s Public Health Association. Focus group 2 comprised 23 high school students  living in Oslo, Norway .Participants in the beta test were invited to download a private  release of FightHPV for Android through the testing facilities provided by Google Play. They were encouraged to advance as far as they could in the game and report any flaws they encountered. After beta testing, summary data were collected from Google Analytics for quantitative descriptive analytics, which captured different actions performed by players, including wins, fails, and retries for each level. Following approval from the Data Protection Agency, improved versions of FightHPV were made available through Google Play for Android and TestFlight for iOS.Participants of focus group 1 downloaded version 2 of FightHPV to their mobile devices, 1 week before attending the focus group discussion held in Oslo, Norway. Participants of focus group 2 downloaded version 3 of FightHPV on their mobile devices and played the game for 2 hours before the focus group discussion held in the participants’ school. Focus group 2 was selected to evaluate how a generation that is used to playing mobile games would respond to a game that teaches lessons about the generation’s own health and its willingness to share the information learned with others who may find it relevant. Although the focus of this research project is cervical cancer, we included boys as they can benefit from vaccination both directly and indirectly  and can Focus group discussions lasted 45 to 60 mins, were semistructured and led by members of the research team, and were audiotaped at the consent of the participants. For focus group 2, girls and boys had separate sessions, moderated by a female and male member of the research team, respectively. The goal of these discussion sessions was to receive both general and specific feedback on FightHPV. A predetermined set of questions about knowledge and attitudes on HPV and sexual health and how information regarding sexual health can be conveyed to the public was used as a guide. At the start of each focus group discussion, participants were encouraged to freely discuss their experiences with FightHPV, addressing the usefulness of a mobile game to disseminate information about health and their willingness to share this information with others.Of the 29 individuals who participated in focus group discussions, 26 (4 from focus group 1 and 22 from focus group 2) returned a questionnaire about the game and a test of their knowledge of HPV before and after playing the game. The data from 22 players from focus group 2 were analyzed and tested for statistical significance using the nonparametric Wilcoxon signed rank test. The tests were 1-sided, with null hypotheses of no difference in scores before and after, against alternative hypotheses of a higher score after playing FightHPV.FightHPV is part of a project approved by the Norwegian Regional Ethical Committee (REK 2015/1926) and the Institutional Data Protection Officer. A liability and copyright terms and conditions of the game, along with logos from Oslo University Hospital and the Cancer Registry of Norway, have been incorporated into the app to enhance players’ trust in the content.Epithelial cell, Low-risk HPV, High-risk HPV, Wart, Ointment, Precancerous cells, Excision, Intercourse, Prevention Method, HPV Vaccine, Immune System, HPV Antibody, Exfoliated cell, and Screening are displayed on a frame of game board–based puzzles. The main character is Epithelial cell and the challenge is to unify all the Epithelial cells on the game board by changing their positions swiftly, using as few moves as possible. The other characters interact with each other and with Epithelial cell  ial cell .At the beginning of each level, the characters appear on concentrically placed hexagons or rings, and the player is instructed to solve the challenge by moving the characters on the game board. Each character has a maximum of 6 surrounding positions, which can be taken by any other character on the game board. Furthermore, 2 characters located next to each other trigger the predefined interaction, which can be either positive or negative for the player to solve the challenge .We selected, amended, and simplified health messages into 60 puzzles (levels), which were then organized into 6 episodes with separate story lines, containing 10 levels each. Information is communicated using relevant characters with predefined rules, which appear in advancing levels within each episode. Gaming difficulty advances gradually from level 1 (simple) to level 10 (more difficult) within each episode. Every new level in the episode either repeats previously introduced information in a more demanding puzzle or introduces a new piece of information.In episode 1, Epithelial cells, we communicate the role of intact/healthy epithelial tissue and introduce the game mechanics to the player. The actual HPV life cycle is dependent on exploiting the biological process within the epithelial tissue, which covers the outer surfaces of the cervix . EstabliPrevention Measure (which resembles a condom) to protect Epithelial cell against HPV in the game. In episode 5, HPV Vaccine, the principles of vaccination are conveyed by presenting the interplay among the characters Vaccine, Immune System, Low-risk HPV, and High-risk HPV [The properties of low- and high-risk HPV to transform normal epithelial cells to warts  and precrisk HPV ,33. ScreCommunication of health information is reinforced with short messages that appear at the beginning of each puzzle and are related to the goal players have to