Although a growing body of literature has indicated that unemployment has a positive association with suicide, the dynamic aspects of unstable employment have not yet been considered in suicidology. This study explored the association between employment stability and completed suicide among people aged 25–34 years in 20 OECD (Organization for Economic Cooperation and Development) countries with time-series data (1994–2010). In order to consider the different aspects of unstable employment, we tested the impacts of employment protection legislation indicators as another proxy of job insecurity  apart from unemployment rates. Covariates, including economic growth rates, GDP per capita, fertility rates, and divorce rate, were controlled for. The analysis was designed to be gender- and age-specific, where observations with ages of 25–29 were separated from those with ages of 30–34. Random effect models were applied to examine changes over time in suicide rates, and other models were presented to check robustness. The results showed that it is a low level of employment protection, rather than unemployment itself, that was associated with increased suicide rates among all of the studied populations. The magnitude of the effect differed by gender.  Studies exploring the impact of economic determinants of suicide have been conducted for more than a century. Unemployment is one of the most frequently used proxies of these economic determinants because the status of being unemployed implies a loss of income for individuals, and aggregated unemployment rates are associated with decreased levels of national wealth ,2. Many Whether these studies showed a relationship or not, they share a common problem in understanding the nature of unemployment. The problem is that unemployment has been understood as a signifier of the macro-socioeconomic environment. However, unemployment is affected not only by the economic environment, but also by political factors, such as labor market and welfare state policies, and may not correspond to macroeconomic fluctuations ,11. In aGiven that we understand unemployment as an independent concept, the dichotomous and static distinction in the traditional understanding of unemployment between employed and unemployed status does not reflect all of the dimensions of employment instability ,14. To bAnother limitation of previous research is that most studies exploring the epidemiology of suicide have been interested either in the general tendency among entire populations, or in particular age groups, mainly youth aged 15–24 and the elderly aged 65 and above, because of high suicide rates in these age groups ,19. ExisBuilding on the contributions and limitations of previous theories and empirical studies, this paper aims to examine the impact of unstable employment on suicide rates in young people aged 25–34 years old in 20 OECD countries. Specifically, this study will investigate unstable employment by dividing it into two different aspects: unemployment and employment protection for the employed.This study consists of 20 OECD countries due to the availability of data, and the observation period is 1994–2010. It should be noted that some countries have missing values for some variables see . EmploymData on suicide rates for the gender-specific age groups 25–29 years and 30–34 years were obtained from the Eurostat database, Statistics Korea, and Statistics Japan. Suicide was defined as intentional self-harm on the basis of ICD-10, according to the International Classification for Disease. Building on the economic theory of suicide ,23, two We conducted a random effects analysis after confirming that unobserved country- and time-specific effects that might have an impact are independent of the explanatory variables via the Hausman test . A randoThe basic model has the following form:i = 1, 2, …, 20 and t = 1994, 1995, …, 2010 indicate each country and time period, respectively; The subscripts The results of all of the models show that the suicide rates of all the age and gender groups in each country are consistently regressed on EPR. Unemployment rates, by contrast, turn out not to be significant and, indeed, the pattern of coefficients are inconsistent. The negative coefficient associated with EPR can be interpreted as follows: after a country lowers the level of employment protection for regular contracts, the suicide rates for both males and females aged 25–34 in the country increase. Notably, the coefficient magnitudes of EPR are higher for males than for females, and higher for males aged 30–34 than for males aged 25–29. Other models confirm these trends, despite the different size of their coefficients. EPT also has a negative impact on suicide rates for males aged 30–34 in both random and fixed effects models.We now turn to describing the findings for the economic and social variables. To begin with, GDP per capita is consistently negatively associated with suicide rate in all of the studied populations, and the impacts are stronger for males than for females, and for males aged 30–34 than for males aged 25–29, as was the pattern for EPR. These results imply that an increase in the real income in a country has an association with a subsequent decrease in suicide rates. Even though the results of the random effects model did not show significance among females, the coefficient estimates show a consistent negative direction. As for the social variables representing the degree of social integration and regulation, we can find a tendency in all of the different models for male suicide rates to be more regressed on divorce rates, as opposed to female suicide rates, which are more affected by fertility rates, despite the exception of the male (25–29) suicide rates, as shown in The findings of this study reveal that lower levels of employment protection for regular contracts had a consistently negative impact on suicide rates among people aged 25–34, whereas unemployment rates did not affect suicide rates in any population, regardless of the model. In addition, we also found that the size of the impact of employment protection varied by gender. Gender differences also existed in the impact of GDP per capita, divorce rates, and fertility rates.As explained in the introduction, the overall results of previous studies investigating the impacts of unemployment on suicide, despite the heterogeneity of the findings, supported the hypothesis that unemployment is one of the most important socioeconomic factors influencing suicide. This tendency is especially well substantiated by studies that employed individual-level data. For instance, Blackery and Kposawa reported that unemployed individuals died by suicide at rates 2.34 times, and even up to 25.19 times, higher than the employed in several years in New Zealand and the United States, respectively ,27. The There are two provisional reasons why EPR, rather than unemployment, had an impact on suicides. To begin with, EPR is a more precise predictor of the actual figure of unemployment. As opposed to aggregate unemployment rates, which systematically exclude the real unemployed, EPR better reflects changes in the laws and policies that govern labor markets. These changes affect labor market flexibility and the actual size of the unemployed population. EPR, which takes these laws and policies into account is, therefore, a less biased measurement method. In addition to better predicting the real unemployment rates, EPR captures the multidimensional dynamics of unstable employment. A decrease in EPR may indicate an increase in job insecurity because of easier layoff procedures and less regulation, an increase in economic uncertainty because of decreased severance pay, and an increase in unemployment shocks due to a shortened period of required notice of dismissal for workers . These iOne of the most consistent trends in all of the results of the three different models is that unstable employment has a stronger impact on men, and that men in their early 30s are even more affected. This can be seen clearly from the size of the EPR coefficients, but it is also evident in that the EPT was significant only in men aged 30–34. The pattern of this trend is equally represented in GDP per capita, which is a proxy of real income for individuals. These results are consistent with previous studies which reported that male suicide was more sensitive to unemployment and low income levels ,33. The Finally, the gender differentials in the impacts of divorce and fertility rates on suicide found in the results also supported existing studies. Durkheim reported that, while both being married and having children protected males from suicide via increased social integration and regulation, women were less likely to be affected by marital status. In some populations, women were even protected by being unmarried, probably due to the patriarchal nature of marriage . HoweverFour main limitations of this paper can be noted. First, there were some missing observations in suicide rates in some countries , which might have an impact on the results. However, it is argued that the missing observations did not have a systematic pattern in this study and are not widespread enough to have a significant impact on the results. Secondly, this study takes an ecological design. Ecological study designs not only prevent results from the aggregated data from being inferred as causal relationships on the individual level, but also make it impossible to differentiate compositional effects from contextual impacts. Nevertheless, ecological research can offer important provisional research questions that have not yet been answered, and the results of this study are meaningful in the sense that we explored the relationships between multidimensional aspects of unstable employment and suicides. Thirdly, important covariates regarding mental and physical health status at the population level were omitted in our model. This is because we agree that mental health status and socioeconomic factors do not have separate and independent effects and, thus, mental health status can be understood as an intermediator . AccordiUnstable employment had a significant impact on suicide among people aged 25–34. In general, this study showed that macro unemployment rates have limitations in predicting suicide rates, and that changes in EPL, instead, capture the dynamics of employment status associated with suicide rates. Economic factors, especially decrease in GDP per capita, also turned out to be a good predictor of increased suicide rates. The impacts of EPL and GDP per capita on suicide rates were different by gender. Divorce rates and fertility rates also affected suicide rates. The findings of this study have implications for policy-makers trying to come up with a suicide prevention policies for young people: increases in job security, decent levels of income, and family support for young people would be effective means of achieving this goal.


