As health care strives towards the Triple Aim of improved population health, patient experience, and reduced costs, an organization’s readiness for change may be a key factor. The concept refers to the collective commitment of organizational members to a change and belief in their shared ability to make that change happen (efficacy). This study aims to assess the organizational readiness for implementing large-scale change at a clinical department in pursuit of the Triple Aim and to determine key associated factors.n = 403). Descriptive statistics was used to assess overall organizational readiness and single items. The between-group differences in subject characteristics were assessed with independent t-test and non-parametric test. Multiple linear regression was employed to control for potential confounders.A cross-sectional study at a Danish Obstetrics and Gynecology department faced with external pressure to become more efficient without compromising patient outcomes and experience. The Organisational Readiness for Implementing Change (ORIC) questionnaire was distributed to all employees (P = .02) or interim employment were significant predictors of a high change efficacy score after controlling for potential confounders.Response rate was 72%. The level of agreement with the commitment statements was high, and low with the efficacy statements. We did not observe statistically significant differences in the overall score between organizational sections or in relation to gender, age, or profession. Managerial status (B = 3.2, 95% CI = .52, 5.9, Changes related to pursuit of the Triple Aim were seen as something that “has to” be done, but left managers, and even more so staff, wondering what “to do” and “how to” do it. Change strategies should therefore address these uncertainties by translating political “have to’s” proposals that resonate with staff, spark engagement, and clarify “how to” deal with the complexity of large-scale change. Achieving the Triple Aim , 2, i.e.Successful change is influenced by multiple factors, including perceived differences in mental models, values, and an organization’s readiness for change.  Health ccommitment to change is based on “want to” rather than “have to” or “ought to”. [efficacy reflects the perceived knowledge about contextual factors, task demands, and the resources available. [Organizational readiness for change is defined as, “the extent to which organizational members are psychologically and behaviorally prepared to implement organizational change”.  Two dimeght to”.  The leveailable. , 16Multiple frameworks and tools to measure this construct in health care exist. However, many present methodological and conceptual limitations.  The “OrgThis cross-sectional survey study was conducted in the Obstetrics and Gynecology (OB/GYN) department at Aarhus University Hospital (AUH), in Denmark.The Danish health care system is undergoing a major reform that includes large-scale structural changes of hospitals to improve integration, coordination, and capacity utilization.  This redThe specific efficiency requirements set in May 2013 for the OB/GYN department, were to reduce beds by 33% and reduce the budget by 10%, mainly through reductions in nursing staff. The department had ca. 400 employees, 70 beds, 8500 admissions, 100,000 outpatient visits organized in two sections (Gynecology and Obstetrics). The downsizing goals were achieved through significant changes in service delivery pathways, rather than through new organizational structures or layoffs. [Selected staff from different professions met together with clinical managers to revise 46 clinical pathways in a series of off-site workshops using a lean-inspired approach.  In interThe clinical pathways for thirty-seven individual conditions and seven multiple conditions were redesigned, and nine changes were made at the departmental level. The latter addressed referrals, physical layouts, flow and capacity, discharge speed, and managerial support. Between 2013 and 2016, overall expenses were reduced by 8.6, 33% of beds were closed, and productivity improved . Cost reduction was achieved mainly through reductions in nursing staff, who either voluntarily left for other positions or retired.We used the “Organisational Readiness for Implementing Change” (ORIC) questionnaire.  We transTo facilitate analysis, we grouped and labelled the items according to the domain they addressed Table . Staff an = 403) in June 2014 via email. All managers had a clinical background as either physician, midwife, nurse, or medical secretary. The group of managers included both the department heads and the first line managers. Only managers with direct responsibility for personnel were included.The questionnaire was administrated electronically via SurveyXact (Aarhus/Denmark) and distributed (as a closed survey) to all department staff and managers  to implementation. The implementation process began on July 1, 2014, which was when the majority of beds were closed and changes in the care for individual medical conditions and the organization of care units was initiated. However, as this was the start of the summer vacation period, reminders were sent out through September to ensure that all employees received information about the questionnaire. Thus, data collection was conducted from June to September 2014.Participants were informed of the purpose and length of time of the survey, that data collection, analysis and access to the pseudo-anonymized data-set was limited to the research team and that it was possible to withdraw at any point. Respondents were then asked to give their consent to participate at the commencement of the questionnaire.t-test for continuous variables. For ordinal variables, the non-parametric Kruskal-Wallis test was used. For evaluating effect size, the difference between means and 95% confidence intervals was used.Descriptive statistics was used to analyze the respondents’ characteristics, the overall organizational readiness for implementing change, and the ratings (%) of the single items. Means, standard deviations for continuous variables, medians (interquartile ranges) were used for numerical and ordinal variables, and frequencies or percentages for categorical variables. The between-group differences in subject characteristics were examined