Quantitative modelling is commonly used to assist the policy dimension of sustainability problems. Validation is an important step to make models credible and useful. To investigate existing validation viewpoints and approaches, we analyse a broad academic literature and conduct a survey among practitioners. We find that empirical data plays an important role in the validation practice in all main areas of sustainability science. Qualitative and participatory approaches that can enhance usefulness and public reliability are much less visible. Data-oriented validation is prevalent even when models are used for scenario exploration. Usefulness regarding a given task is more important for model developers than for users. As the experience of modellers and users increases, they tend to better acknowledge the decision makers’ demand for clear communication of assumptions and uncertainties. These findings provide a reflection on current validation practices and are expected to facilitate communication at the modelling and decision-making interface. Credibility of long-term projection in quantitative models is continuously under debate and they rely on validation to prove projection accuracy. Here the authors investigated the views on the validation approaches and they show that empirical data plays an important role in the validation practice in all main areas of sustainability science. A broad range of models, including integrated assessment models, impact assessment models, environmental models, systems models, and so forth, address resource management problems in various areas related to sustainability, from ecosystems to energy systems. Some of these models have a prescriptive stance, generating recommendations for action. Others aid decision-making in different ways, for example with long-term projections, while capturing the complexity of various physical, economic and social factors. Standing at the intersection of environmental science, economics and decision sciences, such modelling studies have resulted in influential applications, such as the large modelling framework used by the European Commission for the impact assessment of energy and environmental policies7; that the methods used to deal with uncertainties are often inadequate or unsuitable10; that models routinely extrapolate past data as if it is a good estimate of the future12; and that models usually have a limited scope, and often omit relevant and important processes13.The credibility of long-term projections generated by quantitative models has been the topic of a heated debate. Several critiques in the academic literature and popular media outlets highlighted that models are typically used as if they are precise predictors, and uncertainties are ignored15. In environmental modelling, validity is often used to indicate that model predictions are consistent with observational data, or that the model is an accurate representation of physical reality, or both18. In this study, based on the dictionary meaning of valid as well-grounded and justifiable19, we use the term validation as a general process of evaluating a model’s performance and suitability for its intended use. We do not refer only to the representation accuracy, but we imply establishing confidence in the model by employing a variety of assessment tools.Validation is the modelling step commonly employed to deal with such criticism and to establish a sound grounding for models at the science-policy interface. The definition of validation is equivocal across different scientific fields. In decision sciences, validation usually implies establishing confidence in the model by judging its usefulness with respect to some purpose21. Being rooted in logical empiricism, which argues that knowledge is acquired by observational data and the interpretation thereof through logic and reason, positivist validation approaches focus on an accurate representation of reality and employ statistical tests to compare the model output and the data. The positivist viewpoint on validation reflects the practice in natural sciences. Alternatively, the relativist view on validation originates from the challenge Thomas Kuhn posed on the objectivity assumption in positivism, that is, scientific knowledge is relative since it depends on the paradigm prevalent at the time of a study. The relativist validation approaches value the model usefulness, for instance in the sense of fitness for purpose, more than the representation accuracy and employ semiformal and conversational tools.These different connotations to the term validation stem from different philosophies of science. Positivism and relativism are often stated as the two distinct philosophies of science underlying the validation viewpoints21. Practitioners often acknowledge the value of both, and employ a combination of multiple validation techniques accordingly. In the environmental modelling domain, validation is seen more from a positivist viewpoint. An extensive body of work is devoted to developing, advancing and compiling data-oriented techniques to ensure data and behaviour validity25. Still, many studies suggest integrated frameworks that assess conceptual and methodological validity along with data and behaviour validity29, and some studies offer qualitative frameworks and participatory approaches to involve stakeholder views, and hence to enhance the extent of public trust in modelling studies32.In decision sciences, economics, and management science, validation approaches cover both of these philosophical viewpoints37. The modelling paradigm referred to as exploring multiple plausible futures avoids predicting a best-estimate or probabilistic future for situations where a single reliable model cannot be consolidated and appropriate probability distributions cannot be elicited38. In this paradigm—also named exploratory modelling41—models are used as heuristics to guide decision making. In particular, they are used in computational experiments that link various, sampling-based alternative realisations of uncertain model inputs, that is, parameters, functions or structures, to model outputs. Each computational experiment corresponds to a what-if scenario, hence the model actually generates a large ensemble of exploratory scenarios. Such scenario ensembles can be used to elaborate decision heuristics by, for example, specifying the decision objectives and searching for the most salient scenarios. Therefore, such scenario ensembles can be highly promising for future decision support42. In such alternative paradigms, representation accuracy plays a less important role in validation, because the representation of the system is expected to be uncertain, and validation does not aim to reduce this uncertainty.Conventional validation approaches that aim to ensure that models reflect reality with appropriate accuracy support a modelling paradigm that tries to predict a best-estimate future by reducing the uncertainty in future projections. However, they may not align well with alternative paradigms that urge a stronger acknowledgement of uncertainties in modelling, analysis and communicationThis study investigates existing viewpoints on and approaches to general model validation practice, and when models are used specifically for scenario generation to explore multiple plausible futures. The underlying motivation is two-fold. Firstly, we expect to provide model developers and users with reflections on and insights into their practice. Secondly, the information about existing validation viewpoints and the factors that affect them can facilitate communication at the interface between modelling and decision making. With better communication, the parties can further elaborate on the requirements for a model’s validity and its contribution to decision-making.To get an overview of the concepts and viewpoints governing the model validation practice, we examine a broad academic literature using text-mining tools. We employ two datasets of publications focusing on validation. The first one contains publications from various fields with model validation in their keywords, while the second dataset, being a subset of the first, includes scenario as a keyword, too. (See Methods section for the specification and sizes of these datasets.) The first observation on this body of literature is that the number of model validation publications has significantly increased over time, hence the weight of recent publications in our dataset is higher. However, only a small fraction <1%) of modelling studies focus on validation explicitly regardless of time.  method47 that addresses equifinality and accepts multiple models as valid based on statistical inference. However, the use of such approaches have remained limited to producing uncertainty intervals around the average model output48.Validation in the general modelling context: The survey questions on model validation primarily address the representativeness and usefulness views on validation. The representativeness view is based on positivism, yet a purely positivist validation based on observational data is argued to be impossible50. Policy problems require a comprehensive critique of the scientific enquiry rather than a purely rationalist one, for instance to include practical and ethical concerns51. Therefore, using models as heuristics can provide a broader and multidimensional view on policy problems. It can assist the formulation of alternative policies which can deal with various and often unexpected situations. It also allows experimenting with different value systems of stakeholders, especially in participatory settings with citizens where models are used as metaphors to identify implicit norms affecting a policy problem52. Therefore, this way of using models has potential implications for consensus building. A model can be used in several other alternative ways, from data condensing to training users for a particular behaviour49. Therefore, a model that can provide benefits for any of such purposes would be considered useful.The impossibility of an accurate representation and projection leads to the usefulness view in validation, where usefulness can be defined as how well a model fits for a given purpose. Many scholars object to using models for prediction in the first place, and argue that they should rather be used as heuristics to enhance understanding and guide decision-makingThese fundamental issues have been discussed for decades, yet they are still the main topics of debate, especially for models that cannot be limited to physical systems and a natural sciences perspective due to the involvement of human and decision-making factors. Therefore, the dichotomy between representativeness and usefulness, the role of empirical data in validation, and the view of decision-makers on validity, are the key dimensions we consider while investigating the existing viewpoints on validation.n = 164) show that practitioners value both the usefulness and representativeness of a model. Seventy-nine percent of the respondents agree or strongly agree that the most important validity criterion is usefulness, while 67% think that it is representativeness . About one third of the respondents agree and another one third disagree that validity cannot be linked to the replication of the past since multiple models can achieve this (Question 4), indicating an absence of consensus about the equifinality principle in validation. A large majority (69%) responds negatively to Question 5, implying that they support the usability of models for prediction purposes. These viewpoints about the role of data are not dependent on the background of the respondents. Overall, these findings indicate that objections to relying on data-oriented validation approaches due to the impossibility of a purely positivist validation have not been widely reflected on the practice.Concerning the view of decision-makers, e.g., the clients of models, on model validity (Questions 6–8), most respondents (62%) think that decision-makers find a model credible if it replicates the historical data, and if the assumptions and uncertainties are communicated clearly (65%). Decision-makers’ interest in comprehensiveness and detailedness of the model receives a weaker, yet significant acknowledgement (48%). Therefore, practitioners think that data-driven validation is demanded by decision-makers, and they acknowledge the call for clarifying uncertainties and assumptions, which can be considered as best-practice in contemporary modelling. The acknowledgement of the communication of uncertainties and assumptions depends on experience level. Surprisingly, more of the respondents with moderate experience (2–10 years) disagree with this statement, compared to the respondents with very short and long experience  as in data-driven validation, or based on the scenario ensemble (Question 4), following a brief information about the terms ‘baseline scenario’ and ‘scenario ensemble’. 