accomplish. Longer articles that relate to each episode have been written for the mobile app, and links to these articles are available on the puzzle screens for users who want to read more in-depth information.Several elements are used to increase players’ motivation to complete the levels, and there are several conditions that determine whether players have successfully completed the levels. Effects and actions in the game are highlighted with sound and character animation to encourage players to retry the level in case of failure. Immediately after completing the level, a score on the scale of 1 to 5 stars with appropriate animation and sound is displayed for the player. The numerical score is calculated on the basis of the remaining number of movements and the time taken to solve the puzzle for that level . PlayersPlayers with a Norwegian personal identification number, that is, those residing in Norway, have been invited to participate in a separate study to determine the effect of FightHPV on cervical cancer screening attendance (results will be presented in a future article). Once enrollment in that study is finalized, the option to participate in the study will be removed from the FightHPV app.Development of the first version of FightHPV started in April 2015, and beta testing was carried out in December 2015. Version 2 of FightHPV was released and discussed with focus group 1 in June 2016 and version 3 of FightHPV was released and discussed with focus group 2 in November 2016 . FeedbacIntercourse and Prevention Method were slightly changed. Game mechanics, that is, how to move the characters on the game board, was intuitively understood by participants. However, the instruction session on how to solve puzzles was made more explicit and easily available throughout the game  reported that they liked the game, and 81% (21/26) stated that the game was challenging. Participants from focus group 2 had little a priori knowledge about HPV and HPV-related diseases, whereas participants from focus group 1 reported medium to high knowledge. During the discussion session, participants in focus group 2 specifically raised questions about HPV and how it can affect their health. They found the game to be thought provoking and requested more information on HPV. The girls’ group suggested that this type of health information should be mandatory in schools, and they considered information about HPV to be a relevant topic for their well-being. Of the 22 participants in focus group 2 who returned a questionnaire, all showed a statistically significant improvement in their knowledge about epithelial cells, HPV, and HPV transmission, with a median and interquartile range (IQR) that ranged from very low to low before playing FightHPV, to low and medium after playing FightHPV. Concepts about HPV vaccination were best understood, with the highest IQR . All parTo the best of our knowledge, FightHPV is the first game to be released globally that gamifies health information about HPV and cervical cancer prevention. Participants in our user groups reacted positively toward educational game, and we were able to demonstrate a statistically significant positive effect of FightHPV on knowledge. In addition, focus group discussions revealed a significant lack of knowledge regarding HPV before playing the game, confirming the need for enhanced communication regarding HPV to the population. Furthermore, FightHPV was designed to create a network for knowledge sharing among people by employing social media, which has become integrated in our daily lives. Gamification and nudging have already been explored in other domains, such as fitness apps, with some success, which suggests this approach could be equally beneficial in communicating serious health information, raising awareness, and eliminating misconceptions about HPV.Use of FightHPV can influence behaviors that are relevant to individual decisions regarding whether to receive HPV vaccination or attend cervical cancer screening. Social cognitive theories and empirical studies suggest that directed educational interventions that influence attitude, knowledge, and motivation are most effective when accounting for the context in which the targeted health behaviors take place . As sociLow-risk HPV and High-risk HPV —trying to threaten other characters, that is, the Epithelial cell, and a hero, that is, the player, who needs to use tools  to defeat the enemy. Visually appealing characters with interactive animations were created to further increase players’ motivation to advance in or to repeat the game.To improve individual learning, we incorporated the following features into FightHPV, which are typical in digital game–based learning : (1) a sIntercourse character illustrates the main route of HPV transmission among humans. A character, Prevention Method, was also introduced, which helps the player get protected against HPV released from Intercourse. As a result of how these characters behave in the game, the puzzles featuring them become harder, depending on how long it takes to use a Prevention Method. This helps to communicate the importance of prevention. The episode HPV Vaccination presents 3 characters: (1) the Immune System, which is not able to fight HPV by itself, (2) the HPV Vaccine, which gives powers to the Immune System to fight HPV, and (3) the HPV Antibody, which appears after HPV Vaccine and has the ability to clean the board of HPVs.Beliefs that HPV infection and cervical cancer are not real threats to an individual’s health and fatalistic beliefs that nothing can be done to reduce one’s risk of dying from cancer have been reported