Wearable activity trackers have the potential to be integrated into physical activity interventions, yet little is known about how adolescents use these devices or perceive their acceptability.The aim of this study was to examine the usability and acceptability of a wearable activity tracker among adolescents. A secondary aim was to determine adolescents’ awareness and use of the different functions and features in the wearable activity tracker and accompanying app.Sixty adolescents (aged 13-14 years) in year 8 from 3 secondary schools in Melbourne, Australia, were provided with a wrist-worn Fitbit Flex and accompanying app, and were asked to use it for 6 weeks. Demographic data  were collected via a Web-based survey completed during week 1 of the study. At the conclusion of the 6-week period, all adolescents participated in focus groups that explored their perceptions of the usability and acceptability of the Fitbit Flex, accompanying app, and Web-based Fitbit profile. Qualitative data were analyzed using pen profiles, which were constructed from verbatim transcripts.Adolescents typically found the Fitbit Flex easy to use for activity tracking, though greater difficulties were reported for monitoring sleep. The Fitbit Flex was perceived to be useful for tracking daily activities, and adolescents used a range of features and functions available through the device and the app. Barriers to use included the comfort and design of the Fitbit Flex, a lack of specific feedback about activity levels, and the inability to wear the wearable activity tracker for water-based sports.Adolescents reported that the Fitbit Flex was easy to use and that it was a useful tool for tracking daily activities. A number of functions and features were used, including the device’s visual display to track and self-monitor activity, goal-setting in the accompanying app, and undertaking challenges against friends. However, several barriers to use were identified, which may impact on sustained use over time. Overall, wearable activity trackers have the potential to be integrated into physical activity interventions targeted at adolescents, but both the functionality and wearability of the monitor should be considered. In recent years, there has been a proliferation of commercially available wearable activity trackers  on the market. The popularity and appeal of these devices, combined with decreasing costs, have resulted in a significant uptake by individuals to self-monitor physical activity levels, such as how many steps they take ,2. HowevMore recently, researchers have begun integrating wearable devices into physical activity promotion interventions in a range of populations -13 and tOne of the biggest concerns associated with wearable activity trackers is whether individuals continue to engage with the technology over longer periods of time . For exaAn integral component of wearable activity trackers is the automation of physical activity tracking in real time ,15. ThisTherefore, the aim of this study was to examine the usability and acceptability of a wearable activity tracker among adolescents. A secondary aim was to determine adolescents’ awareness and use of the different functions and features incorporated into the wearable activity tracker and accompanying app.This study drew on data collected via focus group discussions conducted with adolescents aged 13-14 years after they were given a Fitbit for a 6-week period. Participants had not previously owned or used a Fitbit. The project received ethics approval from Deakin University Human Ethics Advisory Group  and the Victorian Department of Education and Training.Secondary schools located within an approximate 40 km radius of Deakin University Burwood Campus were identified using the publicly available My Schools website and stratified into tertiles of area-level socioeconomic status (SES) using the Socio-Economic Index for Areas . A stepwAdolescents in year 8 (aged 13-14 years) were randomly selected by a school liaison teacher and invited to participate in the project. The research team was not involved in the participant selection process. A minimum age of 13 was used due to the terms and conditions stipulated by Fitbit concerning the age of use. As this was a formative evaluation study, we aimed to recruit approximately 20 adolescents  per school. To be eligible to participate in the project, students could not currently own or have previously used a Fitbit monitor. Sixty adolescents from 3 schools were invited, and all provided written parental consent and student assent to take part (60/60 or 100% response rate). The participants were evenly split across school and sex.This study investigated the acceptability and usability of the Fitbit Flex . Acceptability was defined as the perceived usefulness of the Fitbit Flex for tracking activity behaviors, while usability was defined as the perceived ease of use of the device. The Fitbit Flex is a small, wrist-worn monitor that collects minute-by-minute real-time information on steps taken, estimated energy expenditure, physical activity intensities, and sleep. Twenty behavior change techniques are integrated into the Fitbit and accompanying app . FeedbacEach participant was provided with a Fitbit Flex  and asked to wear it for 6 weeks (September 2015-November 2015). As participants had not previously owned or used a Fitbit device, the research team helped them to set up their Fitbit Flex. This setup process included creating a personal Fitbit account and familiarizing them with the basic functions and features of the device, including charging, syncing, and using the Web-based portal or mobile phone app for viewing their data. Such information is also provided within the packaging of the device. In an attempt to mirror experiences of consumers using the device following purchase, no other information was provided to the participants about the use of the monitor .Demographic data  were collected via a Web-based survey completed during week 1 of the study. At the conclusion of the 6-week period, all adolescents participated in focus groups (up to 10 adolescents per group) that explored their perceptions of the acceptability and usability of the Fitbit Flex, accompanying app, and Web-based Fitbit profile. Adolescents’ awareness and use of the different functions and features were also discussed. A qualitative approach was used to respect the expert knowledge of the participants and to enable them to provide insights into their experiences . The focPen profiles, an increasingly utilized technique, were constructed from verbatim transcripts using a manual protocol ,34. SuchConsistent with recommended approaches , one resAs no thematic differences between participants attending schools in high-, mid-, and low-SES areas emerged, data are presented collectively in 3 pen profiles. Two pen profiles broadly focus on facilitators and barriers to Fitbit use, whereas the third pen profile focuses on specific features and functions of the Fitbit Flex, which have been linked to particular behavior change techniques ,26.The facilitators of Fitbit Flex use are presented in Adolescents described a number of Fitbit features and functions that they either used or were aware of that reflected 7 specific behavior change techniques: social support, self-monitoring or tracking, social comparison, prompts or cues, feedback, rewards, and goal setting . AdolescA number of barriers to use were raised by participants . These rWhile Fitbits were provided to the adolescents participating in the study, in order to access their physical activity data via the app, they often had to use the data allowance that was associated with their mobile phone at a cost to the participants. This emerged as a barrier to use across all focus groups, regardless of SES. Finally, some adolescents demonstrated a lack of understanding regarding how to use various app components, such as personalizing their daily step goal , suggesting that participants neither used the monitor as the manufacturer intended nor accessed the various features available to them¸ particularly in the app.The main aim of this study was to examine adolescents’ perceptions concerning the usability and acceptability of the Fitbit Flex when provided with the device to wear for 6 weeks. Adolescents generally found the Fitbit Flex easy to use and reported that it was a useful device for self-monitoring their day-to-day activity. They noted that this ability to self-monitor their activity increased their awareness and knowledge of their activity levels. However, a number of potential barriers were also identified, which may impact on whether they would sustain their use of the Fitbit over time. A secondary aim of the study was to examine adolescents’ awareness and use of the different functions and features incorporated into the Fitbit Flex and accompanying app. The adolescents utilized a range of functions and features of the device and app, which corresponded to 7 behavior change techniques. Together, these findings provide insights into how adolescents engaged with the Fitbit Flex, which in turn may help to identify how to integrate it into physical activity interventions for adolescents and what factors may need to be addressed to try to facilitate long-term use.There is currently a dearth of research that has examined the acceptability and usability of wearable devices by youth . ResultsThere were contrasting findings in relation to comfort and wearability, with some adolescents noting that they found it comfortable to wear on the wrist (7 mentions) while others found this was a barrier to wearing the device (4 mentions). The biggest issue noted by the adolescents was the manner in which the device fastened around the wrist (25 mentions), with concerns being raised that this was not secure. Previous research has noted that loss of a device (or fear of losing the device) is a major barrier to an individual’s experience and engagement . InteresIn general, adolescents noted that they did use the Fitbit Flex to track a range of data, including steps taken, distance traveled, and sleep. This appeared to increase their awareness of their activity levels, with several adolescents noting that they used this feedback to increase their overall activity levels. Others have noted similar findings, suggesting that the use of a wearable device can trigger short-term increases in physical activity levels , particuA positive finding was that adolescents reported using a range of features and functions of the Fitbit and the accompanying app, which are based on behavior change techniques that are known to influence behavior ,26. In aInterestingly, other features of the app that are considered to reward physical activity behavior  were not particularly valued by most and, in general, were not seen as a significant achievement. This is in contrast to previous studies in adolescents that combined a Fitbit Flex with a Facebook group, where the badges were seen as a reward for effort, reinforced activity behaviors, and also provided opportunities for social comparison and support within the group ,37. ThosOne of the concerns of wearable technology is whether an individual sustains their use of the device over the longer term . It has The strengths of this study include the assessment of the feasibility of a wrist-worn wearable device in young adolescents in free-living settings, the inclusion of adolescents from low-, medium-, and high- SES backgrounds, and the use of qualitative methods to explore adolescents’ thoughts and experiences in depth. However, there are several limitations that should also be noted. First, the liaison teacher at participating schools was asked to randomly select adolescents to receive an invitation to participate. The only selection criterion that we stipulated was no previous use or ownership of a Fitbit device. However, as we were not involved in the random selection of students, it is possible that students may have been specifically invited based on characteristics unknown to the research team to participate by their teacher. Second, the Fitbit used during the study has since been superseded by a newer model, which has addressed issues relating to waterproofness and automatic sleep tracking. These were 2 barriers identified by the adolescents in this study. Third this study assessed the adolescents’ experiences after a 6-week period. While this study provides insights into their initial experiences of using the device, it is not known how this may have influenced long-term use, if at all. Longer-term studies are needed to establish how use of the device changes over time. Finally, no information was collected from the adolescents concerning their experience of using other wearable devices. It is possible that they had previously used other devices , which may have influenced their perceptions of the Fitbit Flex. However, it should be acknowledged that none of the adolescents in the focus groups compared their experiences of the Fitbit Flex with other wearable devices that were commercially available at the time of the study.Wearable devices provide an opportunity to promote physical activity to adolescents, yet little is known about how youth engage with and use such technology. Overall, this study found that a wearable device (Fitbit Flex) was highly acceptable to adolescents, and the device was used to self-monitor activity levels (and other behaviors). Adolescents reported using a range of functions and features that could be integrated into comprehensive physical activity interventions, reinforcing the potential of these technologies for promoting activity levels in this population. Potential issues were also noted, which may decrease the feasibility of using such technology within an intervention or health promotion program, though barriers related to knowledge of using the different functions and interpreting data can be addressed using supporting techniques. Other barriers related to the specific device used, highlighting that these must also be considered during intervention development.