32 and 33% of respondents agree and disagree, respectively, with validation based on a baseline scenario, indicating discordant views. The scenario ensemble option receives 34% agreement, much higher than disagreement (14%). Still, most respondents are neutral about the use of scenario ensembles in validation, which may be due to unfamiliarity or ambiguity of the concept. The last two questions compare the importance of model output and structure for validation (Questions 3 and 5). Seventy-nine percent of respondents disagree with the relative importance of model output, therefore it can be said that the respondents do not favour an output-focused validation over a structure-focused one when the model purpose is scenario generation. Most respondents who disagree with the output being more important agree or remain neutral about the structure being more important 64. In an LDA implementation, the user specifies the number of topics (bags), and then the algorithm probabilistically allocates each document to one of these bags to a certain extent. This extent signifies the topic probability of a document, and depends on the frequency of a document’s words in each of these topics. In other words, the topics are not necessarily mutually exclusive in terms of the documents and words they include. Resulting from this process, LDA forms document-topic and topic-word pairs based on the words included in each document.To identify the main concepts and themes in the literature, we employed a text-mining tool called topic modellingThe results in this paper discuss the topic contents based on the topic-word pairs. The topics are named based on the most defining, i.e., the most frequent, words in them. For instance, if a topic has water, soil, crop among the 50 most frequent words visualised in a word cloud, we name it Agriculture and Hydrology topic. The topics include many words in common, yet such common words occur in them with different probabilities and with a different set of neighbouring words. Supplementary Table For the preparation of data, we removed all general stopwords from the abstracts prior to the text-mining analysis, as well as the words that do not have any significant meaning in this particular case, such as model, validation, research, analysis etc. We also stemmize all the words, meaning that the words with the same root, for instance calibrate and calibration, are considered the same.To disclose individual views on the topics widely discussed in the validation literature, we employed a short online survey circulated among researchers and policy analysts in academia, policy organisations and industry. The survey contained three groups of questions about validation in general, and about scenario generation in particular. The first group of questions was about the organisational background, modelling experience, role and area of the respondents. For the organisational background and the modelling area, respondents could choose multiple options. The second group of questions contained a set of statements  reflecting the published viewpoints and issues, and asked to what extent the respondents agree or disagree with these statements This group also involved a question about the validation techniques used in the studies the respondents have been involved in. The last group of questions was about the validation of models specifically used for scenario generation. A set of statements were provided for Likert scale questions, and an additional question was asked about the prioritisation of scenario attributes important for a model’s validity.For organisational background, the respondents were allowed to choose multiple options from Academic/Research Institute, Industry, Governmental policy organisation, Non-governmental policy organisation or None. Modelling experience asked for how many years the respondents have been involved in modelling or model-based studies. For the modelling role, the respondents were asked if they consider themselves model developers (with hands-on model building activities), model users , with both of these roles, or none of these roles. For the modelling area, the respondents could select multiple options from a pool of research areas from energy to population dynamics.65, were taken into account. To establish a common understanding, the survey included prior information about the modelling context, the definition of validation, philosophical roots, and the terms such as baseline scenario and scenario ensemble. Recalling a question with a different formulation is employed for the questions that require a comparison, such as representativeness vs. usefulness and the model output vs. structure. We used a continuum of 5 options on a Likert scale from Strongly Disagree to Strongly Agree.The survey questions were prepared by the authors based on the literature discussed in the first two sections of this paper. The factors important in survey design, such as a common understanding, recalling the questions, and specifying what is to be rated and the continuum of ratingIn survey design, we unavoidably had to balance several trade-offs, especially because the modelling domain is very broad, and the views are very diverse. For instance, we intended to keep the survey as short as possible so that the respondents would not have to spend a long time. Due to this, we avoided long explanations and more questions. We also kept the questions general in order to suit to a wide variety of modelling backgrounds. We included a comments section, where the respondents could share their opinions in a more elaborate manner either on the subject or on the survey design. We assessed the survey questions, especially their understandability, in a pilot run among a small group of researchers, and revised them according to the feedback we received.The survey was circulated among the professional networks of the authors via emails and social media, and the responses were collected over a two-month period. One hundred and eighty-eight responses were collected in total, and only 164 of them are included in the analysis since the rest did not answer the validation-related questions. Only 6 of the 188 respondents have mentioned in the comments that they had difficulty to understand some questions, and chose the neutral option as a response.No personal data is collected in this survey, and all the responses are recorded anonymously. The respondents were informed about the potential use of their responses in scientific publications.https://www.surveymonkey.com/r/IIASA_validation.The entire list of questions can be seen at We investigate whether the responses to the Likert scale questions, hence the validation viewpoints, are dependent on the background of respondents recorded in the following three dimensions: Modelling role , experience with modelling , and organisational background .The statistical tests of independence we conduct are based on contingency tables for each question and the background factor. These tables are composed of the number of responses (observed frequencies) given to each Likert score. Table 66, which is often the case in our data. Fisher’s Exact Test calculates the p-value for the null hypothesis of independence, based on a hypergeometric distribution of which the parameters are the observed frequencies in the contingency table. In particular, we use the software implementation of the Fisher Test in the R package stats67 (with Python interface) to calculate the p-values. For tables larger than 2 × 2, this calculation is computationally intense, which is why we use a Monte Carlo approximation with 108 simulations. We reject the null hypothesis, and hence claim that the responses are significantly dependent on the background factor, for p < 0.05. Such p-values are not obtained for the questions on scenario generation. Therefore, we use p < 0.1 only to mention a potential relationship, not to claim dependence, as in the case of the effect of experience level on the responses to Question 1.Although the chi-squared test is usually used to test the independence of two variables of classification, Fisher’s Exact Test is suggested for cases when expected frequencies are less than fivep-values are presented in the Supplementary Tables The resulting https://github.com/sibeleker/Validation_Perspectives, or available from the corresponding author upon request.This study uses custom computer code written in Python for the text-mining of academic publications, and to analyse the data collected from the survey. All the scripts (IPython Notebooks) can be accessed on Supplementary InformationPeer Review FileDescription of Additional Supplementary FilesSupplementary Data 1


Despite the ever-increasing numbers of mental health patients presenting to United States emergency departments, there are large gaps in knowledge about acute care of the behavioral health patient. To address this important problem, the Coalition on Psychiatric Emergencies convened a research consensus conference in December 2016 consisting of clinical researchers, clinicians from emergency medicine, psychiatry and psychology, and representatives from governmental agencies and patient advocacy groups.Participants used a standardized methodology to select and rank research questions in the order of importance to both researchers and patients.Three working groups  reached consensus on 26 questions within their respective domains. These questions are summarized in this document.The research consensus conference is the first of its kind to include non-clinicians in helping identify knowledge gaps in behavioral emergencies. It is hoped that these questions will prove useful to prioritize future research within the specialty. Emergency departments (ED) across the country are increasingly a point of care for patients with acute mental and behavioral health needs. From 1992–2001, approximately 53 million visits to United States (U.S.) EDs were due primarily to mental health concerns.Since the 1994 Macy report, promotion of research within emergency medicine (EM) has had a number of successes, including the successful establishment of the Emergency Medicine Foundation.10Given that EDs now provide the majority of care for patients who are admitted,To address this need, the CPE convened a research consensus conference with experts from both psychiatry and EM. Unlike previous consensus conferences in this area, which included only clinicians and/or research scientists,23The objectives of the conference were to highlight and prioritize areas of greatest research need within selected domains of emergency psychiatry while taking the patient perspective into account, and then to summarize these recommendations into consensus documents.CPE includes over a dozen professional organizations, patient advocacy groups, and systems of care,This structured expert consensus conference was held December 7, 2016. The overarching question of the conference was to investigate whether early treatment might positively affect outcomes for patients with mental health crises,17The 35 participants in the conference were sorted into working groups by self-identified interest and expertise. While participants each worked in a single group, they were able to provide feedback and comments on the priorities identified by other working groups both during the conference and after. Each workgroup appointed a moderator who conducted the consensus building during the conference (see below), and a group leader who identified relevant articles prior to meeting in person. Each participant was provided with these articles and was free to contribute any additional articles desired.Consensus building on research questions within each domain was accomplished by use of the nominal group technique in person.Specific research ideas, questions, and question variants were voted on in person using the dot method. Questions that received more votes were deemed to be more important, and thus were ranked more highly within each domain. As research on behavioral emergency questions are of importance to industry, representatives of pharmaceutical companies were permitted to attend. However, those representatives were not allowed to vote on the final wording or rank order importance of any question.At the end of the conference day, all groups presented their research questions to all stakeholders. Stakeholders from other priority domains were permitted to ask questions or make clarifying points, but were not permitted to vote on any research question. After the conference, each group was allowed to form additional consensus on the final form of each question in any manner desired, typically by email. However, stakeholders from other priority domains were not permitted further opportunities to revise or edit these questions.Identification of relevant stakeholders  was accomplished primarily by a web search for publications in each particular domain. The search strategy was not conducted with formalized keywords, but identified stakeholders were expected to have either one or more publications in the relevant domain or have given lectures in this area at a national conference. As this method of identification would be expected to weight the participant list most heavily towards researchers, clinicians with relevant interest and expertise were also identified by member organizations on the CPE steering committee. Individuals representing patient advocacy groups and governmental agencies, also nominated by member organizations on the CPE steering committee, were included in order to create a robust and diverse set of expert opinions. The inclusion of non-clinicians and non-clinical researchers was an important difference between this conference and previous conferences of this type.A total of 35 stakeholders , including 13 non-clinicians, with an average of 17 years in their relevant fields participated in the consensus conference. The research priorities identified by each working group are listed more fully in the accompanying articles. However, the following themes emerged from the conference and had consensus from both the participants in each group and non-group stakeholders. With regard to geriatrics, more research is needed on identification, screening, and management of older adults at risk for worse outcomes because of behavioral emergencies.With regard to substance use, more research is needed on screening and intervention for substance use in the ED.31Despite initial agreement on some important questions by the suicide workgroup during the conference, this working group was unable to agree on the final format of research questions after the conference. Consequently, although the expert participants recognize the importance of suicide-related research to both patients and families, no key research questions are available from this group.Summaries of the most important recommendations from the working groups are outlined below.Tables 1More research is needed in the area of acute mental and behavioral health disorders in order to care for patients in the acute care setting more effectively. This research consensus conference, organized by the multi-disciplinary Coalition on Psychiatric Emergencies, was the first of its kind to build consensus from a group with diverse expertise and experience to prioritize research goals in four domains within mental health and behavioral emergencies. Continued consensus building among diverse stakeholders in this field should be an ongoing priority, as research in these domains has implications for both practicing medical personnel and the individuals in their care.