using the independent Multiple linear regression was employed to control for potential confounders. The total ORIC, efficacy, and commitment scores were the dependent variables. Explanatory variables were selected based on earlier research  and simpN ≥ 200, ratio of N to the number of variables in a model (p), N/p ≥ 10. The minimum sample size was satisfied, with a final sample size of 284. Completeness was checked after the questionnaire had been submitted. All items were completed. The full dataset was used with no missing value.Sample size was calculated based on Myers et al.  criteriaThe reporting followed the checklist for Reporting Results of Internet E-Surveys (CHERRIES). Response rate was 72%. The frequency distribution of the study population is presented in Table The overall ORIC score had with a median  of 39 , with a median change commitment score of 19 and a median change efficacy score of 21 .A majority (56–88%) of the respondents agreed (agree + strongly agree) with the change commitment statements C1-C5). For change efficacy (E2-E7), this proportion was lower, ranging from 24 to 43%  and interim employment, yes ; were significant predictors (Table P = .03) and interim employment, yes  were significant predictors  and interim employment were significant predictors of the dependent variables change efficacy score and total ORIC score  to implement large-scale changes in pursuit of the Triple Aim. The percentage of agreement with the efficacy statements was lower and approximately a third of the organizational members answered that they neither agreed nor disagreed. Clinical managers and interim staff scored significantly higher – they perceived the department to be both more ready for the change and have a higher efficacy, i.e. knowledge about “what to do” and “how to do it”.The descriptive pattern of high commitment and lower efficacy, suggests that, when faced with large-scale changes brought upon through efficiency and downsizing demands, staff and managers may feel uncertain as to whether and how the organization will be able to successfully implement the requisite changes. Among staff, the uncertainty inherent to this complex change may be linked to their perception that the Triple Aim is inherently paradoxical and does not resonate with their mental models.  They mayThe pattern of higher commitment and low efficacy can provide important insights for managers facing complex change processes. In a previous study of lean-based improvement in ambulatory care, the pattern was associated with low engagement levels among physicians and non-physicians and burnout among the latter.  Working That clinical managers and interim staff perceived the department to have a higher change efficacy than staff could be related to the managerial role and to a lack of organizational history, respectively. Managers were all directly involved in and responsible for the change processes, thus they may have had a better understanding of the resources available, tasks to be completed, and the overall situation. Interim staff were not directly involved in the change process, did not participate in workshops, nor were they engaged as change agents in the implementation. Their median employment length of 1 year may have spared them memories of previous challenging change initiatives, which can be a barrier when organizations have to stretch to reach a challenging goal.  Thus, inThe lower agreement with the change commitment items linked to “want to” and “being motivated to implement the change” suggests that change commitment could have been related to staff and managers “having to” implement this change as stipulated by the external efficiency demands. This does not resonate well with those staff members who understand the drivers of change in health care to be related to research, evidence, or technology.  This wouThe generalizability of our findings is limited by the focus on a single department facing a broadly defined Triple Aim challenge. However, this study was part of a larger longitudinal case study,  from whiStriving towards the Triple Aim is a complex change process that involves high levels of uncertainly that can negatively impact an organization’s readiness for implementing change, in particular employee’s belief of the organization’s ability to actually implement the changes. More can be done to address the issue of change efficacy, such as strategies specifically targeted to address and deal with staff well-being, the uncertainty associated with large-scale change efforts, and developing increased clarity about “how to” deal with the complexity of change in health care improvement. Translating political “have to’s” into clear strategies that resonate with staff and spark motivation and engagement in order for staff to “want to” is another challenge that managers and researchers should consider exploring in more detail.


In this study we explored metaphor and idiom competencies in two clinical populations, children with autistic spectrum disorder (ASD) and children with Klinefelter syndrome (KS), (age range: 9–12), compared to typically developing (TD) children of the same age. These three groups were tested with two multiple-choice tests assessing idiom comprehension through iconic and verbal alternatives and a metaphor comprehension test composed of novel, physical-psychological metaphors, requesting verbal explanations. To these instruments, another test was added, assessing basic sentence comprehension. Performances on the different linguistic tasks were examined by means of discriminant analysis which showed that idiom comprehension had a very small weight in distinguishing children with ASD from TD controls, whereas metaphor explanation did distinguish them. This study suggests that figurative language comprehension is not a “core deficit” per se in individuals with ASD. Only when the task requires to explicitly construct and explain a semantic mapping between the two terms of a metaphor does the performance of children with ASD significantly deviate from the typical population. These results are interpreted in terms of a difficulty in children with ASD and KS with complex cognitive and linguistic processes and also in relation with clinical assessment. Figurative language is often used as an umbrella term to refer to all