Following a clinical trial in which the Halsted mastectomy was compared to the less invasive quadrantectomy, no differences were reported in terms of local recurrence, disease-free or overall survival between the two. As a result, Umberto Veronesi was the first in the world to state that the radical mastectomy appeared to involve unnecessary mutilation in patients with breast cancer of less than 2 cm and no palpable axillary nodes.To date, the Veronesi quadrantectomy is routinely considered for breast cancer treatment. This brief review, which highlights the main advances over the last 50 years, is dedicated to Professor Umberto Veronesi. Some years ago, I purposed, during a scientific meeting, to compare the traditional mutilating mastectomy with a new conservative surgical approach . At this time, I sensed that the radical Halsted mastectomy was not always necessary. This was not well received by the audience and they thought I was a crazy physician.’‘New England Journal of Medicine.Some years later, following a clinical trial, this evidence was published with great success in the No differences were reported in terms of local recurrence, disease-free survival or overall survival (OS) between the Halsted mastectomy and the quadrantectomy surgeries. Veronesi was the first in the world to state that the radical mastectomy appeared to involve unnecessary mutilation in patients with breast cancer of less than 2 cm and no palpable axillary nodes .To date, the Veronesi quadrantectomy is routinely considered for breast cancer treatment. This brief review, which highlights the main advances over the last 50 years, is dedicated to Professor Umberto Veronesi.At the end of 1950s, Umberto Veronesi conceived a new approach to the treatment of cancer. At the time, the aim was to give the ‘maximum tolerated treatment’ in the hope of curing disease. However, as treatments and diagnostic techniques were improving, Veronesi realised that a new approach was necessary and developed the new concept of minimum effective treatment’.The first studies of Umberto Veronesi were focused on the treatment of cutaneous melanoma. The author verified that clinically uninvolved lymph node dissection should not be performed , and subThe modern prospective study of Umberto Veronesi now focused on breast cancer, a much commoner cancer than melanoma and the main cause of cancer death in women worldwide.The randomised study conceived and conducted by Veronesi was the first to demonstrate that conservative breast surgery plus radiotherapy, which leaves the breast intact, can substitute mutilating mastectomy and yet obtain the same cure rates.During this period, mammography was being introduced and this was able to detect much small tumours, so that breast cancer could be diagnosed at a much earlier stage. Increasing knowledge about tumour biology and carcinogenesis, opened a new concept of breast cancer treatment, in which the Halsted mastectomy was, in certain cases, an excessive approach .In 1969, the World Health Organisation in Geneva convened a meeting of investigators to evaluate the methods of diagnosis and treatment of breast cancer. Umberto Veronesi was among the 15 invited experts. He presented a proposal for a randomised trial to compare the traditional mastectomy with a new conservative approach consisting of wide resection , followed by radiotherapy. The proposal stimulated intense discussion which in the end was unexpectly accepted.The study began in 1971 with a number of clinical tests to verify the feasibility of the treatment, along with its cosmetic and psychological results. Randomisation started in 1973 and the accrual of patients continued until December 1980.Milan I: A total of 701 patients with breast cancer were recruited, 349 were randomised to the standard treatment  and 352 were assigned to the quadrantectomy plus axillary dissection plus post-operative breast radiotherapy . Eligible patients had infiltrating carcinoma up to 2 cm (cT1N0).The trial was called Initially, the term ‘quadrantectomy’ seemed more appropriate for this surgical procedure as the operation maintained the radicality that characterised a mastectomy  , 5.Cancer in 1977 [To inform the scientific community about the purpose of the trial an interim report was published in the journal  in 1977 .New England Journal of Medicine published the first results of the trial. These showed very clearly that there was no difference between the two groups of patients as regards local recurrences and survival [On July 1 1981, the The publication in this journal was greeted with great interest by the medical profession worldwide and hailed by the public, especially women, as a more acceptable surgical approach. Several major newspapers and magazines devoted considerable space to the findings; The New York Times, The Washington Post, The Los Angeles Times are just some of the cited newspapers.However, it was not clear whether the results were due to the surgery or to the radiotherapy. To clarify this point, Veronesi proposed a second randomised trial in 1985 to compare quadrantectomy with tumourectomy combined with complete axillary dissection and radiotherapy .Tumourectomy removed the tumour mass with only a limited margin of surrounding tissue, so that the task of ensuring local control was entrusted mainly to the radiotherapy. This second trial concluded in December 1989 recruited 705 patients from 1985 to 1987. Inclusion criteria were similar to the first study ‘Milan I’ except that the tumour volume could be up to 2.5 cm. instead of 2cm.The two groups differed significantly in terms of frequency of tumour relapses, although the OS was identical, demonstrating that local failure does not impact on survival.The conclusion of Milan II trial was that a wide resection such as quadrantectomy was necessary to reduce the risk of local tumour relapse.The Milan III trial would clarify the impact of radiotherapy within the QUART protocol. It was a randomised study that compared QUART with quadrantectomy plus axillary dissection without radiotherapy (QUAD); 567 patients were enrolled in this trial between 1987 and 1989, 294 were randomised to QUART and 263 to QUAD respectively [The results demonstrated a notable difference in the rate of local relapse. In particular in the QUAD group, a higher frequency of local failure was verified in the pre-menopausal sub-group particularly. Importantly, overall survival did not differ between the two main arms of the study.In subsequent years, the results of the trial were updated and presented to the scientific press. In addition to the first main trial, two novel randomised studies clarifying the role of both ‘extent of surgical resection’- and of ‘postoperative radiotherapy’, both conducted by Umberto Veronesi, were published .Conclusive data were published in 2002 and the results clearly demonstrated that survival rates in the two groups were absolutely identical .The Veronesi quadrantectomy represents a great milestone in the treatment of breast cancer, and currently, it is the first conservative protocol scientifically validated.The rationale of Umberto Veronesi during his long career was the minimum effective treatment obtaining the maximum of results in terms of oncological radicality, offering a high quality of life (QoL) with the best long term survival. Veronesi contributed many other important discoveries in addition to the breast quadrantectomy during his career. Sentinel lymph-node biopsy, intraoperative radiotherapy, mastectomy with skin and nipple areola sparing, neo-adjuvant treatments are just a few examples. To date, several therapeutic approaches are based on this concept, including minimally invasive surgery and more recently robotic surgery.Don’t rush, stop!.... take care of that patient.’Alongside these important scientific innovations, the best contribution of Umberto Veronesi in terms of patient care was the attention given to each oncologic patient. He said in one of his interviews: ‘Umberto Veronesi died in Milan on 8 November 2016.We are proud to recognise the Veronesi contribution to the scientific community, and we trust that these results will strengthen our commitment to advancing clinical cancer diagnosis, treatment, research, and QoL for the patient.


The Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project sought to inform the interpretation of iron and vitamin A biomarkers  in settings of prevalent inflammation as well as the prevention of and control strategies to address anemia. Our purpose is to comment on the contributions of the BRINDA to advance global knowledge with regard to iron and vitamin A status assessment in women and preschool children and to analyze the findings in terms of their rigor and usefulness for global nutrition research and programs. BRINDA investigators found that the acute-phase response is so prevalent that it must be assessed in surveys of iron and vitamin A status for valid interpretation of micronutrient biomarkers. Furthermore, they found that C-reactive protein and α-1-acid glycoprotein provide important and different information about these responses and that common survey variables cannot replace the information they provide. Developing a method for adjusting micronutrient biomarkers for the independent influence of inflammation is challenging and complex, and BRINDA has brought greater clarity to this challenge through the use of large and diverse data sets. When comparing approaches, the regression methods appear to perform best when sample sizes are sufficient and adequate statistical capacity is available. Further correction for malaria does not appear to materially alter regression-adjusted prevalence estimates. We suggest that researchers present both adjusted and unadjusted values for the micronutrient biomarkers. BRINDA findings confirm that iron deficiency is a common and consistent risk factor for anemia globally and that anemia control must combine iron interventions with control of infection and inflammation. Anemia control strategies must be informed by local data. By applying the knowledge in these studies, researchers, program planners, and evaluators working in populations with prevalent inflammation can use and interpret biomarkers with more confidence, tempered with necessary caution. Malnutrition is the largest single factor underlying the global burden of disease, and micronutrient malnutrition is an especially prevalent form . ApproxiIt is not surprising, therefore, that accountability around nutrition and around the effectiveness of investments is at an all-time high in the context of national and global development. On 1 April 2016, the UN General Assembly declared 2016–2025 a decade of action on nutrition. The World Health Assembly adopted nutrition targets to be achieved by 2025. One of those is to reduce by 50% the prevalence of anemia in women of reproductive age (WRA).Valid approaches to assessing malnutrition, including iron and vitamin A deficiencies, are crucial to achieving and measuring progress. Valid assessment is essential to screening individuals, targeting populations or subgroups, measuring benefit or harm from interventions, and monitoring nutritional adequacy. By valid, we mean accurate  as well as reliable  across time and place.A well-known threat to the validity of iron and vitamin A status assessment is the role of inflammation and the acute-phase response (APR). For both of these micronutrients, several nutritional biomarkers exist that are considered accurate and highly informative in healthy individuals in metabolic homeostasis. These include the biomarkers that are the focus of this supplement: serum ferritin and serum transferrin receptor (sTfr) for iron and serum retinol and retinol binding protein (RBP) for vitamin A. However, the assessment of micronutrient malnutrition is most urgent in individuals and populations who are likely to have concurrent ill health, including a wide variety of subclinical inflammation, and these perturb micronutrient biomarkers in complex ways. This puts us in a weak position to assess iron and vitamin A status in the populations of the greatest global interest and vulnerability.The overall goal of the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project was to inform the interpretation of iron and vitamin A biomarker values in settings of prevalent inflammation and, furthermore, to inform prevention and control strategies to address anemia . The met1) to identify risk factors of inflammation as defined by commonly measured acute-phase proteins (APPs);2) to assess the relations between inflammation and biomarkers of iron and vitamin A status and to compare adjustment approaches in pursuit of more accurate assessment of micronutrient status of populations; and3) to assess factors associated with anemia among preschool children (PSC) and WRA and to estimate the proportion of anemia associated with iron deficiency.The primary purpose of the present article is to comment on the contributions of BRINDA to advance global knowledge with regard to iron and vitamin A status assessment in vulnerable populations and to analyze the findings in terms of their rigor and usefulness for global nutrition research and programs. Neither of us were involved in the conception or implementation of BRINDA, and the authors of the BRINDA articles allowed us early access to their findings and the opportunity to comment freely on the work.First, we summarize the major findings of the articles in this supplement issue. We then comment on findings related to each of the 3 aims, as listed above.The outstanding strength of BRINDA was its large and representative data set, which included both women and young children. The authors used primary data sets from 17 nutrition surveys, each of which used a sampling scheme to be representative of a nation or region. This avoids the common pitfall of research study data sets in populations chosen to have somewhat extreme characteristics . Although these data sets are not representative of the entire world, they do include all 6 WHO regions. The data included observations on ∼30,000 PSC and 26,000 WRA.Furthermore, the data sets are relatively recent (post-2004). Although fundamental human biology does not change from decade to decade, environments and assays do. The surveys used comparable methods for measuring the biomarkers of interest, reflect the health environments after the “child survival revolution,” and were concurrent with widespread efforts in this century to control HIV and malaria. This is important to point out, inasmuch as the results of the BRINDA are not intended to be used to explain the past but rather to predict the health and biology of populations of women and children in the future and in settings not included in the BRINDA data.The defining biomarkers of the BRINDA analyses, namely ferritin, sTfr, total body iron (TBI), RBP, and the APPs C-reactive protein (CRP) and α-1-acid glycoprotein (AGP) are commonly used and measured. The findings are therefore relevant to many research and program evaluation endeavors.BRINDA did not, however, answer the set of questions for pregnant or postpartum women, populations of great interest for micronutrient malnutrition in the first 1000 d of life and in biological states that could fundamentally influence the findings of BRINDA. BRINDA findings should not be extrapolated to pregnant women or even women in the early postpartum period. At best, BRINDA’s methods and key findings may inform future inquiries into these high-priority population groups  across the BRINDA data sets and whether demographic, anthropometric, or morbidity symptom variables were consistently and significantly associated with elevated CRP or AGP. The prevalence of elevated CRP or AGP was variable between surveys, and in many surveys was very high. Elevated AGP tended to be more common than elevated CRP. Both AGP and CRP were more commonly elevated in PSC than in WRA. The prevalence of ≥1 elevated APP ranged from 26.0% to 67.3% in PSC (9 surveys reported both CRP and AGP) and from 13.9% to 33.6% in WRA (4 surveys). Survey variables were inconsistently associated with CRP and AGP between surveys, and the variables associated with CRP differed from those associated with AGP. Notably, for nutrition assessment, elevated AGP was consistently associated with stunting in children, whereas elevated CRP was consistently associated with obesity in women.The observed relations with stunting and obesity are not new findings. The causal relation between overweight or obesity and CRP is well established ; adiposeFor nutritionists, it is important to note that the relations between inflammation and nutritional assessment variables are complex and multidirectional. Inflammation likely causes stunting by suppressing the IGF-I growth stimulus , 15. On BRINDA investigators support the conclusion that the APR  is so prevalent that it must be assessed in surveys of iron and vitamin A status for the valid interpretation of biomarkers. Furthermore, they support that CRP and AGP provide important and different information about these responses and that common survey variables cannot replace the information that they provide.The second aim of BRINDA was to assess the relations between inflammation and biomarkers of iron and vitamin A status and to compare adjustment approaches in pursuit of a more accurate assessment of micronutrient status of populations. The impact of the APR on nutritional biomarkers is well known and documented in the literature –18. The The BRINDA analyses for ferritin are based on data from 15 large cross-sectional surveys in PSC and 8 in WRA with a smaller set (5 for PSC and 3 for WRA) to assess the need for additional adjustment for malaria. The data sets covered a wide and varied geography and included data from countries in Latin America, Africa, South and Southeast Asia, and North and South America. PSC data sets had a considerable variability in age range (8.3–41.5 mo), inflammation prevalence range , and malaria prevalence (19.7–32.5%). WRA data sets were fewer and less variable on these factors.1) elevated CRP and AGP, as well as positive malaria status, influenced ferritin concentrations, although the strength of association between ferritin and CRP and AGP varied considerably across countries; 2) adjusting for both CRP and AGP increased the prevalence estimate for depleted iron stores, with a larger increase for PSC than for WRA; 3) adjusting for both CRP and AGP increased the prevalence estimate for depleted iron stores more than adjusting for only one of the inflammatory biomarkers; and 4) ferritin concentrations were influenced at concentrations well below the conventional CRP and AGP cutoffs.The BRINDA analyses showed that To explore methods for determining iron deficiency prevalence on the basis of serum ferritin, the BRINDA analysis compared 4 different adjustment approaches:1) excluding individual observations if CRP or AGP is elevated;2) applying a higher cutoff (30 μg/L) in populations with elevated CRP and/or AGP;3) applying an APP-determined infection stage with the use of a correction factor based on a healthy reference population  applying CRP and AGP correction factors derived from linear regression coefficients to adjust ferritin concentrations among individuals with elevated CRP or AGP concentrations.Currently, the WHO recommends the first 2 approaches .In populations with a high prevalence of inflammation, the first approach can result in a substantial loss of precision due to excluding subjects with inflammation. In the BRINDA analyses, there was a loss of ∼50% of the sample when excluding subjects with elevated CRP or AGP. Moreover, this approach assumes that subjects with and without inflammation are similar; this is a tenuous assumption, which, if not true, would lead to a biased estimate of population iron status. The second approach is simple and generated equivalent results to the regression coefficient approach in contexts without malaria. However, there is a need for more robust evidence to substantiate the higher fixed cutoff . The third option has the advantage of adjusting ferritin concentrations on the basis of the inflammation profile of a population but depends on having a sufficient sample size to calculate a reliable internal correction factor.In contrast to these options, the BRINDA authors recommend applying age-specific correction factors derived from the BRINDA studies. We agree that the BRINDA correction factors are likely to be more accurate than those from a previous meta-analysis  that werAfter a 2004 expert consultation, sTfR alone or in combination with ferritin was recommended by the WHO and CDC as an alternative iron status biomarker in populations with a high prevalence of inflammation. This recommendation was made, in part, because sTfR concentration reflects erythropoietic activity and is considered a useful marker of early functional iron deficiency independent of concurrent inflammation or infection. The BRINDA data addressing the question of whether and how to adjust sTfR concentrations for CRP and/or AGP were based on 11 and 7 surveys for PSC and WRA, respectively, and for malaria on 5 and 3 surveys for PSC and WRA, respectively. Eligibility criteria for inclusion in the BRINDA sTfR analyses, namely subjects with no missing