To assess pediatric clinical nutrition research by analyzing clinical studies in the Middle East (ME) and globally.ClinicalTrials.gov, the numbers of clinical studies in the ME and globally were analyzed.Using The majority of clinical nutrition trials are in North America and Europe. The ME accounts for 4% of all nutrition trials. The majority of pediatric nutrition studies in the ME are in the later phases or are observational and/or epidemiological studies with a focus on poor nutrition or nutrition disorders. Industry funding in the ME is mostly by regional or local companies; few major global companies are involved.The ME is not well represented in clinical nutrition studies involving children. Effort should be expended to rectify this. Nutritional disorders have become an important worldwide disease burden during the last several decades. The development of effective therapies for nutritional disorders requires clinical trials in the affected populations. Our results showed that although the Middle East currently has the highest proportion of children worldwide, it is not well represented in clinical trials on nutritional studies in children. Furthermore, there is suboptimal funding from the multinational nutrition industry. This analysis indicates that there is a reasonable rationale for inclusion of the Middle East in nutritional clinical research in children, and that there is an untapped opportunity for the expansion of clinical research in this region. Nutritional disorders and undernourishment are important health problems globally, although the disorder spectrum and underlying root causes can vary considerably according to the level of development of the country . While mPrevention, diagnosis and treatment of nutritional problems arising in childhood are important as these conditions can lead to profound and irreversible developmental problems . The higAlthough the causes of poor nutrition and its consequences have been investigated in various geographical regions , the degClinicalTrials.gov is a database of privately and publicly funded clinical studies conducted worldwide, and is the world's largest publicly available clinical trials registry and results database [ClinicalTrials.gov, we identified ongoing clinical nutrition trials in the ME according to region, country, age group, funder and phase. Countries were assigned to regions according to the ClinicalTrials.gov database, and the searches were conducted during the fourth quarter of 2017.database . Currentdatabase . The Wordatabase ,12. UsinClinicalTrials.gov was searched using the advanced search function. All medical conditions containing words relevant to ‘nutrition’ were included in the search terms . The age group from birth to 17 years old was selected as the eligibility criterion for inclusion, and adults (18–64) and older adult (65+) populations were excluded where necessary. Studies for both male and female sexes were included. All study types, interventional, observational (including patient registries) and expanded access studies were analyzed. All studies with or without results were included regardless of the recruitment status. Additional analysis criteria were funder type  and study phase . Cyprus, Iran, Iraq, Israel, Jordan, Kuwait, Lebanon, Oman, Qatar, Syrian, Turkey, United Arab Emirates and Yemen with at least one study listed in ClinicalTrials.gov, were categorized in the ME region and were included in the search for the ME.ClinicalTrials.gov was the first online registry for clinical trials and is the largest and by far most widely used, it is not the only registry for clinical trials. Therefore, it is expected that not all nutritional studies, but the vast majority of such studies are registered at ClinicalTrials.gov. In addition, some countries do not strictly require clinical trial registration, but strongly encourage it. Therefore, it is possible that some nutritional studies are not listed in any of the registries. Finally, some trials, although registered, could have been reported in an imprecise or incomplete manner and therefore may not appear under the appropriate category in the registry for analysis.Although First, we investigated the regional distribution of clinical nutrition trials. Around three quarters of all ongoing nutrition clinical trials are in North America and Europe  and one quarter in the rest of the world  . The ME Second, we investigated the distribution of clinical nutrition studies involving children. Despite the high proportion of children in the ME, the proportion of clinical trials was low (4%), similar to total nutrition clinical trials in the ME (4%) . FurtherEarly phase interventional studies are conducted more frequently in developed regions; developing countries are generally included in later developmental phases. Only one Phase I trial is being conducted in the ME; the majority are at later phases or are observational or epidemiological . FurtherWe also investigated the medical conditions targeted by the ongoing clinical nutrition trials in the ME. Poor nutrition or nutrition disorder studies predominated  in the ME, followed by metabolic disorders, anemia and allergy studies .Next, we analyzed the sources of funding  for clinical nutrition studies. Industry is sponsoring fewer pediatric nutrition studies relative to total nutrition studies both globally (14 vs 26%) and in the ME (16 vs 31%) A. The hiThe feasibility of a particular country or region for inclusion in a clinical study has well-defined clinical, regulatory, technical and operational components . The avaThe ME has the youngest population in the world and a high incidence of nutritional disorders, mostly due to poor health awareness . We inveSelection of a country for inclusion in clinical studies is dependent on the patient pool as well as the Good Clinical Practice (GCP) laws and regulations, the number of feasible sites, and the availability of qualified and experienced investigators . It has Our results showed that, globally, the largest number of studies are at Phase II, followed by Phase III, Phase IV and Phase I. This is similar to the situation regarding other therapeutic areas, as Phase II is a bottleneck in product development ,20. Few Next, we investigated the medical condition targeted by the ongoing clinical studies in the ME. Despite the low socioeconomic status and poor nutritional awareness in certain parts of the region, the proportions of studies on poor nutrition and nutritional disorders were identical in the ME and globally . Studies on metabolic disorders, anemia and allergy comprised a minor proportion of those ongoing in the ME. Furthermore, there was no difference between the ME and the rest of the world in terms of the proportion of trials on poor nutrition and the rates for both were considerably high . This result was expected as there was marked emphasis on studies on poor nutrition due to an increased awareness of their importance. It has recently been reported that poor nutrition is not only detrimental for the early stages of life but also for midchildhood (5–9 years) and adolescence (10–14 years) [According to Day and Jackson, the nutrition industry plays a fundamental role in transforming clinical research into new products and is a key partner for driving clinical nutrition studies . TherefoIn summary, the majority of ongoing clinical nutrition studies involving children are in North America and Western Europe; far fewer are being conducted in the ME, despite its high proportion of children. In the ME, the majority of ongoing clinical nutrition studies involving adults and children are in Israel, Turkey and Iran. Ongoing studies in the ME are predominantly at later phases or are observational and/or epidemiological studies of nutrition disorders or poor nutrition. The level of nutrition-industry funding for clinical nutrition studies involving children is lower than that for studies involving adults both in the ME and globally. Few major nutrition companies are funding clinical studies in the ME.Due to the high proportion of children, high birth rate and high prevalence of poor nutritional status, countries in the ME are suitable for conducting clinical nutrition studies in children. Realization of this potential would have positive ethical, medical and marketing implications for the region, and the nutrition industry will be likely to play an important role in achieving this through funding activities.The clinical development arena is highly competitive when it comes to timely recruitment of subjects for clinical studies. Designing a sensible clinical study with tight timelines requires careful consideration of the worldwide distribution of patients with the disease of interest and the number of competing studies for the same population in a specific region. A high proportion of children combined with high prevalence of poor nutritional status make the ME a suitable place for conducting clinical nutrition research in children. Fast adoption of the ICH-GCP guidelines, increasing the number of qualified investigators and improving the operational infrastructure will all be equally important in the realization of this potential. The nutrition industry is likely to play an important role in achieving this through its funding. This analysis is an example of how we can best utilize the clinical trial registries to identify opportunities, thereby optimizing clinical studies and increasing the efficiency of clinical development. We envision that such analyses will be valuable in the future and will potentially be of benefit to both nutritional and pharmaceutical industries.Nutritional disorders and undernourishment are becoming important health problems globally, necessitating the development of effective therapeutic measures supported by clinical research.Our analysis showed that the majority of nutritional clinical research is conducted in North America and Europe, with all remaining regions, including the Middle East (ME), accounting for about one quarter of all studies.Despite its relatively high pediatric population and high prevalence of malnutrition, the ME is not currently well represented in clinical studies for the pediatric population.The condition spectrum of investigations in the ME is strongly predominated by poor nutrition or nutrition disorder studies.For the ME region, industrial funding relies strongly on regional or local companies, with only limited participation of international nutrition companies.We concluded that there is an important opportunity for expansion of nutritional clinical research in the pediatric population in the ME, which can possibly be driven by the multinational nutrition industry.