the expressions—from single words to complete sentences—whose interpretation requires to go beyond the literal meaning of every lexical constituent and retrieve the interlocutor’s communicative intention appropriately . In thisFor what concerns metaphor, many types of single lexical items such as nouns, adjectives, and verbs may be used with a metaphorical meaning, and also be combined to form metaphorical sentences. A paradigmatic form of such sentences is the so-called ‘nominal metaphor’, which is formed by two components, A and B, where A is called the ‘tenor’  and B isSeveral authors argued that metaphors are language ‘devices’ that support the building of abstract concepts ,4,5,6. FUnlike metaphors, and novel metaphors in particular, the figurative characteristics of idioms are always conventionalized, and can be felt by locutors as being more or less transparent. For example, the idiom “To lose oneself in a glass of water” can suggest by itself the incapability to face modest difficulties, contrary to other cases, such as, in English: to “spill the beans” = to reveal a secret, or “to kick the buck” = to die, or, in Italian “con questi chiari di luna!”  = in such difficult times. Concerning idiom comprehension, the theoretical debate essentially opposes two positions, one that points to lexical access and/or retrieval, and the other that suggests that idioms are represented in a distributed way and processed as complex expressions.  condition . In thisActually, many atypical cognitive profiles  can be fKS, the most frequent gonosomic anomaly, is a testicular dysgenesis due to a gonosomic polysomy as 47,XXY (80%), or 48,XXXY, 48,XXYY, 49,XXXXY, or 46,XX/47,XXY (20%). The incidence is 1:600 male born. Klinefelter syndrome (KS) is frequently under-diagnosed due to its high clinical variability. In fact, the characteristic hypogonadic eunuchoid phenotype may be observed less frequently than an almost normal phenotype, characterized by the only constant clinical signs as microrchidia  and azoospermia , which can be detected in adulthood, especially in the case of infertility. During childhood, suspicion can be advanced in cases of cryptorchidism , hypogenitalism , hypospadias , and the length of the lower compared to upper limbs. At puberty, evaluation often attests low volume of testes (<3 mL at 11 years), pubertal delay, modest development of secondary sexual characters, and the appearance of gynecomastia. Clinical diagnosis is then confirmed by the examination of the karyotype and the hormonal dosage (hypergonadotropic hypogonadism).For what concerns the cognitive profiles of individuals with KS, a relevant aspect underlined by the majority of the researchers is a clear delay in basic language competencies, attention and executive deficits, learning difficulties, and, in some cases, autistic-like symptoms ,16.Metaphor comprehension in individuals with ASD has been extensively studied from the early 1990s in a search for factors likely to be correlated to this particular type of semantic processing. These studies were partly based on experimental research ,21,22,23The pioneering study by Happé  exploredNevertheless, when Norbury  used theIn a more recent study, Kasirer and Mashal  administConcerning idiom comprehension, Kerbell and Grunwell  and NorbFor what concerns the population with KS, according to Bishop and Sherif’s review , studiesIn this study, we analyzed idiom and metaphor competencies in children with ASD and KS compared to a TD control group. The comparison between the two clinical populations was justified by the fact that language development can be a critical area for both. Nevertheless, as we have seen above (1.2) there is a certain asymmetry in the studies exploring figurative language because children with ASD received far more attention than children with KS. Our contribution aims at enriching the picture about these two populations. To this end, we used two types of tasks, one relying on multiple choice and the other, on verbal explanation. We wondered to what extent the profiles of these two groups could overlap. We expected both groups of children, those with ASD and those with KS, to show levels of idiom comprehension, as assessed by a multiple-choice task, comparable to those of their TD peers. On the contrary, we expected the same children to perform lower than the TD controls on metaphor explanation, as assessed by a task that requests analogical reasoning based on explicit verbalization.F = 0.9; p = 0.417). The first group  was composed of children with ASD, the second  of children with KS, and the third, of TD controls . The first and the second group had previously received their diagnosis and were recruited at the Department of Pediatrics and Child Neuropsychiatry; XXXX). Some of the children with ASD were diagnosed at preschool age on the basis of Diagnostic and Statistical Manual of Mental Disorders, IV (DSM IV) [Diagnostic and Statistical Manual of Mental Disorders 5 (DSM 5) [Autism Diagnostic Observation Schedule 2 (ADOS 2) [Autism Diagnostic Interview-Revised (ADI-R) [Three groups of 10 children each (age range: 9–12 years), all males, participated in this study. To verify if there were mean age differences between the three groups (expressed in months), a one-way ANOVA was run, that showed no significant difference ((DSM IV) , and the(ADOS 2) ,45 and A (ADI-R) ,47. Two  (ADI-R) ,49.All the children belonging to the ASD and KS group were enrolled in inclusive schools in the grades corresponding to their age, and were therefore exposed to the same type of everyday linguistic usage. Regarding the TD controls, as we were not allowed to administer the WISC IV , we obtaWe assessed figurative language competencies and basic sentence comprehension with the following tests, devised for Italian-speaking children:(1) A Metaphor Comprehension Test (MCT) for children aged 9 to 14, the MCT (It: TCM) .The MCT is composed of 12 metaphorical items in the ‘X is Y’ form. Ex: “Intelligence is a skyscraper”. Metaphor comprehension is viewed as the solution of a semantic conflict that underlies each metaphor, a process that can be implemented at different levels. The assessment scale comprises four of these levels, corresponding to the following scoring.