values for sTfR, CRP, AGP, or malaria in countries that measure malaria, resulted in only 40.1% and 43.8% of observations being used from the data sets from PSC and WRA, respectively. Among measured variables, only child age differed between the included and excluded participants, but the high sample loss requires the results to be interpreted with caution. Although no universally accepted cutoff for STfR exists, the analyses defined concentrations of sTfR >8.3 mg/L as indicative of iron-deficient erythropoiesis with the use of values obtained from results of the VitMin Laboratory .Although sTfR is known to be less reactive to inflammation than ferritin, the BRINDA analysis confirms that inflammation cannot be ignored when using sTfR as a biomarker. With their large data sets, the BRINDA investigators found a weak but positive association between sTfR and CRP and AGP, which was stronger in PSC than in WRA, and therefore suggest that concentrations of sTfR be adjusted for inflammation with the use of AGP concentrations and, in malaria-endemic areas, for the presence or absence of malaria. Furthermore, they recommend the internal linear regression approach for APP adjustment as the most “valid” approach, provided the sample size is adequately large and statistical expertise adequately capable. Alternatively, they recommend creating a 2-group internal correction factor  in nonmalarious contexts or a 4-group correction factor  where malaria is prevalent. The authors correctly express caution about the interpretation of sTfR as a proxy for nutritional status without adjusting for other factors that influence erythropoiesis.Serum retinol concentration is widely used as a population-based indicator of vitamin A status that is recommended by the WHO, although the current threshold for defining deficiency  does not account for inflammation or infection status. With the use of data from 8 surveys in PSC and 4 in WRA to assess adjustment approaches for RBP concentration in settings with inflammation and malaria, BRINDA authors concluded that an internally derived, regression-based adjustment, where possible, be used to estimate the prevalence of vitamin A deficiency in PSC. They concluded that such an approach was not needed in WRA due to weak correlations between RBP and inflammatory biomarkers. Finally, they recommend that the unadjusted and adjusted vitamin A deficiency prevalence values, along with the prevalence of inflammation, be presented. We agree with these conclusions.Last, BRINDA aimed to assess factors associated with anemia among PSC and WRA and to estimate the proportion of anemia concomitant with iron deficiency. With regard to the risk factors considered, BRINDA was not designed to be novel inasmuch as it reflected the content of previous surveys and indeed confirmed the a priori conceptual framework posited by the BRINDA investigators . We agreThe authors also report the proportions of anemia with concomitant iron deficiency, for PSC and women, stratified by the infection burden of the country surveyed. These should be interpreted with caution, for several reasons.One potential (and unwarranted) use of these proportions is to “partition causality.” We are certainly curious to know how many cases of anemia in a population are caused by iron deficiency and how many are due to another factor, such as malaria. But this becomes meaningless if a single case of anemia is caused by multiple factors : for exaSecond, these proportions have little external validity, even within infection category. This is strikingly illustrated by the comparison of the 2 nationally representative surveys from Kenya included in BRINDA, dated 2007 and 2010. The proportion of children who have anemia with or without iron deficiency (after adjustment for inflammation) varies substantially, even between these 2 surveys in a single country. As Engle-Stone et al.  is not the entire solution. BRINDA findings also confirm that iron deficiency is the most common and consistent risk factor for anemia globally , 8. HoweThe BRINDA project has made a substantial contribution to the knowledge of iron and vitamin A assessment with the use of common biomarkers  and further confirms the need to adjust for the APR in surveys and research. Developing a method for adjusting micronutrient biomarkers for the independent influence of inflammation is challenging and complex, and BRINDA has brought greater clarity to this challenge. The complexity stems from the fact that inflammation can spuriously influence micronutrient biomarkers, but can also truly deplete micronutrient concentrations, leading to deficiency. It is difficult, if not impossible, to separate one from the other. Inflammation and infection may temporarily result in abnormal values of biomarkers, and the emphasis of the BRINDA effort was to develop more robust methods to account for this distortion. However, infections and inflammation can simultaneously truly worsen micronutrient deficiency through a reduction in food intake, impairment of nutrient absorption, and greater catabolic losses of the nutrient. The APP adjustment approaches described in these BRINDA articles are unable to separate these concurrent phenomena. It is impossible to ascertain unbiased measures of micronutrient status in the absence of a true “gold standard.” Nevertheless, BRINDA has advanced the field through the use of large and diverse data sets and thoughtful statistical approaches. By applying the knowledge in these articles, researchers, program planners, and evaluators working in populations with prevalent inflammation can use ferritin, sTfR, and RBP with more confidence—as well as with some necessary caution.Although, increasingly, micronutrient status assessment surveys and studies include the measurement of ≥1 APP, the collection of both CRP and AGP should become standard practice. If only one can be afforded, AGP seems to be the better choice on the basis of BRINDA analyses.1) the unadjusted prevalence of micronutrient deficiency by subpopulation or risk group; 2) the prevalence of inflammation as indicated by elevated concentrations of CRP and AGP; 3) the APP-adjusted prevalence of micronutrient deficiency, specifying the adjustment method used; and 4) a description of the prevalent infections that likely contribute to inflammation in the given context, most notably malaria, but not only limited to malaria. It is important for researchers and the users of survey or research data to interpret prevalence values—adjusted or unadjusted—with caution . When sample sizes are sufficient and adequate statistical capacity is available, the regression methods recommended by BRINDA do appear to perform “best” among adjustment approaches for all 3 nutritional biomarkers: ferritin, sTfR, and RBP.The question of how to adjust for the effects of elevated APPs on micronutrient biomarkers does not, in our view, lend itself to a simple answer. As the BRINDA articles suggest: “It depends.” It depends on the nutrition biomarker in question, the extent of inflammation in the population, the subgroup of interest , the sample size , and the statistical capacity to perform and interpret results from the more complex linear regression method. At a minimum, it is our view that presenting all of the following information is vital to help guide programmatic and policy decisions: The BRINDA authors acknowledge the limitations of their data sets to show additional or independent effects of specific infections, such as asymptomatic malaria infection, which may differentially affect the interpretation of biomarkers of micronutrient status. Recent evidence from a malaria-holoendemic region of Burkina Faso suggests that asymptomatic malaria, defined by elevated histidine-rich protein II concentrations, was associated with iron and vitamin A status even after adjustment for APP, which led to a higher estimate of iron deficiency prevalence (from 38.7% to 50.6%) and a lower estimate of vitamin A deficiency (from 33.4% to 27.7%) .The BRINDA findings strongly confirm the need for approaches to anemia control that combine iron interventions with control of infection and inflammation, and that these approaches must be informed by local data. The variable and frequently very high prevalence rates of the APR in these nationally representative data sets should direct our attention beyond hallmark infectious disease per se, such as malaria or HIV, to the possibility that young children  live in environments where the APR is nearly normal (meaning the norm), although not healthy. Whether this arises primarily from clinical infections or whether a substantial proportion of this response is due to subclinical stressors is a worthy subject of further research. Subclinical environmental enteric dysfunction or dysfunctional microbiomes (or both) may be responsible for a substantial proportion of the elevated CRP and AGP seen in these surveys. Understanding the sources of this phenomenon may have far-reaching benefits, including more accurate assessment of iron and vitamin A status as highlighted by BRINDA and more effective control of anemia and stunting –29.We support BRINDA’s recommendation for the need for additional research, preferably longitudinal and intervention studies, to assess the association of APPs and micronutrient biomarkers in response to micronutrient interventions. Cross-sectional analyses of risk factors are weak evidence to predict the effect size of actual interventions on those risk factors.1) how close to the threshold of inaction the unadjusted values are, 2) the extent and severity of inflammation in the risk population, 3) the consequences of the deficiency, and 4) the potential harm of providing micronutrients to those whose status is adequate.Finally, countries will face decision dilemmas when the prevalence of micronutrient deficiencies based on unadjusted values of nutritional biomarkers exceed a threshold for action but when APP adjustment brings the prevalence to below that threshold, particularly in contexts of high inflammation and infection. Which prevalence value should countries use to justify the initiation, continuation, or termination of a micronutrient intervention? There is no single answer to this question. Several factors need to be weighed in choosing an appropriate course of action, which include but are not limited to


Introduction: Health technology assessment (HTA) in Poland supports reimbursement decisions via the Polish HTA Agency (AOTMiT), whose guidelines were updated in 2016.Methods: We identified key changes introduced by the update and, before guideline publication, analysed discrepancies between AOTMiT assessments and the submitting marketing authorisation holders (MAHs) to elucidate the context of the update. We compared the clarity and detail of the new guidelines versus those of the UK’s National Institute for Health and Care Excellence (NICE).Results: The update specified more precise requirements for items such as indirect comparison or input data for economic modelling. Agency–MAH discrepancies relating to the subjects of the HTA update were found in 14.6% of published documents. The new Polish HTA guidelines were as clear and detailed as NICE’s on topics such as assessing quality of evidence and economic modelling, but were less informative when describing (for example) pairwise meta-analysis.Conclusions: The Polish HTA guidelines update demonstrates lessons learned from internal and external experiences. The new guidelines adhere more closely to UK HTA standards, being clearer and more informative. While the update is expected to reduce Agency–MAH discrepancies, there remain areas for development, such as providing templates to aid HTA submissions. Health technology assessment (HTA) is the systematic evaluation of the properties and effects of a health technology. The health technologies in question include medicines, devices, procedures and organisational systems that can be used to promote health, to prevent, diagnose or treat a disease, or for rehabilitation or long-term care . HTA is Agencja Oceny Technologii Medycznych i Taryfikacji; AOTMiT) in 2005, which plays the role of an advisor to the Ministry of Health (MoH); (2) issuing the first HTA methodological guidelines in 2007 [The interest in harnessing health technology assessment (HTA) in Poland has been growing in the last decade, with major milestones being (1) the establishment of the national HTA Agency , which include HTA reports. The HTA report is shared with AOTMIT for its own assessment  and the subsequent appraisal process. The MoH may also commission the AOTMiT to reassess health technologies and services funded by the national health insurance system, to revise their coverage status.1 The Council prepares a statement to be considered as part of the final recommendation issued and published by the President of AOTMiT. There is a standardised format for the recommendation, which covers: a statement on public financing, rationale, objective of the recommendation, a brief note on the health problem, description of the technology