The cholera outbreak in Yemen has become the largest in the recent history of cholera records, having reached more than 1.4 million cases since it started in late 2016. This study aimed to identify risk factors for cholera in this outbreak.A case-control study was conducted in Aden in 2018 to investigate risk factors for cholera in this still-ongoing outbreak. In total, 59 cholera cases and 118 community controls were studied.The following risk factors were associated with being a cholera case in the bivariate analysis: a history of travelling and having had visitors from outside Aden Province; eating outside the house; not washing fruit, vegetables, and khat  before consumption; using common-source water; and not using chlorine or soap in the household. In the multivariate analysis, not washing khat and the use of common-source water remained significant risk factors for being a cholera case.Behavioural factors and unsafe water appear to be the major risk factors in the recent cholera outbreak in Yemen. In order to reduce the risk of cholera, hygiene practices for washing khat and vegetables and the use and accessibility of safe drinking water should be promoted at the community level.  Vibrio cholerae. It is considered to be laboratory-confirmed when V. cholerae O1 or O139 is detected in any patient’s diarrhoea or vomitus. The first cholera pandemic began in 1817, and the current (seventh) pandemic started in 1961in Indonesia and is caused by the El Tor biotype. After starting in Indonesia, it spread to Asia, Africa, Europe, the Middle East, and Latin America [Cholera continues to be a significant public health problem in many developing countries. It manifests as an acute watery diarrhoeal disease, and it is mainly transmitted through the faecal-oral route by contaminated water or food. The disease is caused by the bacterium Yemen is situated in southwest Asia on the Arabian Peninsula. The country has a diverse topography, with mountainous areas in the north, desert in the east, and a coastal landscape in the south and the west. The country is divided administratively into 23 governorates (provinces) and 333 districts. The population of Yemen is more than 30 million as of 2017 .The emergence of the armed conflict in March 2015 in Yemen has exacerbated the already critical economic, political, and humanitarian situation that had prevailed for more than a decade. Approximately 4 years into the conflict, the country’s GDP has contracted by more than 42%, and the humanitarian situation has been further aggravated by increased fighting, population displacement, the lack of basic commodities and services, and an accompanying overall breakdown of public and social services [The occurrence of epidemics, especially cholera, is known to be an obvious sign of the disruption of basic services . SeveralThe war in Yemen has left 18.8 million people in need of assistance or protection, including the need for access to safe drinking water and sanitation, and an estimated 14.8 million people have no or limited access to basic healthcare. Moreover, there is a chronic shortage of medical supplies, and about half of the health facilities are no longer functional . Public The cholera outbreak in Yemen is the largest in the recent history of this disease. The magnitude of this outbreak can probably be explained by the overall breakdown of public services, including hygiene and sanitation, associated with the war in Yemen. However, evidence on specific risk factors is needed to guide an appropriate public health response. This study aimed to identify such risk factors for the recent large cholera outbreak in Yemen.Catha edulis) is a flowering plant that grows in the horn of Africa and in Yemen. It is socially accepted in Yemen, and its green leaves are regularly chewed by the majority of people and used as a cognitive stimulant. The amphetamine-like alkaloid cathinone in khat is known to cause excitement, loss of appetite, and euphoria [Khat . Further inclusion criteria were being a resident of Aden and age ≥2 years because cholera is not common in children younger than 2 years [This case-control study was conducted from April 1 to 30, 2018. A case was defined as any person suffering from watery diarrhoea between January 1 and March 31, 2018, whose illness was confirmed as cholera based on a laboratory analysis , and a desired odds ratio (OR) to be detected of 3.A standardised questionnaire was used to collect data on events that occurred during the 10 days preceding the onset of diarrhoea. The questionnaire was adapted from the cholera investigation form developed by the National Institute for Communicable Diseases in South Africa . The queData were entered into Excel spreadsheets, and all data were checked and cleaned by the local field supervisor. Double-checking was done by the principal investigator (FD). Exposure-related variables were included in the logistic regression analysis used in the multivariate model if they displayed a p-value<0.05 in the bivariate analysis. We calculated the ORs and 95% CIs associated with the independent variables. Data were analysed using SPSS version 25.0 .Formal permission to conduct this study was obtained from the MoPHP Ethical Committee in Aden, Yemen. All participants provided oral and written informed consent before the interview. For participants below 18 years of age, parents or guardians granted consent on their behalf and accompanied them during the interview. No identifiable personal data were associated with the reported results, as the questionnaires were coded by numbers only.The whole study population consisted of 177 participants: 59 cases (33.3%) and 118 (66.7%) controls. The distribution of participants by district is presented in The demographic and socioeconomic characteristics of the study population are presented in Cases were less likely to use indoor municipal tap water as their main source of drinking water  and to use chlorine to treat water in the household . However, they were more likely to use common-source water as their primary source of drinking water . Washing khat before chewing was significantly less prevalent in cases . Eating outside the house was significantly associated with being a case .In the multivariate analysis, only the practices of not washing khat before chewing it  and drinking from common-source water  were significantly associated with being a cholera case.This study aimed to identify risk factors for the cholera outbreak in Yemen, based on a case-control study with 59 cases and 118 controls in Aden Province in southern Yemen. In the bivariate analysis, several factors were shown to be associated with being a cholera case: a history of travelling; having had visitors from outside the province; eating outside the house; not having washed fruits, vegetables, and khat before use; use of common-source water; and not using chlorine or soap in the household.In the multivariate analysis, only not washing khat and using common-source water  remained significant factors, whereas a history of travelling and eating outside the house were not significantly associated with being a case. These results support findings from other studies that have identified similar risk factors -23.People in Yemen regularly chew khat on a daily basis, and it has been proposed to be a potential risk factor for cholera because many people chew khat without washing it properly. The findings of this study support this hypothesis.This study has a number of limitations. First, it was conducted in conditions of war and insecurity, which made the study logistics and data collection rather complicated. Second, the age distribution was not fully comparable between cases and controls, as there were more children aged 3-10 years among the cases than among the controls. Third, the confidence intervals of the ORs were often large, making interpretations difficult. Demographic variables  were not tested as risk factors. Finally, the interviews were carried out some time after patients’ recovery . Therefore, recall bias may have occurred.In conclusion, this study supports the association of cholera outbreaks with a breakdown of social infrastructure and poor hygiene measures and practices, in particular safe water supply. The findings of this study confirm a number of known risk factors for cholera, such as travel history and food hygiene. Moreover, it was demonstrated that not washing khat before chewing is a specific risk factor for cholera in Aden.