- Level 0 (score: 0): the semantic conflict is either denied or refused. Refusals and/or denials can take the following form. (a) No answer: blanks or “I don’t know” answers; (b) “No, it’s nonsense”; (c) Metonymic answers: “A skyscraper is full of people who work in it”; (d) Answers exclusively focused on vehicle or on tenor: “If you are intelligent you are grown up and tall”, “It (“intelligence”) never stops functioning”, “It (“the skyscraper”) can go up to the sky”.- Level 1 (score: 1): the conflict is faced but tentatively, with a common ground based on features midway between physical and symbolic: Ex.: “Intelligence and skyscrapers are high and have many floors”; “It (“intelligence”) gets built gradually”; “It (“intelligence”) is something which goes higher and higher”.- Level 2 (score: 2): the conflict is explicitly acknowledged and the structure of the metaphor is justified; both psychological characteristics of the tenor and physical characteristics of the vehicle are mentioned but on a clearly distinct basis. “It may mean that there are different levels of intelligence in people, as there are floors in skyscrapers”.- Level 3 (score: 3): This is a refinement of the previous level, based on a deeper and more exhaustive analysis of the psychological characteristics of the target “intelligence”, in relation to the base “skyscraper”. Ex.: “You grow up in intelligence as you go upstairs, floor after floor, in a skyscraper. You can look at things from an upper level and understand them better, as in skyscrapers you discover things and they look small.” Maximum total score = 36. The MCT has high reliability, as measured by Cronbach’s alpha (0.70) and high interrater agreement, as measured by Cohen’s K (0.75 for the 9-year-olds and 0.81 for the 13-year-olds).Batteria per la Valutazione del Linguaggio 4–12; Eng: Language Assessment Battery, LAB, henceforth) [(2) A subtest, Idiom Comprehension , from a comprehensive battery to assess language competencies in children aged 4 to 12 (ceforth) . IC asse(3) A subtest, Iconic Metaphors  of a battery for children aged 5 to 14, the Abilità Pragmatiche del Linguaggio-Medea  . Actuall(4) The NEPSY II Instructions Comprehension test  ,54, whicWe are aware that these tests do not cover the whole range of figurative language competencies but, to our knowledge, they were the only validated instruments for Italian pediatric population available when this study was conducted. In addition, as both the children with ASD and children with KS were recruited and assessed in a clinical context, the outcomes were part of the monitoring process. All the tests were administered by two psychologists especially trained for this type of assessment.The performance of the three groups of participants in each linguistic task of our study is reported in It can be observed that the standard deviation for the MCT test is very high in the ASD group. Actually, this high variability is generated by one participant with an outlier score of 24. In order to reduce the impact of this univariate outlier in our analysis, we followed Tabachnick and Fidell’s  suggestiTo explore whether the performance of the three subgroups of children showed statistically significant differences we used a discriminant analysis .F value  = 4.19; p < 0.001). Thus, the combination of the four linguistic measures used in our study accounted for a significant 65.3% of the between-group variance (1-Lambda*100).The Wilks’s Lambda test in a discriminant analysis considers the overall relationship between the combination of predictors and the groups identifying the unexplained variance. In our analysis, the Wilks’s Lambda value was 0.347, which corresponds to a significant The second question that can be explored by means of a discriminant analysis is whether the combination of variables allowed to predict the participants’ group membership. The classification of participants, where actual group membership is compared to predicted group membership, showed that correct classifications were 80% for the TD group, 80% for the ASD group and 70% for the KS group. Thus, the combination of our linguistic measures was good at predicting membership to any of the three groups.df = 8; p < 0.001). Such function, as shown in F = 7.62; p < 0.001 and F = 4.64; p < 0.01) whereas the distance between the ASD and the KS groups was not significant.The third question explored by a discriminant analysis is which group was differentiated from the others in a statistically significant way. As there were three groups in our study, the analysis produced two discriminant functions but only the first turned out to be statistically significant  matrix of correlations between the predictors and the first discriminant function see  showed tIn sum, the combination of linguistic abilities explored in our study differentiates in a statistically significant way TD participants from both ASD and KS participants. The ability to highlight the metaphoric relationship between tenor  and vehicle  on explicit grounds is the best predictor of membership to a TD group versus a clinical group (either ASD or KS). In turn, this type of ability represents a form of reasoning on metaphors.To clarify whether the low ability of reasoning with metaphors in children with ASD or KS was due to specific factors or to a general cognitive difficulty, we selected from our clinical sample only those participants whose total IQ was higher than 85. Mean raw scores and standard deviations in each linguistic task in the two clinical groups are reported in It clearly emerges that children with ASD or with KS had a lower performance than TD controls only in Instr.Compr. and in the MCT.F = 4.57; p < 0.01). Thus, the combination of the four linguistic measures used in our study accounted for a significant 53.3% of the between-group variance (1-Lambda*100). The classification of participants showed that correct classifications were 90% for the TD group, and 90% for the A + KS group. Thus, the combination of our linguistic measures was very good at predicting membership to both groups. In a significant discriminant analysis with two groups, only one (significant) function is produced and distances between groups are obviously significant.In this analysis, the Wilks’s Lambda value was 0.467, which corresponds to a significant F value (The structure (loading) matrix of correlations between