and alternative technology/technologies, their efficacy, safety, relation of costs to health effects, impact on the payer’s budget and relevant recommendations from foreign HTA agencies, among others [Once the assessment by AOTMiT is complete, any interested stakeholder (mostly MAHs) can appeal the AOTMiT’s assessment by submitting comments within seven days, before a final recommendation is issued . AOTMiT g others –8. The eDue to the development of the new Polish HTA methodological guidelines in 2016 , the objFirst, an analysis of key differences between the new (2016) and obsolete (2009) HTA methodological guidelines was carried out based on published, final documents. In addition to this task, a review of available, published AOTMiT’s assessments  and subsequent comments from MAHs during the appeal process from 2015 was performed, prior to the publication of the guideline update, to gain better understanding of the context for implementing the new HTA guidelines. AOTMiT’s verification analyses and subsequent comments submitted by MAHs during the appeal process were identified on the AOTMiT website . An expeA second research stream consisted of the analysis of similarities and differences between the new Polish guidelines and those from the English HTA body, NICE. The NICE guidelines considered in this research were: 1) ‘Guide to the methods of technology appraisal’, April 2013 , and; . By comparison, the previous guidelines from 2009 required only basic information about the disease, including its natural history and prognosis as well as therapeutic and diagnostic management. Further, the new HTA guidelines also recommend description of the intervention of interest by providing its regulatory status, mechanism of action, Anatomical Therapeutic Chemical (ATC) classification code and link to the ICD-9-CM code , while the obsolete guidelines required merely a description of the marketing authorisation status and, if licensed, the date of approval in Poland or in other European Union (EU) member states (if not authorised in Poland). Third, the search strategy to identify information for a systematic literature review, as per the new guidelines, should be pursuant to the recommendations of the Cochrane Handbook  and the The new guidelines also propose a new approach to indirect comparison . Namely,Moreover, new guidelines provide more specific criteria for the selection of clinical trial outcomes presented in the HTA report. In contrast, the guidelines from 2009 neither fully described nor extensively explained these criteria. For instance, the old guidelines did not require a specific description and justification of outcomes in the description of the health problem.The new HTA guidelines provide more exhaustive and precise advice for economic analysis, particularly with respect to the modelling approach, cycle length, requirements for input data, and the need for external validation. These elaborate explanations were not provided in the 2009 guidelines. The perspective for the economic analysis became broader, with the new guidelines imposing a joint patient and payer perspective for technologies entailing co-payment, while in the 2009 guidelines such joint perspective was not envisioned.Polskie Towarzystwo Farmakoekonomiczne; PTFE). These databases were not mentioned by the obsolete guidelines from 2009. As a result of AOTMiT’s involvement in EUnetHTA’s activities, the new Polish guidelines are now better aligned with EUnetHTA’s outputs –22. SpecEighty-seven assessments carried out by AOTMiT in 2015 were identified, with a total of 103 official documents listing the comments submitted by MAHs in response to the Agency’s assessment during the appeal process. Agency–MAH discrepancies that were related to the subjects of the 2016 HTA guidelines update were found in 15 (14.6%) of these official comment documents.One of the most frequent issues which prompted AOTMiT to challenge the MAH’s HTA submission was related to the use of inappropriate input data for modelling. Another subject of disagreement between the Agency and MAHs concerned aspects of the search strategy and sources of information. The Agency argued that the search approach was too narrow, overlooking some important sources of information, such as Embase or the Cochrane Library. Ranking third as a source of discrepancy was the way in which the quality of trials and systematic reviews had been assessed; namely the Agency’s assessments differed from the ones performed by the MAHs .Polish HTA guidelines (2016)  display HTA guidelines from both agencies provide very similar and exhaustive recommendations on economic evaluation, including perspective and time horizon. Both guidelines list a range of acceptable types of economic evaluation, such as cost-effectiveness, cost-utility and cost-minimisation analyses. In addition, the two guidelines both define the acceptable time horizon as long enough to reflect all important differences in costs and outcomes that the technologies in question entail, and present descriptions of preferred measures, instruments and sources of utility data in similar detail. For modelling, there are clear recommendations for the components of a model, a checklist for critical appraisal and a summary of good practices in both guidelines; likewise, both contain an explanation of direct and indirect costs (followed by examples), and identification and accepted measures of resource use. To incorporate uncertainty analysis into the HTA process, the Polish and English guidelines provide explanation of the methods for deterministic and probabilistic sensitivity analysis, and outline the forms of results presentation .The analysis we conducted revealed that Polish HTA guidelines seem to touch upon some key components of an HTA report less comprehensively than the NICE guide. For example, the latter discusses measures of resource use and associated costs , and provides pre-prepared sample templates for presenting a comparative summary of trial methodology, statistical analyses and study participants. This is not the case in the new Polish guidelines.Differences between Polish and English guidelines continue with the provision of guidance on pairwise meta-analysis and key prerequisites for data synthesis, such as appropriate population, sample size and validity of evidence by the NICE guide. AOTMiT’s guidelines, in turn, describe the methods for meta–analysis only briefly and in a rather non-instructive manner, referring to external documents such as the Cochrane Handbook .NICE in its guide considers the impact of adverse events on both health effects – measured by Health-related Quality of Life (HRQoL) decrement – and costs, transparently stating that this impact should be included in the cost-effectiveness analysis by accounting for the costs of managing adverse events associated with the technology in question. In the Polish guidelines, however, there is no clear recommendation for including the cost of adverse event management in the cost-effectiveness analysis. Adverse events are considered only in the context of the safety analysis. A summary of the comparison between the AOTMiT and NICE guidelines is presented in The main purpose of this study was to look closely into the nature of the changes introduced during the update of the Polish HTA guidelines, and to benchmark the new guidelines against the NICE guide. The NICE guide was chosen as the reference since, in England, a positive NICE recommendation is critical for securing National Health Service funding for the technology. Moreover, NICE guidelines are often referred to by other countries (including Poland) because of the perceived robust methodology of their review process.The need for updating the HTA guidelines arose from the continuous evolution of HTA methods and other aspects of the process, and appears to have been inspired by both internal Polish HTA experiences and pan-European cooperation . Since tOur results showed a significant number of disagreements between the Agency and MAHs regarding the assessments performed in 2015. These disagreements matched the topics of the guideline update in 14.6% of official documents listing comments from MAHs. This illustrates that efforts made to clarify the potential topics of Agency–MAH disagreement, and to provide more detailed guidance, represent an approach that draws on internal experiences from the HTA process. We analysed only one year out of five that passed since the process of public consultations to AOTMiT’s verification analyses had been introduced, which may explain the somewhat small proportion of disagreements; however, the subject diversity of the identified disagreements led us to consider this sample fairly representative of the various types of issue encountered by MAHs during the HTA process. Although it is safe to say that some potential differences between AOTMiT and MAHs can be avoided thanks to the new, more precise guidelines, it is worth noting that disagreements may still appear, since their source lies in the complex nature of medical conditions and health technologies in question, and the associated difficulties with their assessment. For example, AOTMiT has challenged MAHs’ HTA submissions on grounds such as insufficient number of patients included in the groups of a randomised clinical trial (RCT). In another instance, the Agency challenged the evidence for an assessed technology due to the lack of RCTs. So far, there is no consensus on all the methodological aspects of HTA. In the aforementioned cases, even ideal HTA guidelines would not have prevented the Agency–MAH discrepancies from arising.Our analysis demonstrated that the new Polish HTA guidelines are more in line with the UK HTA standards as represented here by the NICE guide, making a step towards the harmonisation of HTA processes and outputs in Europe – or at least in those countries where HTA is more economically driven , with clinical effectiveness as an important part of the assessment feeding the cost-effectiveness analysis. This could, for instance, mean that it will become easier for MAHs to prepare an HTA submission for a group of countries that share a similar approach to HTA. In Poland, the trend for drawing on external good HTA practices could mean that, in the future, AOTMiT’s recommendations may play a decisive role in the reimbursement of health technologies, similar to the recommendations of NICE in the UK. Nonetheless, recent years showed that positive AOTMiT recommendations were rather poorly associated with positive reimbursement decisions by MoH, agreeing in only 47%, 37% and merely 5% of cases in 2012, 2013 and 2014, respectively .Kolasa et al.  performeSince HTA is an ever-evolving field in terms of the methods, processes and stakeholders, another update of the HTA guidelines is inevitable in years to come. AOTMiT may take example from the NICE guidelines and consider providing reporting templates and other tools to aid the submission of robust HTA reports in the future. Our comparison of the new Polish HTA guidelines and the NICE guide might be biased by arbitrary judgment of what constitutes a ‘sufficient and clear’ recommendation. However, our approach involved two researchers making independent judgments, and reaching a consensus in case of disagreements, which mitigates the bias to some extent. Moreover, we looked at fairly objective measures, such as the provision of reporting templates by the NICE, which facilitates drafting an HTA report, or referral to external documents by the AOTMiT, which may impede straightforward understanding of a particular piece of recommendation. We made common-sense judgements on what meets the requirement for being comprehensive and providing clear guidance  and what displays shortcomings , although not every issue was black-and-white.AOTMiT has been striving for years to advance the HTA process, and the latest update of its HTA guidelines has contributed markedly to that progress. The update is an example of lessons learned from the appeal process. It is expected that there will be fewer discrepancies between AOTMiT’s assessment and MAH’s HTA report in the future, thanks to the more precise and detailed guidance on various areas of HTA such as modelling or indirect comparison. The new guidelines, with their more comprehensive approach, seem to adhere better to the NICE standards, through their improved clarity and level of detail, which is of pivotal importance for an impartial and transparent HTA appraisal, and gives rise to a more meaningful appeal process. Being more in line with HTA standards of countries where HTA plays a decisive role in the P&R process, the new HTA guidelines – as well as the international cooperation with EUnetHTA, coupled with a continuous internal learning process – are expected to result in an overall more transparent HTA process. In spite of the progress made with the recent HTA guideline update, there is still room for future improvements based on external HTA experiences, and, arguably, new needs that could emerge from the ever-evolving HTA process.