This study investigates the consumption of paracetamol and the risk of potential drug-drug interactions and assesses the clinical impact hereof in patients admitted to a department of geriatric medicine.  A retrospective and longitudinal study was conducted in patients who had been receiving paracetamol upon or during hospitalization. The hospital files of the included patients were reviewed, including documentation of concomitant medications, diagnoses, biochemical values, and adverse incidents during admission. These parameters were used as a clinical follow-up when assessing a clinical probability impact of the identified drug-drug interactions.  In total, 104 patients were admitted during the study period. 91 (87.5%) of these (mean age 86 years) received a prescription or were treated with paracetamol. Of these, 10% were evaluated as being at risk of potential drug-drug interactions with paracetamol. Seven of the potential drug-drug interactions were related to treatments with warfarin, one with valsartan and one with phenytoin. Of the nine patients at risk, six did experience either abnormal biochemical values or potential related clinical incidents. Four patients experienced increased INR (range 3.2–4.6), of which one patient suffered from anaemia and one with hematemesis. Two patients experienced increased ALAT/ASAT . One experienced hypertension.  A large majority of the patients in this study received treatment with paracetamol. Six patients were evaluated as having abnormal biochemical values or were experiencing clinical incidents during their hospitalization potentially related to the identified potential drug-drug interactions. The geriatric population is the fastest growing segment of our society, and this population is very heterogeneous , 2. PainR-warfarin which leads to inhibition of CYP2C9 that metabolizes S-warfarin. This can result in increased concentration of the S-isomer, which is five times as potent as the R-isomer [Several studies have reported and investigated pDDIs with paracetamol and the anticoagulant warfarin –21. ThisR-isomer –26.The aim was to investigate the use of paracetamol in elderly patients, who have been hospitalized in a department of geriatric medicine at a secondary hospital providing comprehensive health services. The focus was to identify the number of patients at risk of pDDIs with paracetamol and to provide a follow-up assessment of the clinical impact hereof by thoroughly investigating the patients' journals.The Department of Geriatric Medicine at Bispebjerg Hospital is a department with the capacity of 28 beds and a coverage area of appr. 400,000 citizens in an area that is part of greater Copenhagen and with a very diverse population. The department has a yearly admission of appr. 900 patients per year, whereas appr. 60% is admitted directly from the emergency department. Data for all admitted patients during appr. 5 weeks were collected and reviewed (in the period 1st of September to 10th of October 2016).All electronic journals of patients aged 65 years or more, hospitalized in the Department of Geriatric Medicine at Bispebjerg and Frederiksberg, were screened for registration of any prescribed or consumed paracetamol upon or during their hospitalization. If paracetamol was used or prescribed upon or/and during admission, the patient's relevant biochemical values were registered; diagnoses upon and under admission and chronic and temporary diagnoses were identified by reviewing the anamneses and patient files. Also, clinical incidents during hospitalization were registered. These incidents were defined as the potential consequences of the DDIs described in the applied DDI databases. The remaining medications were also registered . The number of drugs was categorized and registered as the fifth level of ATC, both as needed medication (PRN) and regular prescription.The percentage of the patients receiving any treatment with paracetamol was calculated, including both the number of regular medications and PRN. For those who did receive any paracetamol treatment, the average administration of paracetamol per day per patient was calculated and compared toward the maximum recommended dosage.third-line pDDIs were identified by using the databases Micromedex (MM), interaktionsdatabasen (ID), and pro.medicin (PM). Only pDDIs classified as major and moderate severity at MM and critical and potential problematic at ID were considered for this study.The known pDDIs with paracetamol and third-line pDDI was defined as a pDDI including the drug that also causes a pDDI with paracetamol. For instance, simvastatin-warfarin is a third-line pDDI because warfarin also can lead to a pDDI with paracetamol. This third-line pDDI may influence the pDDI between paracetamol and warfarin. A third-line drug was defined as the drug that had a pDDI with the same drug that was identified to have a pDDI with paracetamol. For instance, simvastatin is the third-line drug in the example of third-line pDDI. The patients at risk of a pDDI with paracetamol were identified, and subsequently, more thorough assessments of the patients were done. The assessments included an overall medication review of the patients' remaining medication.A Eventually, the patients at risk of pDDIs with paracetamol were evaluated due to any relation between the pDDIs with paracetamol and their biochemical values, diagnoses on admission or incidents noted in their journal during hospitalization. Incidents were identified according to key words in the applied DDI databases.During the data collection period, 104 patients were admitted to the Department of Geriatric Medicine and their patient files were reviewed. As seen in The different pDDIs with paracetamol are shown in As seen in third-line pDDIs in the range of one to five other third-line drugs. The pDDI of paracetamol and warfarin can lead to bleeding and anaemia, one of the three patients who had moderate anaemia experienced bleeding and hematemesis, during the hospitalization. The pDDI of paracetamol and phenytoin can lead to insufficient effect of paracetamol and an increased risk of hepatotoxicity. The patient at risk of this pDDI had both an episode of pain breakout and as well a suspicion of hepatotoxicity mentioned in her journal. The pDDI of paracetamol and valsartan can lead to tachycardia and hypertension, and the patient at risk had hypertension mentioned in her journal. She was known to have irregular hypertension according to the hospital records.As seen in In the aggregate, four of the nine patients experienced incidents during their hospitalization that could be related to the pDDIs with paracetamol.As seen in Four of the patients that experienced increased INR  were either admitted with or diagnosed during admission with an infection (three with urinary tract infection and one with pneumonia). The patient in risk of pDDI with phenytoin and paracetamol was hypotensive and had malnutrition.To sum up, six patients had either influenced biochemical values  and/or experienced incidents  during hospitalization that relates to the outcomes described in the applied databases.This study shows that most patients hospitalized at a department of geriatric medicine received treatment with paracetamol, not surprisingly, indicating that many elderly patients experience pain. A previous systematic review described that, in Denmark in 2013, 23% of patients in age group 65–79 years and 45% in age group 80–89 years received prescribed paracetamol . This inThe inconsistency between the applied electronic drug-drug interaction databases as seen in third-line drugs and their dosage regime might be able to influence the outcome of the interaction between paracetamol and warfarin. Also, infections are thought to increase the risk of supratherapeutic INR with or without antibiotic exposure, but to our knowledge, this is only showed in a study that investigate patients receiving warfarin and who develop an acute upper respiratory tract infection [To our knowledge, no previous studies with focus on pDDIs with paracetamol in the geriatric inpatients have been conducted. The present study showed that approximately 10% of elderly patients receiving paracetamol was at risk of pDDIs hereof. A Swedish study from 1993 described the risk of pDDIs with paracetamol in elderly outpatients, showing that 8.7% of outpatients were at risk of pDDIs with paracetamol . The drunfection . The undnfection . All in poor metabolizers of the CYP2C9 will also have decreased clearance of warfarin, as the more potent S-isomer of warfarin is metabolised by this enzyme [Despite no serious outcomes like severe bleeding or death, four of the investigated patients developed abnormal biochemical values or clinical incidents that could be caused by this well-documented DDI with warfarin and paracetamol. The heterogeneity of elderly patients can explain why some are more prone to this DDI than others. Patients who are s enzyme  and be ms enzyme . The pats enzyme , as wells enzyme . This cas enzyme –38. Due s enzyme . In combThe last patient at risk of a pDDI was the patient receiving valsartan. During hospitalization, the patient experienced hypertension. A previous study showed a significant increase in blood pressure in patients treated concomitantly with paracetamol and valsartan, but the mechanism of the hypertensive effect is not fully understood . The patThe knowledge of the widely used paracetamol's potential to interact with other drugs appears to be limited as none of the healthcare providers seemed to suspect the incidents to be related to the pDDIs with paracetamol, which might have been the case.The finding and objective of our study was not to evaluate if the patients should have reduced or withdrawn their paracetamol treatment. Paracetamol is still the first-line analgesic even in patients at risk of pDDIs , 41. In A challenge is also when patients purchase paracetamol over-the-counter in ordinary shops. Due to free trade and a lack of required information, patients can encounter potentially dangerous situations with the drug.The strength of this study is that several parameters have been investigated to assess patients at risk of a DDI with paracetamol. It was not only the patients' prescribed medications that were analysed, but also the administration of medication, the incidents during hospitalization, and relevant biochemical values were collected and analysed. These parameters were used as a clinical follow-up, providing a clinical probability impact of the identified DDIs.The limitations were, as for all retrospective studies, the missing possibility to investigate relevant questions to the patients' medication and diagnoses and uncertainty or errors in information from the hospital's files. This study was made on a small number of patients, and a more extensive study is needed to support and empower our findings. This study was an exploratory study investigating the need and feasibility for a greater study to be conducted in the elderly patients consuming paracetamol.third-line pDDIs, other diseases, inflammation, metabolism, and malnutrition can contribute to the outcome. Six patients were assessed to experience either influence of biochemical values or incidents during hospitalization that could be related to the identified pDDIs. This study highlights the importance of carefully reviewing the need of paracetamol in a vulnerable group of patients and always considering nonpharmacological treatment before beginning a chronic and long-term treatment; or in case of lack of effect in a long-term treatment, consider the possibility to deprescribe the drug to avoid serious adverse reactions due to interactions with other drugs and in general in order to avoid unnecessary polypharmacy and irrational medical treatment.A large majority of the patients admitted to a department of geriatric medicine at a large urban secondary hospital received treatment with paracetamol. Approximately, 10% of the patients treated with paracetamol were at risk of pDDIs with paracetamol, and warfarin was the most frequent drug to act with paracetamol, imposing a risk of a serious clinical incident. None of the patients experienced any serious outcomes, suggesting that heterogeneity and confounding factors as concomitant medication,