the predictors and the discriminant function see  suggest recognition of a given form of figurative language within a range of pre-coded alternatives, conceived by adults, which might not reflect children’s spontaneous thoughts. On the other hand, explanations go beyond recognition and involve rephrasing capabilities, and these, in turn, require semantic and lexical competencies in addition to language planning abilities. We also agree with Winner’s statement [In the present study we wished to explore metaphor and idiom competencies in two clinical populations, namely children with ASD and children with KS. We approached the issue with different instruments, two multiple-choice tasks to assess idiom comprehension through iconic and verbal alternatives (IM and IC) and a metaphor explanation task (MCT). We are aware that the competencies these tasks assess are different in nature. In agreement with Winner , we belitatement  that a sWhile idioms in IC’s and IM’s items were conventionalized forms, metaphors in MCT’s items were all novel, physical-psychological metaphors. In addition, we checked basic sentence comprehension through the Instructions Comprehension Test of the NEPSY II ,54.We hypothesized, in line with Kasirer and Mashal’s study , that weWe performed a discriminant analysis that showed that idiom comprehension had a very small weight in distinguishing children with ASD from TD controls, whereas metaphor explanation did distinguish them even when children with ASD were selected for having an IQ higher than 85.Thus, the outcomes of our study, in line with the main conclusions of Kalandadze et al. ii’s meta-analysis , suggestOur sample of children with ASD also showed some difficulty in the Instructions comprehension task, that assesses basic syntactic competencies. This task proved to be the second variable contributing to differentiate children with ASD from the TD controls. This finding appeared even more evidently when the participants with ASD were selected for having an IQ higher than 85, and was also highlighted by a high correlation with the discriminant function. Thus, our sample of children with ASD had a weakness in sentence comprehension, and this weakness probably also affected tasks in which language had to be processed in depth, such as MCT.Another aim of our study was to compare the two clinical populations to one another, the sample with ASD and the sample with KS. The outcomes of our study showed that all the aspects of the linguistic profile of children with KS were close to those of children with ASD, even when they had an IQ higher than 85. Thus, for children with KS, similarly to what was found in their peers with ASD, difficulties basically emerged in the explanation task (MCT), and these can presumably be linked to marked difficulties in expressive language, as pointed out by Leggett et al. .We aware that the results of our study can only be considered as preliminary, either with respect to the respective profiles of two clinical populations, and with respect to the relationships between these profiles. This cautious position is due to the following limitations. The first is the reduced size of the sample. The second is the lack of IQ in the control group due to the reasons already pointed out. The third regards a part of the assessment, namely Instructions comprehension, where semantic and syntactic competencies could have been explored also at the productive level. The fourth limitation is that we only considered quantitative outcomes, based on the type of statistical processing we used to highlight major differences.At the same time, we believe this study has also some elements of originality. First, it investigated a clinical population scarcely explored from the point of view of figurative language competencies, namely children with KS ,38, and Secondly, the age range, which we circumscribed to the interval from 9 to 12, targets a significant period in the development of figurative language in children without neurodevelopmental disorder .Thirdly, we assessed two different types of competencies—recognition (idioms) and explanation (metaphors)—generally confused under the overall term “comprehension” . These cAs a fourth point, we will mention the relevance of the above distinction between recognition and explanation for clinical assessment. For example, when assessing children with KS or children with ASD, using only multiple-choice tasks might overestimate their performance. We will mention an example drawn from our study, for the Italian idiom “Prendere un granchio”  where the possible answers were:Answer n.1: to make a mistakeAnswer n 2: to take a crab with one’s handsAnswer n 3: to go to the seaside.A child with ASD said: “I withdraw the word ‘crab’ from the second answer, the word ‘seaside’ from the third answer because ‘crab’ and ‘seaside’ have something in common with the expression “To take a crab”, then, the right answer is the first one”. Apparently, then, the child was aware of the non literal meaning of this expression and also that he did not know it. In this situation, he opted for a default strategy that led him to the correct answer. While this may seem an adaptive metacognitive strategy it does not warrant that the child really grasped the meaning in depth. These cognitive pathways are precisely what should be investigated in future research if we wish to illuminate reasoning about figurative language in development.In this study we explored two different aspects of the multidimensional figurative language domain in two clinical populations, children with autistic spectrum disorder (ASD) and children with Klinefelter syndrome (KS), compared to typically developing (TD) children. In particular, we studied the capability to recognize the meanings of idioms in multiple-choice tasks and the capability to explain novel metaphors in a task that explicitly requested to reason on metaphors. The outcomes of this study, although preliminary, support the idea to distinguish different components in figurative language competency. On the one hand, this distinction could highlight strenghts and weaknesses in the abovementioned clinical populations, and, on the other, it could also illuminate the complex computational mechanisms underlying performances that might superficially appear as adequate.