as barriers that prevent women from attending screening and/or accepting to be vaccinated against HPV ,38. InteWe acknowledge that the applied interaction between characters and rules represents a considerable simplification of the real-life situation. On the other hand, simplification allows us to communicate a few take-home messages and address the principle of the increasing difficulty of levels within the episodes to provide a good gaming experience for player.Appropriate instructions have been shown to help learners target relevant information and affect cognitive processing . HoweverFightHPV was also designed to trigger the desire to do something for others: “Should I vaccinate my children?” “Does my mother, sister, wife, daughter, friend, know how frequently they should go to screening?” Players are encouraged to share information with their relatives and acquaintances so that, even though they may not ever play, they can receive the information that we want to transmit. It is somewhat surprising that social nudging has not been used more actively in intervention trials to influence behavior; however, it is gaining attention .Although HPV-related health messages are well suited for gaming, it took us approximately 1.5 years to develop FightHPV, and we encountered several challenges. The design-development-evaluation loop proved to be a useful method to develop different aspects of the game. At the start, the results from beta testing reassured us that using puzzles in a board game format engaged the players and that the mechanics of the game were simple and easy to learn, which made the game intuitive and easily approachable by almost all age groups without any previous gaming knowledge. However, along with being simple, the mechanics should also provide an adequate challenge to keep players engaged. To avoid user frustration at the early stages of the game, or boredom and lack of challenge at the end, it must have an increasing level of difficulty . In the An important part of raising awareness about HPV prevention through FightHPV is to attract as many users as possible and engage them to play through all the levels in the game. In this way, they will receive all the important health messages. Furthermore, receiving information repetitively over several playing sessions will help the user retain this knowledge for the future. Achievements and leader boards are commonly used game elements that increase user engagement. In addition to completing the levels in FightHPV, we created 44 side missions that users can complete by playing levels multiple times. Each time players complete one of these missions, they get a badge acknowledging their achievements. Global leader boards were created on the basis of the sum of players’ scores in each level. Replaying some levels can help players get better scores and rank higher on the leader board. As FightHPV has been designed for the mobile platforms Android and iOS, we used Google Play Games and Game Center, respectively, to implement these features. They also include some social features so that players can compare their results with friends’ results and challenge them, thus increasing user acquisition and engagement.Although FightHPV was developed in the Norwegian context, it is technically simple to expand or modify the content of the game. The organization of the information into episodes allows developers to introduce new topics with minimal technical effort. For example, in Africa, it might be relevant to add an episode to communicate the interaction between HIV and HPV. Translation of the content to other languages is technically simple; however, we suggest that each country should evaluate the local context and communicate correct guidelines for vaccination and cervical cancer screening. Furthermore, short textual messages can be redesigned into pictograms to reach a wider audience. Hence, FightHPV can be adapted for use in different cultural and medical contexts.This paper describes our experiences in creating the very first game-based learning tool to convey simplified health information on HPV to a layperson. A few, if any, textbooks were available to provide guidance on how to design such a tool or to provide information on the pros and cons of using different development methods. We strongly feel that the iterative design, which has been widely applied in software engineering for agility and realizing a good product or market fit, was an optimal choice. Arguably, enhanced size and compositions of the evaluation groups could have improved the variety of the feedback; however, we were able to evaluate and redesign the app on the basis of almost all of the relevant suggestions provided by the user groups. The development team might have benefited from incorporating aspects of cognitive psychology in the evaluation of the feedback from the user groups. However, we feel that the methodology used was sufficiently rigorous to conform to a traditional systematic approach. Employees of the Cancer Registry of Norway participated in the beta test and most of these people are familiar with the concepts surrounding HPV and cervical cancer. They essentially tested only the playability of the game, without paying much attention to the medical content. This was observable because of the low number of visits to the information section of the app .Focus group 1 had a small sample size (6 women), and although the women’s qualitative feedback led to several game adjustments, it is not possible to suggest that these modifications would have appealed to the entire intended target group. Focus group 2 comprised high school