Consumers increasingly demand sustainable food production, including using world resources efficiently, avoiding environmental damage and ensuring good welfare of animals. Reports have suggested that beef production is costly in relation to world resource use and greenhouse gas production, so some consumers avoid beef. However, many reports refer mainly to feedlot systems. Ruminants can eat leaves that humans cannot eat, so if they are not fed grain, systems can be sustainable and valuable. This paper presents an analysis of the production of beef comparing all aspects of the use of land and conserved water for four production systems. It is suggested that conserved water use is a useful measure. Land use was the highest in extensive unmodified pasture systems, especially if the land became degraded. Less land was used in both feedlot and fertilised pasture systems and much less in semi-intensive silvopastoral systems. Conserved water use was the highest in feedlot systems, partly because of the grain fed to the cattle, lower in pasture systems and lowest in semi-intensive silvopastoral systems. This research indicates that, when beef production systems are being selected or consumers are deciding which beef to buy, extensive systems that degrade the land should be avoided, and well-managed extensive systems, especially semi-intensive silvopastoral systems, should be preferred to feedlot systems.This analysis, using published data, compared all land and conserved water use in four beef production systems. A widespread feedlot system and fertilised irrigated pasture systems used similar amounts of land. However, extensive unmodified pasture systems used three times more land, and semi-intensive silvopastoral systems used four times less land, so the highest use was 13 times the lowest. The amount of conserved water used was 64% higher in feedlots with relatively intensive rearing systems than in fertilised irrigated pasture; in extensive unmodified pasture systems, it was 38% and in semi-intensive silvopastoral systems, it was 21% of the fertilised irrigated pasture value, so the highest use was eight times the lowest. If there was no irrigation of pasture or of plants used for cattle feed, the feedlot water use was 12% higher than the fertilised pasture use and 57% higher than that in semi-intensive silvopastoral systems. These large effects of systems on resource use indicate the need to consider all systems when referring to the impact of beef or other products on the global environment. Whilst the use of animals as human food should be reduced, herbivorous animals that consume food that humans cannot eat and are kept using sustainable systems are important for the future use of world resources. Consumers increasingly demand that the production of food, and of other products, should be sustainable and they consider the ethics of production methods when evaluating product quality . A systeBos taurus, zebu (Bos indicus), or zebu-cross beef breeds were used for the calculations. Data are not available for animals matched for breed where each of the four systems were operated in one place. Indeed, these data would not be meaningful as the breed would not be adapted to each of the conditions. Whilst some of the data used were for comparisons within a geographical area, there were no areas where all four systems were commercially usable, so comparisons within an area would not be valid.In this study, the usage of land and conserved water (defined below) were estimated for all aspects of four methods of beef production. These included the production of plants that the animals eat directly and imported feed, mainly grain. These production methods were selected because of their importance now, their expected future importance and the availability of data. Most of the data used came from South America and North America, but some came from Australia, FAO, or other world sources, and they were selected because they are typical of world production. Apart from the world data, in each of the datasets for the systems utilised here, the beef produced is a significant part of national production, and some is exported to different parts of the world. This study provides evidence for consumers and others, when they are deciding which beef to buy, about the relative impacts on the use of land and water in four production systems. It is not an attempt to match systems in one area. The species of plant grown varied from area to area, but the four beef production systems could use different plant species in different regions of the world. There was variation among breeds of animals, but the breeds for beef production were those that are normal for the system in the locality from which the data were taken. B. taurus cattle per unit of food consumption, as they are better adapted to higher temperatures [In relation to the use of world water resources, zebu cattle are important because they use approximately 71% of the water consumed by eratures . Water uThe first step in the approach and general model for analysis used in this study was to obtain a representative figure for beef production in each system in an area where data for land and water use exist. The second step was to find the density of animals at each stage from birth to slaughter and the land usage and direct water usage in the production of the animals converted to a standard temperature. The third step was to calculate land and water use for food and other resources for animal production in each of the four systems. The area of land and the amount of conserved water per unit of meat production was then calculated for each component of the beef production process. Details of the components of the calculation model are explained further in the sections below. All data used are either quoted here or are in the references cited. The data used came from world calculations by FAO, comparative studies of systems where they exist and are valid, individual studies of systems and studies relevant to the industry as a whole, for example land and water use in a beef processing unit. For some aspects of the analysis, data were scarce, but all of the data used were evaluated as being representative. Although statistical methods were used to obtain most of the data points used, no overall statistical model for the simple calculations conducted was possible. Carefully quantified data for each of the many components and analyses explained below would take many years to collect. However, the results presented are of immediate value for system comparison and are relevant to decisions about which systems are sustainable and should be used in the future.A widespread, traditional beef production method is to rear the cattle throughout their lives on pasture, initially with their mothers and then in age-related groups. A widely used system considered here consists in leaving manure from the animals on land which is not treated with artificial fertiliser and is not irrigated. The typical live weight when the zebu or zebu-cross animals are slaughtered at 30 months of age is 468 kg, that becomes 255 kg hot carcass weight .B. taurus animals, depending on temperature and vulnerability to tick-borne diseases, being finished in feedlots. The cattle are often kept on fertilised, irrigated pasture when young and then in feedlots at high density with high levels of concentrate feeding for the last few months of life. Some animals are kept extensively prior to the feedlot period, so this situation is also considered in the results table. A typical duration of rearing on fertilised pasture is 16 months, so this duration was used for these animals, but 20 months may be needed to reach the same weight if the animals are on extensive systems, so 20 months was used in these calculations. The site of the feedlots is usually different from that for the earlier rearing, and animals may be transported long distances to the feedlot site. In Mexico, the feedlots are often more than 1000 km from the rearing areas, and the concentrate food is frequently imported from the United States. The data for feedlots correspond to the following time-course: months 0–9 in a suckler herd with the mothers, months 9–16 without the mothers in a paddock and months 16–20 in the feedlot. Some feedlot animals are reared in more confined situations, and some remain in the feedlot for longer or shorter times; the system considered here is frequently used in North and South America. A second system used in many countries, involves zebu or If the animals are in a feedlot for the last 4 months, their final weight is higher than if they were on the fertilised pasture throughout. Hence, the figure is based on the common situation of 20 months to slaughter, rather than the normal 30 months on pasture. The final weight used in the calculations was 491 kg live weight, which became 268 kg of hot carcass weight for animals from the feedlot.B. taurus breeds, but zebu and zebu-cross were also used at lower altitudes. The irrigation was provided as needed during each year, and fertiliser application was typical for pasture managed by farmers who could afford fertilisers. No supplementary concentrate feed was provided. The animals reached a weight of 468 kg at 30 months of age, similar to those on extensive unmodified pasture, but the density of animals was higher, as food availability was greater.This system is used in many countries, but most of the data used here were from Colombia at altitudes that provide a sub-tropical or warm temperate climate ,12. For Leucaena leucocephala, together with trees, some of which also have edible leaves. Such trees are especially valuable in times of low rainfall [Silvopastoral systems with shrubs and trees in addition to pasture plants are used for beef production in Colombia, Brazil, Australia and other countries. The semi-intensive systems utilise a shrub with edible leaves, such as the high protein leguminous shrub rainfall ,11,12,13With the exception of the feedlots, the systems analysed here were also used for milk production, with dairy or mixed-use animals, but only beef cattle data are shown here.In this comparison, all land used for keeping and