Ontologies are key enabling technologies for the Semantic Web. The Web Ontology Language (OWL) is a semantic markup language for publishing and sharing ontologies.The supply of customizable, computable, and formally represented molecular genetics information and health information, via electronic health record (EHR) interfaces, can play a critical role in achieving precision medicine. In this study, we used cystic fibrosis as an example to build an Ontology-based Knowledge Base prototype on Cystic Fibrobis (OntoKBCF) to supply such information via an EHR prototype. In addition, we elaborate on the construction and representation principles, approaches, applications, and representation challenges that we faced in the construction of OntoKBCF. The principles and approaches can be referenced and applied in constructing other ontology-based domain knowledge bases.First, we defined the scope of OntoKBCF according to possible clinical information needs about cystic fibrosis on both a molecular level and a clinical phenotype level. We then selected the knowledge sources to be represented in OntoKBCF. We utilized top-to-bottom content analysis and bottom-up construction to build OntoKBCF. Protégé-OWL was used to construct OntoKBCF. The construction principles included (1) to use existing basic terms as much as possible; (2) to use intersection and combination in representations; (3) to represent as many different types of facts as possible; and (4) to provide 2-5 examples for each type. HermiT 1.3.8.413 within Protégé-5.1.0 was used to check the consistency of OntoKBCF.OntoKBCF was constructed successfully, with the inclusion of 408 classes, 35 properties, and 113 equivalent classes. OntoKBCF includes both atomic concepts (such as amino acid) and complex concepts  and their descriptions. We demonstrated that OntoKBCF could make customizable molecular and health information available automatically and usable via an EHR prototype. The main challenges include the provision of a more comprehensive account of different patient groups as well as the representation of uncertain knowledge, ambiguous concepts, and negative statements and more complicated and detailed molecular mechanisms or pathway information about cystic fibrosis.Although cystic fibrosis is just one example, based on the current structure of OntoKBCF, it should be relatively straightforward to extend the prototype to cover different topics. Moreover, the principles underpinning its development could be reused for building alternative human monogenetic diseases knowledge bases. The majOntologies are key enabling technologies for the Semantic Web . Ontologmotivation of our work is to demonstrate the feasibility of providing formal and computable clinical information and molecular genetic information, derived from an ontology-based knowledge base, via an electronic health record (EHR) interface. Molecular genetic information plays a key role in medicine; this information, however, is not the kind that is traditionally included in an EHR system. Therefore, we aim to build an Ontology-based Knowledge Base prototype on Cystic Fibrosis (OntoKBCF) [The specific application of ontologies includes standard conceptual vocabularies, services for queries, and reusable knowledge bases, all of which can facilitate interoperability across different systems . BiomedintoKBCF) ,9 to supCFTR) gene causes cystic fibrosis.Cystic fibrosis is used as an example disease in building OntoKBCF for a feasibility demonstration. The reasons for this choice include the following: cystic fibrosis has a relatively stable and comprehensive molecular genetic profile; it is one of the most common, fatal genetic diseases in the United States , especiaknowledge base model to refer to the logic specifications of a knowledge base at the abstract level and a knowledge base prototype  to refer to the physical artifact that we eventually built at the concrete level, based on a knowledge base model. We use a knowledge base prototype instead of a knowledge base because we include different levels of facts in OntoKBCF, for example, nucleotide changes, amino acid changes, and clinical phenotypes. The facts are not exhaustive at any horizontal level within OntoKBCF; however, the facts are sufficient to organize the relationships at cross-horizontal levels [An ontology-based knowledge base is built on top of domain entities, properties, and relationships ; however, it also includes sharable instances, rules, and inference capabilities , which el levels ,9 and tol levels ,15.domain coverage of OntoKBCF. In contrast, this paper provides a holistic view of the construction principles of OntoKBCF, including the representations of the integration between OntoKBCF and an EHR. As such, this paper may provide a reference for content developers operating in the Semantic Web space, especially in building knowledge bases and knowledge base modeling on monogenetic human diseases.An overview of the project, showing how OntoKBCF supplies computable and formally represented molecular and health information to an EHR in a dynamic manner has been published previously , as has OntoKBCF was built using Protégé-OWL . We chosThe main axes used in OntoKBCF are time and problem in line with the content of the included domain. The main axes are utilized to organize the atomic, combined, and complex concepts in OntoKBCF. CFTR mutations, particularly those related to health information or phenotypes  [ groups) -28; (3)  groups) ,23-25.The selected content required analysis to set up the construction strategies. Based on the scope and the knowledge resources available, analyzing the facts by utilizing a series of dissections was necessary to make the task realistic and practically accomplishable. The starting point was sentences of facts that were dissected into atomic units   and GeneOntoKBCF was constructed bottom-up  as folloBy way of example, if a group of patients with the Gly542X variant needs to be represented, the following steps would be used see :“Gly” stands for glycine, a type of amino acid; this is a basic concept.“X” is the nonsense codon, which terminates the translation; this is a basic concept.CFTR amino acid chain; this is a combined concept.“Gly542” is defined as an amino acid location in the human CFTR amino acid chain; this is a combined concept.