Current global changes are putting both biodiversity and the processes that depend on it at risk. This is especially true for semi-arid regions and the flagship groups that inhabit them, such as amphibians and reptiles. Semi-arid regions are often thought to have lower biodiversity and thus have been overlooked, resulting in the underestimation of their biological richness. Therefore, the aim of this study was to conduct an inventory of amphibians and reptiles in the semi-arid municipality of Nopala de Villagrán, Mexico, and analyze its biodiversity in relation to the seasons, vegetation and microhabitat. During a year of fieldwork, we found 24 species in the area, most of them of low abundance, and one of which was recorded for the first time for the state of Hidalgo. We documented five amphibian species and 19 reptile species. We also found that observed species richness was higher in the rainy season and in xeric scrub vegetation, although only the season differences were significant according to rarefaction curves. Our findings highlight the importance of seasonality and vegetation type for the species that inhabit this semi-arid region. This study broadens our understanding of the importance of semi-arid regions and, by extension, that of other areas with similar characteristics. Current global changes are affecting both human societies and biodiversity assemblages, putting many of the ecosystem processes that depend upon biodiversity at risk . BiodivePriority should be given to important species and regions that have been recognized as conservation flagships or are understudied regions for biodiversity. Drylands, such as deserts, semi-arid regions and arid regions, comprise one natural biome that is at risk . The vulDrylands are also of great importance for certain taxonomic groups that are found more commonly in these types of environments . ReptileThe municipality of Nopala de Villagrán is a semi-arid region  in the state of Hidalgo that is located in the Trans-Mexican Volcanic Belt, a highly endemic area where 78.3% of the species of amphibians and reptiles that occur there are endemic . FurtherAlthough some biological inventories that assess amphibian and reptile biodiversity have already been carried out in Hidalgo, they have been conducted mainly in the northern areas due to the natural reserves located there . The munThe aim of this study was to document the biodiversity of amphibians and reptiles in the semi-arid municipality of Nopala de Villagrán, Hidalgo, and to describe the current patterns of biodiversity with respect to the type of vegetation, seasonality and microhabitat. Identifying and describing the distribution of these amphibians and reptiles will make it possible to inform conservation decisions and management strategies for this and other similar regions in Mexico.Our study was designed to determine the diversity of amphibians and reptiles in the municipality of Nopala de Villagrán in the southwestern part of the state of Hidalgo, Mexico , beans, forage oats and agave  vegetation, based on the three types of vegetation found in the municipality ; (2) season (rainy and dry); and (3) microhabitat, based on nine categories modified from To test for differences in species richness for each taxonomic group (amphibians and reptiles) by vegetation  and seasonality (dry and rainy) we performed a sample size rarefaction curve . This apWe made rank abundance curves in the package BiodiversityR  for bothLampropeltis ruthveni  in the municipality of Nopala de Villagrán. The amphibians are grouped into four families and four genera, and the reptiles in six families and ten genera . Among truthveni . The snauerétaro . None ofuerétaro . Furtheruerétaro . At Nopauerétaro ; Table 1uerétaro .The accumulation curve for sampling effort reached an asymptote in the sixth month, suggesting that the number of species encountered remained constant regardless of an increase in sampling effort. The exponential model expected the number of species collected in this study; while the Clench model suggested an additional six species could be encountered in the municipality if sampling effort was increased . FurtherThe highest richness for both amphibians and reptiles was found in the xeric scrub, followed by the oak forest and croplands . HoweverAspidocelis gularis. One species was restricted to the oak forest the lizard Sceloporus scalaris. Finally, the snake Coluber schotti was observed only in croplands . No amphibians were found in the arboreal microhabitat or human areas, and no reptiles were found in the riparian microhabitat.In general, both amphibians and reptiles showed a preference for the terrestrial microhabitat, as all species were found there except the rattlesnake  aquilus . HoweverDryophytes eximia and the frog Dryophytes arenicolor (Sceloporus) were always present in the higher abundances, suggesting that they are dominant in all vegetation types and seasons. Subtle differences existed in the order of dominance of this three species for each vegetation type and the displacement of the lizard S. torquatus to fourth rank by the snake Conopsis lineata in the dry season , which was observed during the fieldwork though no voucher was obtained for species identification (probably A. velasci). Another species that is probably present is the lizard Phrynosoma orbiculare, which has been mentioned by the local people of the town of Nopala. Other species potentially occurring in the study area due to geographic proximity are: the lizard Barisia imbricata, the coral snake Micrurus tener and the rattlesnake Crotalus polystictus . Nevertheless, in both croplands and oak forest a unique species was found for which low abundance did not seem to be the reason for the resulting pattern. Additionally, oak forest and croplands had the lowest similarity (80%). This can be related to unique microenvironmental characteristics of each vegetation type ) or to aed areas . An incrFurthermore, the oak forest had the highest proportion of endemic species as indicated by the Webb index (2.75). Oak forest is known for its importance for endemic vertebrates in Mexico , for whiOur data show that seasonality is an important factor in the richness of amphibians and reptiles. The rarefaction plots showed that the differences in richness were significant and higher for the rainy season for both taxonomic groups . FurtherDryophytes eximia were found in fossorial and decaying trunks, these are not considered typical microhabitats for this species since they have not been reported in other general accounts of D. eximia  a meter above the ground . These four Spiny lizards may be generalists capable of adapting to disturbed habitats, given that they were usually dominant according to our rank-abundance curves in all the vegetation types and seasons (Sceloporus microlepidotus; Dryophytes eximia and D. arenicolor; Most of the species were not found in human areas, except for four species of Spiny lizards (The species reported in this study fill an important geographic gap in our knowledge of amphibian and reptile diversity in the state of Hidalgo, Mexico. The information obtained may be of use in developing a management program for the municipal reserve of Cerro Nopala that was decreed, and thus help preserve amphibians, reptiles and other animal groups. Clearly, additional studies are necessary to better understand the habits of amphibians and reptiles in semi-arid regions, and the impact of humans on them, since these often ignored areas shelter a considerable diversity of amphibians and reptiles.10.7717/peerj.4202/supp-1Appendix S1Click here for additional data file.