feeding the animals was calculated. The area of land used for meat processing was included but was very small . The lanThe land required for beef cattle on extensive unmodified pasture at 27 °C would vary according to water availability and soil type. The figures used here are from FAO  and fromThe density of beef cattle in feedlots varies, but the typical figure of 140 animals per hectare during the last four months before slaughter was used here. These figures and those for the space required for the rearing with the mothers and the period at pasture before transport to the feedlot were taken from ,18 and . Each fe−1 [−1. The land used to produce 1 kg maize using the world mean is therefore 0.000174 ha. The amount of concentrate fed to an individual animal during earlier rearing and whilst in the feedlot was calculated from data in [Beef cattle whose production is completed in feedlots are fed a ration composed almost entirely of grain whilst in the feedlot and receive some supplementary feed during earlier rearing. The majority of this feed is maize, but soya and other food sources are also used. Small quantities of concentrate feed fed to beef cattle are by-products of human food, but it was not possible to take account of this. In calculating the land required for this feed production, the maize grain figure was used, as this is the major component of feed. Other feeds, all grown in cultivated fields, are fed to beef cattle; “green maize” production was more kg per ha than maize grain, whilst soya, wheat and barley were less. The maize grain data were considered the most representative. The figure for the amount of land required for maize production was calculated from the world mean maize production of 5755 kg ha−1 . Whilst  data in  to be 19Fertilised pasture, often called improved pasture, is used in many parts of the world for beef production. In hotter periods, such as the 27 °C condition considered here, it is often irrigated. The space used from the comparative studies  is reporThe semi-intensive silvopastoral system provides more nutrients, especially more protein, to cattle than monoculture pasture, so the animals can be at a higher density to achieve the same weight at 30 months of age. In the studies used in this analysis ,16, the The water use calculated here was entirely conserved water. Rain falling on pasture or on fields for crop growing was not included in these calculations unless conserved in human-controlled water storage systems. These included water collected from public and farm reservoirs, human buildings, streams, lakes, wells and aquifers. It is suggested that the figures for conserved water use are more relevant to beef farming and its impact than the total rainfall figures. The amount of conserved water used can be controlled to some extent by farmers, companies and governments, so it is valuable to know the different amounts used in different systems. In many countries, a high proportion of rain runs off rapidly, so it is never used for drinking by cattle or for production of their food. Would the amount of rainfall affect the conserved water data? Drinking by animals in feedlots would scarcely be affected by rain falling in troughs. The amount of water in storage systems is clearly affected by rainfall, so all data presented refer to the lifetime of the animal and, hence, group together periods of greater and lesser rainfall. The amount used for irrigation of pasture would be affected by the amount of rain falling on the land, so a mean figure for several years was used. Some of the water used in beef production is purified for human consumption, and this was noted if the data presented purified water.The ready availability of relatively cheap water in many countries where detailed studies of animal production systems are carried out has resulted in there being little concern about water usage, except as a relatively small monetary cost. However, much beef production is carried out in countries where water shortage is increasingly common, aquifers are declining in size, and most producers are becoming more aware of the cost of water. In some countries, however, the true cost is not charged to farmers, so some governments are subsidising the beef industry . Since water consumption by cattle is substantially affected by ambient temperature , figuresThe data for mean water drunk from birth to slaughter by beef cattle in extensive unmodified pasture were for zebu cattle in Brazil at 27 °C . The calThe data for the amount of water drunk by cattle from birth to slaughter, finishing in feedlots, were from Nebraska . For aniBeef cattle in feedlots are fed much more concentrate feed than cattle in other systems, not just when in the feedlot but also during earlier rearing. The data on the irrigation of maize for feed were from FAO  for the The irrigation of pasture during 16 months of pre-feedlot production of beef cattle could be zero but would normally be at the fertilised pasture rate. In the calculation, data relating to 16 months were used instead of those for 30 months of production in that system. A typical amount applied at 27 °C is shown in Table 2  togetherWater is used for fertiliser production, and a typical fertiliser used for maize and for pasture is urea . The meaA typical application of fertiliser on pasture is 200 kg N per ha per year, which is equivalent to 428 kg urea × 1.54 = 659 kg water per ha per year. For the feedlot system of 20-month growth, 16 months were on fertilised pasture, so the land per kg of meat was 0.0052 ha, with 659 kg water × 0.0052 × 17/12 = 4.6 L water per kg hot carcass.The amount of water drunk by beef cattle on fertilised irrigated pasture was measured in Colombia to be 25% more than that for silvopastoral systems . PastureThe application of fertiliser to pasture was calculated as for the feedlot animals during rearing on fertilised pasture, but the land per kg hot carcass weight was 0.01 ha, and there were 30 months of growth, so 659 kg water × 0.01 × 30/12 = 16.5 L water per kg hot carcass weight.The amount of water drunk by beef cattle on a semi-intensive silvopastoral system was measured in Argentina . The ratNo ethical evaluation was needed for the analysis presented.The data for land use in the four systems of beef production are presented in The data for water use in the four systems of beef production are presented in The rising demand for land, both for agriculture and for human dwellings and commerce, has led to shortages of land for these purposes and to great reductions in the land available for wild animals and plants ,37,38,39In agreement with , a key rThe substantial differences between extensive systems in land use per unit of beef production are important when interpreting results like those of , as it iThe quality of the land for agricultural production may not be the same in the four systems, and this will affect land and water use. Extensively grazed pasture may have been of poorer quality for plant growth before any impact of the livestock, feedlots may be on high- or low-quality land, and silvopastoral systems may be initiated on good-quality land or used as a measure to help the recovery of degraded land. The quality of the land after beef has been produced is of particular importance for system sustainability, and soil quality is improved most by silvopastoral systems . The iniIf the amount of land needed for beef production is reduced, more land can be spared for other purposes such as preserving natural habitats, reducing the rate of extinction of living organisms and increasing biodiversity ,44. If tPermanent, regular or intermittent water shortages in many parts of the world result in efforts to use water more efficiently ,46. In tComparisons by other authors of grazing and intensive beef production  had simiSome conserved water is held and then used to irrigate planted areas or provide water for drinking or other animal production use. Other conserved water is purified so that humans can safely drink it. This purification has monetary and carbon costs, so it is mentioned in the results. The feedlot beef production system generally uses more purified water than the other three, more extensive systems. Comparative information on degradative water use  is not aB. taurus cattle, so the figures presented in B. taurus breeds are used at this temperature.In the extensive unmodified pasture and semi-intensive silvopastoral systems, 89% and 84% of the water used in beef production was drunk by the animals. However, in the feedlot systems where the animals were reared on irrigated pasture and fed concentrates irrigated during production, 12% of the total water used was that drunk by the cattle, while, when fertilised irrigated pasture systems were used throughout, this percentage became 21%. Overall, a widely used feedlot system involves the highest water usage; water usage in fertilised pasture is also high, whereas that in extensive unmodified pasture is substantially lower, and that in the semi-intensive silvopastoral system is the lowest. It is clear from When other sustainability factors were considered, the four systems differed in some important respects. The welfare of the cattle can be worse because fast growth leads to more leg joint disorders , and thiThe efficiency of land and water use in the production of human food, such as beef, is being questioned. Figures concerning beef production externalities, such as land use and water use, are usually not representative of all beef production systems and may just refer to feedlot systems. Some of the public concludes that beef and other ruminant meat production should cease. However, when ruminants utilise food that humans cannot eat, such as the leaves of herbs, shrubs and trees, the production system can be sustainable and of great value in the world. When land use for all aspects of production of beef, including all sources of food and other materials used, were calculated for four production systems, it was the highest in extensive unmodified pasture, especially if the land became degraded, was 63–67% lower in both feedlot and fertilised irrigated pasture systems and 92% lower in semi-intensive silvopastoral systems. In relation to water use, it is suggested that it is valuable to assess the amount of conserved water used, instead of, or in addition to total water. Conserved water use was the highest in two widely used feedlot systems, 26–39% lower in fertilised irrigated pasture systems, 72–77% lower in extensive unmodified pasture systems and 84–87% lower in semi-intensive silvopastoral systems. Whilst not all systems can be used in all places and there are other components of sustainability, notably animal welfare and greenhouse gas production, information about such usage of resources can be usefully considered.Implications of this research are that, when governments, food retail companies, or individual farmers are deciding on which beef production systems to use or consumers are deciding on which beef to buy, extensive systems that degrade the land should be avoided, and well-managed extensive systems, especially semi-intensive silvopastoral systems, should be preferred to feedlot systems. Water shortage makes such choices more important.