“Gly542X” is defined as an amino acid substitution in human “Patient_CF_with_Gly542X” is defined as a group of cystic fibrosis patients with the amino acid change; this is a complex concept.Final facts about the group of cystic fibrosis patients with the Gly542X variant are represented by the combination of both the logical definition of “Patient_CF_with_Gly542X” and its properties.CFTR gene” in UMLS was adapted to “Human CFTR gene”; considering the clinical usage potential, we distinguished the human origins of the CFTR gene.Most of the hierarchies of basic concepts in the knowledge base prototype follow UMLS and GO. In addition, relationships or classes were added or adjusted if there were no obvious choices. For example, in OntoKBCF, “sex_group” was used to connect “population_group” and “female,” and the concept “all possible properties of this group. We used the intersection among basic concepts to represent combined and complex concepts in OntoKBCF. For example, “female adolescent cystic fibrosis patient” is represented as a complex concept in OntoKBCF. philosophy is to use the existing concepts as much as possible and to create new ones only if it is absolutely necessary. If a concept is from UMLS, then the unique concept identifier from UMLS is kept in the Annotations section for future reference . Other construction principles include the following: (1) to represent more types  of facts within the same level; (2) to represent 2-5 examples within the same type, for example, for the single-nucleotide transition of CFTR, we represented 5 examples in OntoKBCF instead of representing all existing facts exhaustively; (3) to have the same representation listed in all possible hierarchies in OntoKBCF; for example, AA2183 _minus_G is listed under Del_A, Nucleotide_deletion_in_ human_CFTR_gene, A_transition_G, and Nucleotide_ transition_in_human_CFTR_gene; and (4) to represent only the facts within the scope of OntoKBCF. The purpose of our work is to demonstrate the feasibility of the construction of a knowledge base by utilizing Semantic Web technology and demonstrating that the facts from the knowledge base can be utilized via an EHR interface dynamically. Therefore, representing the exhaustive list of variations of the same gene is not a priority. In addition, as most of the mutation types have been covered in the current OntoKBCF, we believe it to be extendable. To include an exhaustive list of the variations of the CFTR gene should be straightforward when following our construction principles and approaches.Our To create the potential for broader usage, some of the classes were specifically named for human beings in OntoKBCF, such as “Human_CFTR_gene” and “Human_CFTR_gene_exon”; this differentiates them from any additional classes that may concern other organisms.CFTR mutation name, which did not include the RNA-level description. The reason is that cDNA is used to code protein, and RNA is more of a middle layer with regards to protein synthesis. Amino acids can be named in 1 or 3 letters. There are both amino acids and nucleotides in OntoKBCF, and 1-letter abbreviation names of amino acids can be confused with nucleotides. For example, A can be Alanine  or Adenine. Thus, we use 3-letter abbreviation names for amino acids and 1-letter names for nucleotides.The Nomenclature for the Description of Sequence Variations  is folloAs there are 22 types of amino acids, there are many more possibilities for amino acid changes compared with nucleotide mutations; only the amino acid changes that fell within the scope of OntoKBCF were included. In contrast, because there are 8 types of nucleotides, which consist of DNA and RNA, with a smaller number of possible mutations, the complete set of possible nucleotide mutations in cDNA for deletion, insertion, transversion, and transition were included in OntoKBCF. The symbols “+” or “−” indicate the nucleotide position at the beginning of the intron (+) or the end of the intron (−); this would be represented as “plus” and “minus” in OntoKBCF for nucleotide substitutions. Amino acid substitutions are handled similarly.In OntoKBCF, the final expression of nucleotide mutations can be distinguished from amino acid changes as follows: (1) their labels contained “minus” or “plus,” or “Ins” or “Del” ; or (2) a 3-letter abbreviation name was used for amino acids to avoid confusion. For example, Gly was utilized as the abbreviation for glycine, not G, which can be confused with the nucleotide “G.” “Minus” and “plus” were used to represent the nucleotide position. “Ins” is used for nucleotide insertion, and “Del” is used for nucleotide deletion. In theory, not all nucleotide mutations have to be labeled with one of these 4 values; however, no such example has been found in the construction of OntoKBCF. This strategy avoids the potential limitations of the special characters that one can use in a name.For properties in the OWL representation, only existential restriction “someValuesFrom” was used as the property restriction (appearing as “some” in the text); it would be inappropriate to use allValuesFrom  because it cannot be guaranteed that their value classes are fully specified and mutually exclusive and exhaustive. It is sufficient to use existential restriction in most representations to leave space for future efforts to complete the description. For example, for a cystic fibrosis patient with Gly542X, the subject had the mutation property “some Gly542X” because it is possible that Gly542X is not the only mutation for this type of patient.According to Horridge et al , the “Doatomic concepts, such as diarrhea, nausea, or coughing.In OntoKBCF, the most fine-grain level of biological information starts at nucleobase, which is the most important component for the elementary units (nucleotides) of RNA and DNA. In contrast, for health information in OntoKBCF, the most fine-grain level starts from relatively Currently, OntoKBCF includes answers to only questions about “what” , not about “how”  or “why”  . This isOntoKBCF has been shared via BioPortal . We usedOntoKBCF has been demonstrated to be able to supply personalized, nonduplicate molecular genetic information and health information according to a patient’s characteristics successfully, dynamically, and automatically via an EHR prototype ,15. The OntoKBCF can provide reference facts  and reminders to EHR users. When a user applies the final facts via EHR interfaces, all the basic concepts and combined concepts utilized for building a complex concept can be accessed. Biological information (genotype-related)Nucleotide mutationAmino acid changeGene mutation locationGene or protein mutation dissectionHealth information (phenotype-related)Demographic data SymptomsDiagnostic tests or diagnosisTreatment factsElectronic health record data representation structureOntoKBCF meets our design objectives and has been integrated successfully with an EHR prototype . This paIn OntoKBCF, different groups of cystic fibrosis patients are represented separately. For example, there are cystic fibrosis patients in different age groups or with different genetic variations. Currently, for each cystic fibrosis patient group, we represent only the available facts from the selected resources and within the scope of OntoKBCF. We defined patient groups logically, rather than representing them comprehensively. Some cystic fibrosis patient groups, such as an adolescent cystic fibrosis patient group , are faiFor the complicated groups in OntoKBCF, the representation is far from comprehensive or exhaustive. We feel that if we were to set comprehensive representation as a goal, the task