Infertility is a disease that results in the abnormal functioning of the male or female reproductive system. Systematic research planning on any subject, including infertility is in need of solid data regarding previous efforts in this field and to identify the gaps in the research.The aim of this research is to study the thematic structure of articles related to infertility. In this descriptive-analytical study with a scientometric approach, the PubMed database was searched for research publications indexed under "Infertility" over the period 2011-2015. Specific parameters were retrieved from the PubMed. Articles about infertility were analyzed regarding the journal of publication, topics, and countries using Net draw, Ucinet and RavarPreMap software. Also, the most influential topics were analyzed by indicators in the analysis of the network: closeness centrality, and between centralityThe growth in scientific productions the area of infertility over the mentioned period shows an upward trend with the highest growths seen in countries like the United States, the UK, Netherlands, China, and Germany. Moreover, the contents such as fertilization in vitro, adverse effects, spermatozoa, pregnancy rate, and treatment outcome were among the most frequently-used topics in the sphere.Thematic analysis can provide us the research topics, important expressions, and the relationships between them. Users and policymakers can also have a better understanding of the research status in the sphere and consequently, they can plan to increase the quantity and quality of scientific productions in a more efficient way. Infertility is an inability that results in the abnormal functioning of the male or female reproductive system . From thResearch on "infertility" is among the areas of expertise where researchers and scholars attempt to improve the current situation. It is critically important to access data on different aspects of the area since they are the most significant resources which will help realize scientific and cultural advancements. Based on different classifications, one of the topics in scientometrics is to study the structure of science and its dynamics. Scientific maps -in the format of graphic figures- can break up diverse scientific areas. They can also represent the relationships between these areas and help to understand the structures of sciences . A scienOne of the suitable tools to study the process of research in specialized areas is to focus on research and scientific articles. In the area of infertility, numerous studies have been conducted and there are many scientific productions in this sphere -9. ThereBased on what was expressed, the current study tries to assess the articles published in PubMed database related to infertility using co-words analysis and also scientific mapping. As a result of this method, different objectives can be met including; topic analysis, scientific decision-making and policymaking, developing this area, implementing further research, and managing knowledge and science. Reviewing texts on co-word analysis and topic clustering reveals that various studies have addressed this issue from a different aspect and have examined various fields of science through this method, Including; medicine , integraReviewing background shows co-word analysis is an appropriate method to map the structure of science and to create thematic maps in different areas. This research seeks to take an analytical approach and identify research areas and thematic maps of infertility on PubMed during 2011-2015 using co-word analysis and analysis of social networks. It also tries to study the growth process in topics for the conducted researches in the area. In addition, this study will introduce the countries and Journals that produced documents on PubMed database in infertility area.The current research is of the descriptive analytical type which deals with the thematic analysis of articles with a scientometric approach. The search for articles to be included in this study was carried out on December 2016, using the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed). PubMed was chosen because it is the most widely used database in medicine. The search strategy was the following: "Infertility [MH] AND journal article [PT] AND 2011:2015 [DP]" where MH stands for “Medical Subject Headings,” DP “Date of Publication”, and PT “Publication Type” “Journal Article” includes the following publication types: journal articles, introductory journal articles, and reviews. MeSH is the National Library of Medicine’s controlled vocabulary thesaurus and consists of sets of terms named “MeSH terms” arranged in a hierarchical structure  with more specific terms arranged beneath less specific terms. In other words, due to the fact that required data were gained on PubMed database by searching the heading mesh; validity and reliability of the instruments used in this research are confirmed. After retrieving data, at first, bibliometric methods were applied to find the distribution of the publications within years, the name of journals, and countries. At the second stage all the articles were extracted , the keyword yielded from articles were introduced in PubMed were smoothed with check tags and stop word lists. For instance, adult, animal, child, etc. which were among the check tags were eliminated from keywords. The keywords which were not of contexts  eliminated from descriptors. In the next stage: based on Bradford's law, as many as 76 keywords with frequencies of more than 202 were identified and selected as keywords. These keywords were taken as the main concepts based on which further analyses of the research would be implemented. Following identification of basic topics, the symmetrical co-occurrence matrix of the topics was created using RavarPreMap software. The symmetrical co-occurrence matrix is a square which shows a topic is common with other topics in how many articles. The number of rows and columns in this matrix are equal the number of selected concepts. Moreover, every entry in the matrix resembles the number of times when two keywords for a row and column appear in the same document. Therefore, such matrix is a symmetrical one. The entries on the main diagonal of the co-occurrence matrix equal the total number of frequencies for that keyword in the document. Analyses of data yielded from the maps were completed using formed co-occurrence matrix and also through thematic mapping in the area using Ucinet and Netdraw software. The crucial indicators in the analysis of the network are classified into three categories: closeness centrality, betweenness centrality, and degree centrality.Degree centralityIt is considered as the simplest type of centrality where the value of each node will be calculated by counting the number of its neighbours. The number of neighbours is yielded based on the connectors which adjoin the node. Such measure is defined by the number of direct connections in an operator. The degree centrality of node k (pk) is calculated through the following formula:Betweenness centralityThe betweenness index of a node is the number of times the node is located on the shortest possible distance between two other nodes in the network. The nodes with high betweenness play a crucial role in connecting the networks and have a pivotal status in the network. They also play an important role in the flow of information across the network. The centrality betweenness indicator k (pk) comes from the following formula:Closeness centralityCloseness centrality of a node is the average length of the shortest distances between the nodes of a network. The nodes with higher closeness index are more effective in the network and play a more pivotal role while they are more accessible to other nodes. The closeness index of the node k (pk) will be calculated by the following formula:Statistical analysisAnalysis of social networks was carried out by UciNet software 6. It contains network analytical tools, such as centrality measures and so on. Integrated with UCINET is the NetDraw program which was used to draw thematic maps. Descriptive statistical analysis of the data was done using Excel to draw charts.In total, we found 6424 articles in the field of infertility indexed in PubMed through 2011-2015. About 29.04% of PubMed papers were concentrated in five journals; Fertility and Sterility, Andrologia, Journal of Assisted Reproduction and Genetics, Human reproduction, and Reproductive biomedicine online.Bibliometric analysisThe most frequently-used words or the most active research fields in this area over the period 2011-2015 were identified using Bradford's law. Considering the fact that keywords are considered as indicators and can highlight the topic, Bradford's law shows the thematic distribution of the articles. Based on Bradford's law, keywords are classified into three types: core, close to the core, far from the core. The first and the second types were identified as the most frequently used in this research including 239 Key words in this section, in order to refrain from making the diagram overcrowded and to help the keyword tags represent efficiently; only 10 frequently-used keywords  were takAccording to Thematic analysisTo prepare the for the analysis of social networks used UciNet software 6. It is a comprehensive package for the analysis of social networks. It contains network analytical tools, such as centrality measures and so on.Integrated with UCINET is the NetDraw program that used for drawing diagrams of social networks.Of articles related to infertility, the entire articles extracted from PubMed were processed and then as many as 5,911 keywords were yielded. It is expected that there are averagely at least five keywords in each article. Since the keywords might repeat in multiple articles, the number of keywords would decrease but the frequency of keywords would increase. Of all the keywords processed, the ones with high frequencies were taken and then the co-occurrence map between these keywords was established. In order to yield a more efficient analysis of co-occurrence word network of infertility articles, the frequently-used keywords with closeness centralities other than zero were identified and co-word maps were prepared for them, which can be seen in The results achieved by analyzing closeness centrality in studied articles suggest that thematic topics can be divided into three groups: first, topics such as "fertilization in vitro, adverse effects, assisted reproductive techniques, follicle stimulating hormone, etc." with closeness centrality of 74.000; sec, topics like "embryo implantation, reproduction, pregnancy rate, etc." with closeness centralities of 75.000; and third, "body mass index, oocytes, semen analysis, etc." with closeness centrality of 76.000. Betweenness centrality measures the percentage of the number of shortest distances in a network that pass through the relevant node. If the value of betweenness centrality is less than 0.1, the node has no role. But if the value exceeds 0.1, then the node is the turning or central point. High values of betweenness centrality in scientific maps represent the value of the node. For instance, if a node links two irrelevant clusters, it is of great value in terms of betweenness centrality and if such a valuable node is eliminated, information flow might be interrupted in a network . The results from analysis of betweenness centrality show that thematic topics such as "fertilization in vitro, adverse effects, assisted reproductive techniques, follicle stimulating hormone, etc." (The pink circles) with betweenness centrality of 4.112 are ranked first, followed by others such as "spontaneous, abortion, and more," with betweenness centrality of 3.999, and finally spermatozoa with betweenness centrality of 3.979. In fact, the mentioned keywords have formed the shortest possible distance between the two nodes. As Price mentioned in his 1963 book “Little Science, Big Science”, the number of scientific papers doubles every fifteen years. Such a growth in volume cannot be attributed just to one factor. Therefore, it can be concluded that such growth “is a part of scientific nature” . et al in assessing life cycle .This study provided an alternative perspective to the global research trends in infertility studies during the period 2011–2015. Co-word analysis method enables us to represent the structure of internal and external relationships between thematic factors in an objective manner. This can aid us in recognition of the structure of thematic relationships in any area. Therefore, using the results yielded from this research can help us present clear and satisfactory analyses on current situation, research topics and their relationship, and important expressions in the area of infertility. Moreover, users and researches can have a better understanding of thematic and scientific situation in this area and establish directions for further research. We must, of course, take this limitation into account that studied data are from PubMed database. Searching other databases such as Scopus or Web of Science may lead to different results. However, MeSH headings are only available through the MEDLINE and PubMed interfaces. In addition, performing similar researches using other scientometric techniques such as citation analysis, studying co-authorship and creating scientific maps can act as a complement this research.