This review outlines the requirements for engineering physiologically relevant intestinal in vitro models, mainly focusing on the importance of the mechano-structural cues that are often neglected in classic cell culture systems. More precisely: the topography, motility and flow present in the intestinal epithelium. After defining quantitative descriptors for these features, we describe the current state of the art, citing relevant approaches used to address one (or more) of the elements in question, pursuing a progressive conceptual construction of an “ideal” biomimetic intestinal model. The review concludes with a critical assessment of the currently available methods to summarize the important features of the intestinal tissue in the light of their different applications.The physiological environment of the intestine is characterized by its variegated composition, numerous functions and unique dynamic conditions, making it challenging to recreate the organ  In vitro models are employed to facilitate the study of complex in vivo phenomena in a simplified context, allowing well-controlled and repeatable conditions for the evaluation of cell response. They can be used in many different fields thanks to their wide areas of application including toxicology, drug testing, tissue engineering and nutraceutics  should contain the following features  with the ability of being cultured for the defined assay time without losing their characteristics;2 and have a height between 0.5 and 1 mm  epithelial cells able to be cultured for long periods.As already mentioned, ideally, an in vitro cultures from human tissues. For instance, Lahar et al.  cells. The epithelial cells were cultured on collagen membranes on top of LP cells and allogeneic Epstein-Barr Virus (EBV)-transformed B lymphocytes, in a 12-well tissue culture set-up  monolayer-monotypic cultures, however cells In recognition of the importance of matrix dimensionality, there has been a gradual shift from 2D monolayer cell cultures to 3D models. The multilayer models are a first step in this direction. Addressing the importance of stromal cells and extracellular matrix (ECM) in the homeostasis of intestinal epithelial cells . Again, using acellularized human tissue scaffold to culture bone marrow stem cells, Patil and co-workers  scaffolds, with villi shape, were produced and seeded with Caco-2 cells. They were used as a model to mimic the adhesion and invasion profiles of certain bacteria species, as well as the therapeutic potential of two probiotics. The authors found that the 3D environment affected the probiotic action differently: while The same group employed the PLGA scaffolds to study cell behavior and drug absorption of the Caco-2 and HT29-MTX co-culture model. They observed that the two epithelial cell types on the scaffolds were able to mimic the morphology and differentiation profile verified in native intestinal tissue, as identified by the expression of differentiation markers and by mucus secretion  embedded in a collagen gel. This scaffold and respective cell culture tubular architecture were shown to induce typical physiological responses by favoring accumulation of mucous secretions on the epithelium, leading to low oxygen tension in the lumen, and enabling interaction with bacteria from the gut. Moreover, this 3D intestinal model allowed maintenance of tissue function and cell phenotype for months . They report that the cells differentiated into crypt-villi structures on the scaffold and its colonization was enhanced by coculture with myofibroblasts, macrophages and probiotic bacteria. Remarkably, the implanted scaffolds enhanced mucosal regeneration in vivo , which is the electrical, ohmic resistance of the cell layer  of transparent components  bioreactor was conceived by Sumeri et al. The system consisted of a fermentation vessel equipped with diverse sensors and different pumps to provide the flow of diverse fluids. The work established that such GITS could be successfully used for evaluation of viability of probiotics  were conducted, targeting the micro bioreactor for applications in toxicity testing and drug screening , some authors have developed highly sophisticated systems to recreate the microenvironment of the epithelium.in vitro artificial small intestines. Essentially, a small intestinal bioreactor was constructed using polymeric scaffolds that mimicked the 3D architecture of the tissue. The data obtained from the TEER measurements (since the device was interfaced with an EVOM) indicated that the presence of flow induces characteristics of cell barrier tightness which are closer to the physiological condition with respect to static culture. An increase in cell proliferation was also verified and the authors reported that some cell responses varied according to different regions of the construct and according to different tested flow rates  Brown, . Some veIndeed, different studies have shown that cyclic mechanical stretch induces proliferation, increases tissue organization, and enhances mechanical properties on several cell types, as it briefly illustrated in the following section.When it comes to the intestine, the epithelium should be affected by the repetitive deformation during peristaltic distension and contraction and by the repetitive shortening of villi. In a notable work by Basson et al. Caco-2 cells were cultured on an elastic membrane and subjected to 10% strains (on average), applied with vacuum induced out-of-plane deformation, and it was verified that the cyclic strain stimulated proliferation. This response was higher in the membrane periphery where strain was maximal and, furthermore, it modulated the expression of specific brush border enzymes. The authors concluded that mechanically-induced strains at a physiological frequency and magnitude enhanced proliferation and modulated the differentiation of this cell line in an amplitude-dependent way  that imitated physiological peristaltic motions. This system allowed for a quick polarization of the epithelium that spontaneously grew into folds and formed a high integrity barrier  the Importance of Mechanical Cues for Cells: Bioreactors, the model of gut-on-a-chip by Kim et al. (As the complexity of the biomimetic models increased, they better approximated the m et al.  integratm et al. . In contm et al.  used a sm et al. . Nowadaym et al. .in vivo tissue can be better represented, and appropriate supply of nutrients is ensured for the 3D cell structures thicker than 100–200 μm (Du et al., Indeed, the recreation of the microenvironment of the cells is of major importance, as was underlined in section 3D Architecture. It is expected that emergent biofabrication techniques will allow for the recreation of the complex environment cues of the intestinal mucosa, by creating heterogenous constructs with different biochemical gradients for different cells (Malda et al., in vitro model. However, the question arises: is it really necessary? Or even better: when is it necessary? The answers may vary, but it appears to be consensual that the ideal features of a model depend on its usage.So far, it seemed that the merging of all the presented features in one single system was the best approach to obtain more predictive outcomes from an intestinal Certainly, the applications for tissue engineering require different conditions compared to those required for other fields—as was verified in the studies that started from a 3D cell organoid and opted for a monolayer configuration n of the epithelium. The 3D architecture of a tissue is definitely desirable for regenerative applications, ideally counting on the presence of constituents of other layers of the mucosa as well. But it might not be ideal if the scope of the study is to assess the permeability of a recently discovered compound, for instance.in vitro model depend on its application. Having identified the application, a researcher should refer to the relevant physiological parameters, such as those listed in As a concluding remark, the design criteria of an intestinal All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a shared affiliation at the time of review, though no other collaboration with the authors.


Intimate partner violence is a public health problem worldwide. Many children witness intimate partner violence at home and are affected by it. Regardless of the degree of exposure, children growing up in violent homes experience negative effects in the form of externalising behaviour and internalising symptoms which call for targeted interventions for children. The aim of the study is to map i) the available methods of detecting child and adolescent witnesses of intimate partner violence and ii) the interventions to support them. Three databases, PubMed, PsychInfo and Social Services Abstracts, were searched for scientific publications spanning over 20 years (1997–2017). This resulted in 2,406 publications of which 15 were finally selected after screening. Analysis of the articles resulted in three categories. The process of detecting children and adolescents who witnessed IPV in their homes varied in the included studies. The children were most commonly identified through their mother or other caregivers. Very few studies were based on children’s own reporting of their experiences, but were rather based on the mothers’ proxy reports. Studies distinguishing between the different forms of violence witnessed by children were few. It was uncommon that children were directly identified or screened for witnessing IPV in the family. Intimate partner violence (IPV) defined as both acts and threats of physical, sexual, psychological and emotional violence perpetrated by a current or former intimate partner  is a pubAs the women’s movement in the USA gathered momentum during the late 1960s and 1970s, the focus on women as victims of IPV and domestic violence became apparent. It was not until the 1990s that the impact of domestic violence on children received serious attention . AlthougThe population of interest in this study was children aged 13–18 years who witnessed intimate partner violence (IPV) in the family. With the above objectives in mind, where IPV was the main exposure, a search of literature was conducted in September 2017, spanning over the previous 20 years in the databases Medline and Psych Info. The terms used in the search were: crime victims, exposure to violence, intimate partner violence, domestic violence, disclosure and adolescent, using truncations, AND, OR to combine the keywords. The search yielded 941 articles in Medline and 1464 in Psych INFO. First, all titles (2405) were read, of which 101 were found to be of interest in relation to the study objectives. Next, 101 abstracts were read and reduced to 58 articles of interest for the study. These 58 articles were read and only 12 of the articles were found to partially address the research objectives . Very feOne of the difficulties of conducting the analysis for a literature review was the diffuse definition of IPV as the main exposure. In most of the cases, IPV was not clearly classified, but rather combined with other violence, such as community, school and domestic violence including violence against siblings –16. In aThe process of detecting children and adolescents (henceforth referred to as children) who witnessed IPV in their homes varied in the included studies. The children were most commonly identified through their mother or other caregivers (in 11 out of 15 articles) ,14,17–25Of the studies ,24,25,27It is well established that the consequences of witnessing IPV might result in serious health problems amongst children and adolescents, including behavioural disorders and emotional disorders, as well as PTSD and social and academic problems. Additionally, perpetrators of IPV are more likely to have witnessed IPV as a child than non-perpetrators. Despite the knowledge that children suffer from these kinds of symptoms when witnessing IPV, interventions targeting children with the exposure is scarce. Most research is based on mother’s reporting of children’s exposure to IPV in the family.In most of the articles that were reviewed, children were not directly identified or screened for witnessing IPV in the family, instead mothers were interviewed about their experience of IPV. Children were thus indirectly identified as being exposed to IPV in the family through reporting by those who were subjected to IPV.In the reviewed studies, IPV in the family was often classified in the broad category of family violence which could include child abuse, sibling abuse, etc. Some studies included exposure to community violence in addition to family or domestic violence. Unless IPV is clearly classified as the exposure and child witnesses of IPV identified as the target group neither screening of these children nor targeted intervention can be effective.Since children spend a substantial amount of their time in school, screening at the school those witnessing intimate partner violence might be considered. The school nurse can be a potential resource person using tools to capture this group of children and help them get in touch with professionals who may be able to support them through various interventions. As long as the voices of children and adolescents continue to be unheard it can be difficult to target effective interventions. Also, interventions need to be tailored in terms of the different types of violence that children are exposed to, i.e. community violence, domestic violence, violence in school, etc.