students who were not of screening age, which is between 25 and 69 years in Norway. Although the game and the medical information it communicated were of interest to these participants, it is hard to extrapolate the same level of interest to the screening-eligible age group. It was also hard to know if the participants would have the attention span required to learn about every concept communicated in the game. This is primarily because of app fatigue and the availability of a wide range of apps. We did not observe significant barriers to the discussion of sensitive issues, perhaps as girls and boys were interviewed separately. In addition, there were no dominant voices in any of the focus groups to steer the discussion in only one direction. All focus group discussions included people who either had the Android phone/tablet or an iPhone/iPad based on the iOS operating system. The game was not developed for other mobile platforms; however, the market share for other mobile platforms is low in Norway.We have successfully designed and released the game-based learning tool FightHPV, which at the time of this study, had been downloaded more than 12,000 times in more than 45 different countries on the Android and iOS platforms. Engineering, biology, medicine, epidemiology, art, and technology interventions were incorporated to create a modern platform to convey relevant information on basic biology and anatomy, which is needed to make informed decisions on personal health. Furthermore, FightHPV also has the possibility to nudge people to take action against cervical cancer. The proposed concept is flexible and scalable, and the content of the game can be expanded to large populations and different cultures. The usage of apps for health purposes is receiving some attention, thanks to initiatives such as Research Kit from Apple, as it enables people to create platforms for the communication and monitoring of different aspects of health. However, more studies are needed to quantify the extent to which these apps and games can actually change health behavior.


The choice of a wiki format will allow for further inputs from surveillance experts who were not involved in the earlier stages of development. This will promote an up-to-date refined guideline document.With the current trend in animal health surveillance toward risk-based designs and a gradual transition to output-based standards, greater flexibility in surveillance design is both required and allowed. However, the increase in flexibility requires more transparency regarding surveillance, its activities, design and implementation. Such transparency allows stakeholders, trade partners, decision-makers and risk assessors to accurately interpret the validity of the surveillance outcomes. This paper presents the first version of the Animal Health Surveillance Reporting Guidelines (AHSURED) and the process by which they have been developed. The goal of AHSURED was to produce a set of reporting guidelines that supports communication of surveillance activities in the form of narrative descriptions. Reporting guidelines come from the field of evidence-based medicine and their aim is to improve consistency and quality of information reported in scientific journals. They usually consist of a checklist of items to be reported, a description/definition of each item, and an explanation and elaboration document. Examples of well-reported items are frequently provided. Additionally, it is common to make available a website where the guidelines are documented and maintained. This first version of the AHSURED guidelines consists of a checklist of 40 items organized in 11 sections , which is available as a wiki at  Surveillance of disease has an essential role in protecting the health and welfare of animals and humans. While, human health surveillance commonly relies on notifiable disease reporting and analysis of secondary data, animal health surveillance (AHS) places a stronger emphasis on collecting primary data via active sampling of animal populations. For example, such active surveillance will support the objective to fulfill trade requirements and ensure food safety . A reviehttp://www.fp7-risksur.eu/) developed a series of decision support tools for the design of cost-effective risk-based AHS systems. The need for systematic documentation of design decisions was considered during the development of one of the tools: the design framework (https://survtools.org/wiki/surveillance-design-framework/doku.php). The conceptual idea was that by moving toward output-based standards for surveillance and allowing greater flexibility in surveillance design, there will be an increased need for transparency about design features as well as how the activities are actually implemented. However, although the RISKSUR design tool is comprehensive, there is still a need for guidance on (i) what information is truly critical for assessing the quality of surveillance evidence and (ii) how to report the necessary information in a useful manner to decision makers and stakeholders. This challenge was partly addressed within the SANTERO project (http://santero.fp7-risksur.eu/), where the first steps toward producing a set of reporting guidelines to facilitate consistent and credible reporting of surveillance activities and their outcomes were taken. The work was subsequently followed up in the HOTLINE project (https://www.thehotlineproject.org/), funded by the European Food Safety Authority (EFSA), which aimed to facilitate harmonized assessment and reporting of disease occurrence information .https://meridian.cvm.iastate.edu/reflect) and STROBE-Vet (https://meridian.cvm.iastate.edu/strobe). These recommendations target randomized controlled trials and observational studies reported in veterinary scientific literature. They are based on guidelines already developed for studies in humans (CONSORT and STROBE). Several more are available for studies in the medical field. For an overview, see https://www.equator-network.org/. However, none of these is directly applicable to AHS activities. This is possibly due to the limited use of active surveillance in human health. It can also be related to the different perspective in the need for reporting guidelines. Currently available guidelines aim at enhancing the consistent reporting of scientific studies in peer reviewed journals, and therefore have an academic/editorial journal perspective. In contrast, reporting of disease surveillance is usually carried out by governmental bodies and have a more policy-oriented perspective.The concept of reporting guidelines evolved from the field of evidence-based medicine and serves to improve consistency and quality of information reported in scientific journals. A few reporting guidelines directly relevant to the veterinary field are available, such as REFLECT  and the process by which they have been developed. The adoption of AHSURED will promote a more consistent approach to communication of AHS activities and their outputs, for the benefit of stakeholders, trade partners, decision-makers and risk assessors.Reporting guidelines usually consist of (i) a checklist of items to be reported; (ii) a description/definition of each item, (iii) an explanation and elaboration document  a website where the guidelines are maintained and made available. As part of the process of having the guidelines endorsed by journal editors, it is common to publish the guidelines as well as a description of the process by which they have been developed. Thus, the current manuscript outlines the development process that led to the AHSURED guidelines. An overview of the process is provided in surveillance system was defined as a collection of various surveillance components which are all aimed at “describing the health-hazard occurrence and contributing to the planning, implementation, and evaluation of risk-mitigation actions.”Building upon the outcomes of the aforementioned projects (RISKSUR and SANTERO), a list of items that describe the building blocks of surveillance systems was initially identified. These represent elements that should be thought of and from which decisions are made during the design of a surveillance system. According to the definitions proposed by Hoinville et al. , a surveMirroring the structure of the RISKSUR design tool, the identified descriptive items were grouped into building block sections. That could be either at the surveillance system level, e.g., the context in which the surveillance system specifically operates, or at surveillance component level, e.g., the target population of a specific surveillance component. The items to be included in each section evolved as part of the development process and are described in the results.Number of epidemiological units investigated (per stratum), (b) Test results (per stratum), (c) Surveillance outcomes (objective dependent), and (d) Findings in relation to historical knowledge, or trend. Item (c) means an assessment of the outcome of surveillance in relation to its objective. An example might be, for prevalence estimation, prevalence with an accompanying confidence interval. Furthermore, two sections with only one item each, titled “Interpretation,” providing the conclusions about the status of the population, and “References,” were added. The provisional checklist included 55 surveillance items organized in 15 sections and is available in The RISKSUR design tool does not provide recommendations on how to present outcomes of surveillance activities. Therefore, four items were added under a “Results” section: (a) The provisional list of surveillance items was subsequently presented to international AHS experts, who were identified through the distribution list of the third International Conference on Animal Health Surveillance  and contacted by email. In total, 621 invitations were sent out; of these, 115 were rejected by the mailing system and 506 were delivered.The experts were consulted through a web-based survey and asked to indicate which items should be considered critical, optional or irrelevant to report when describing animal health surveillance designs and outputs. A critical item was defined as a piece of information that is deemed very important to report in order to understand and interpret surveillance outputs. An optional item is an additional piece of information that might enhance the interpretation of surveillance results if reported, but that will not hinder such interpretation if not reported. Items deemed irrelevant usually do not pertain to a specific surveillance objective. For example, items related to timeliness of detection might be unnecessary to report when demonstrating disease freedom.The survey included 55 questions about the proposed surveillance items, 15 note fields to document any comment and/or suggestion  within each section, and five additional questions describing the background of the respondent. One last question asked whether the respondent was willing to further participate in the development of the guidelines. The outline of the survey can be found in The survey was online between 31 October and 30 November 2018, and experts could provide their answers either as individuals or as collective groups of colleagues.Starting from the provisional checklist and taking into account the insights gathered by the survey, the AHS reporting guidelines were finalized through consensus-oriented consultations limited to the group of international experts who had expressed willingness to contribute further to the process (further referred to as the core group of experts). These consultations were conducted through four thematic webinars, where the descriptive items were contrasted against example texts describing surveillance for different objectives  and disease situations . A fictional example of the relation between the items of a checklist for surveillance reporting guidelines and a narrative text aiming at reporting surveillance activities and their outcomes is provided in During each consultation, the checklist was iteratively revised in the light of a new specific surveillance objective. The emphasis of the discussion was on those items where <70% of the respondents of the survey agreed on the relevance of the item, i.e., if it was critical, optional or irrelevant to report. Flexibility was provided in the process to add or modify checklist items as necessary. The items' descriptions were carefully revised, and a new objective-specific assessment of their relevance was carried out by the core group of experts. The same applied to any new item suggested by the respondents to the survey. The four thematic webinars were held between 5 February and 1 April 2019.At the end of the survey period, 33 web surveys were completed by 30 individuals and 3 groups of 5–10 co-workers. The respondents were geographically distributed across several parts of the world, although the majority worked in Europe . Most ofHazard under surveillance; Criteria for identification of suspicions; and Target unit level (unit of interest) were judged critical by 97% of the respondents. In contrast: Enhancements in place; When/how often are samples transferred; Who has performed the analyses; References; and Any other testing protocol details scored almost 50:50 between critical and optional. Only 15 items were considered irrelevant by at least one respondent. Among these, Institution involved and financing was the item with the highest proportion of votes as irrelevant: 9% of the respondents. Details about the number of respondents that judged each item of the provisional list critical, optional or irrelevant can be found in At least 70% of survey respondents agreed on the relevance of 40 of the 55 checklist items, which were all deemed to be critical to report. In particular: Identification of surveillance components), deletion/grouping of some items deemed redundant, and combination of some sections. This iterative process led to a consolidated checklist consisting of 40 items organized in 11 sections, which is summarized in https://github.com/SVA-SE/AHSURED/wiki. The choice of a wiki format was motivated by the fact that the collegial discourse leading up to the inclusion of certain items does not end with this manuscript and refinements and improvements of the guidelines are both expected and welcomed.During the thematic webinars, 10–15 international surveillance experts evaluated the various items in the light of four surveillance objectives. These were: demonstrate freedom, early warning, detect cases, and estimate prevalence. They then re-assessed the relevance of those with inconclusive results from the survey through an iterative process of active discussion and (re)voting, until simple majority was obtained. Outcomes from the discussions included the improvement of item descriptions, the addition of one item that was suggested from the survey , thus allowing a deeper and more specific assessment of the relevance of each surveillance item.The survey as the first step of the development highlighted that some items were prone to ambiguous interpretation of their relevance, as they scored almost 50:50 between critical and optional. This could be due to an unclear description of such items or, more likely, to a real duality of their relevance. For instance, The collection of information on AHS activities is often driven by requirements from national and international reporting bodies. Such requirements often have a strong influence on how AHS is developed and implemented . HoweverUnlike existing tools promoting structured ways to design or evaluate AHS [e.g., RISKSUR design and EVA tools , 11, SERThe indication of whether an item on the checklist is critical, optional or irrelevant to report for a particular surveillance objective is not prescriptive but rather a suggestion on how important that piece of information is considered to be for understanding and interpreting the outputs of surveillance. Of course, any surveillance item can be reported, regardless of its objective-specific relevance. The adoption and ongoing refinement of AHSURED will improve a concise, transparent and consistent documentation and communication of surveillance activities and their outputs. This is crucial for the benefit of stakeholders, trade partners, decision-makers and risk assessors.The datasets generated for this study are available on request to the corresponding author.ALi and AC conceived and designed the study and wrote the first draft of the manuscript. AC implemented the web survey and summarized the results. ALi moderated the webinars. JG, GS, HS, JP, FE, JD, ALo, LE, MH, FC-A, AJ, MM-A, YV, and S-EA contributed to guidelines' refinement and consolidation. AC set up the wiki and all authors approved its content. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer JS declared a past collaboration with one of the authors FC-A.