would be endless, as there are many properties related to the patient groups. The properties can include, among other things, clinical manifestations, treatment plans, nursing care plans, patient self-care plans and patient education. The detailed categories, as well as the actual representation for each property, would result in an exhaustive list. Our pragmatic solution to this scalability problem is to focus on practical applications, stay within the defined scope, and make it possible to expand in the future.There are some common expressions in clinical medicine, for example, “sometimes,” “especially,” “very common,” and “very rarely” that are challenging to represent in a computable and formal manner as their interrelationships are vague. These expressions are very important for human experts (such as physicians) to absorb or to apply the information. For example, for older children with cystic fibrosis, one important symptom is “nasal polys, especially if recurrent” . HoweverIn addition to uncertain concepts, negative descriptions cannot be represented precisely, either. Considering the limited reasoning support, less than ideal reasoning efficiency, and the complexity in modeling concepts, currently, for demonstration purposes, we included only the definite and positive results in OntoKBCF. We do realize that although this is necessary, it is a limitation of OntoKBCF as it does not reflect the real world comprehensively.One of the complex facts represented in OntoKBCF is shown in per se, or that the challenges are in the broader area of medicine, logic, or even mathematics.The challenges of introducing information technologies and computer science applications to medicine have been recognized for a long time . KnowledRegarding OntoKBCF, we sought to determine how many properties are sufficient or ideal to describe a cystic fibrosis patient group. From a pragmatic point of view, setting up the scope of the project is necessary to make the project manageable. Otherwise, the representation would become an endless task, as there are many possible properties related to a group of cystic fibrosis patients, as Davis et al  describeOne critical challenge in building OntoKBCF is a lack of sufficient clinical actionable knowledge that is related to molecular genetic information. This is one of the main reasons that we constructed OntoKBCF as a prototype rather than as a product knowledge base.Other challenges that we faced during the construction of OntoKBCF included the following: (1) how to communicate the construction principles and design considerations in a consistent, explicit, and sharable manner; (2) whether we can make the construction process automatic; and (3) how to update the domain content automatically. Solving these challenges may help us build larger-scale ontologies and help in their integration automatically.all of the following criteria: consistent molecular genetic information and a clinical actionable, machine-processable format that was shareable, reusable, and customizable. We, thus, had to create our own resource to meet all the requirements. Biobanks might be a good source to provide such information. Nevertheless, the UK Biobank [Our work was originally conceived in 2004 and mostly completed by 2009. At the time, there were no available resources that could meet  Biobank  started  Biobank .We used an ontology-based knowledge base to provide customizable molecular genetics and health information to EHR settings successfully. The ontology-based knowledge base provides potential in reusing and sharing, as well as the consistency of information. The creation of knowledge resources with fine granularity (not only disease names) has been recognized repeatedly ,41 as thOne recent example of knowledge base was reported by Samwald et al ,43 who bIn recent years, the broad importance of Semantic Web technologies has been recognized. There are many more studies that have used ontology-based knowledge bases to assist clinical tasks within an EHR. For example, Robles-Bykbaev et al  reportedOntoKBCF is a knowledge base prototype rather than a knowledge base, which may include substantial instances for each class. OntoKBCF, however, includes content from nucleotides to clinical phenotypes across different granularity levels. If we can image a pyramid that moves from gene to protein to cell to tissue to organ up to human beings , we can There has been no formal evaluation of OntoKBCF. However, we do have two limited levels of validation of the work: (1) automated reasoning assures the consistency of underlying ontology and (2) successful demonstration that OntoKBCF can deliver customizable molecular information and health information dynamically via an EHR prototype. As a knowledge base model, these levels of validation provide evidence that the original design objectives of OntoKBCF were met successfully.We have presented the robust construction principles, approaches, design decisions, and challenges in constructing OntoKBCF. OntoKBCF is constructed in OWL and can be utilized as a knowledge resource to provide information on molecular genetics and other health topics dynamically to an EHR. The construction principles and approaches can be referenced for other topic areas, and based on its current structure, OntoKBCF could be expanded in a straightforward manner to a full knowledge base.


A feature distinguishing human hematopoietic and epithelial stem cells from other equally fascinating stem cells is perhaps their easier translation into a clinical setting. We have devoted nearly our entire scientific career in trying to turn our understanding of epithelial stem cell biology into something that could help people suffering from virtually untreatable diseases of squamous epithelia. We have done that as a team, together with our numerous students, postdocs, technicians and valuable collaborators, clinicians, regulators, and, lately, industrial partners. We had rewarding successes and burning failures, but we always did our best. This award, given by friends and colleagues deserving it more than us, has been the most important recognition of our work. Below, we summarize our story. In this Perspective, Graziella Pellegrini and Michele De Luca think back over their nearly 30-year joint effort in translating epithelial stem cell biology into regenerative medicine. Such therapy was still in the initial phases of clinical trials. While flying back to the Burn Unit in Bochum 10 days after the first transplantation, we and Sergio Bondanza, our historical “cell grower,” could not even talk each other. The appearance of a pink and nice epidermis upon removal of bandages from the grafted area was profoundly moving, perhaps the strongest emotion we had in our entire scientific career, and confirmed how awesome science can be. We understood that Hassan's life could be saved.A few months ago, we reported on the regeneration of virtually the entire epidermis of Hassan, a Syrian child affected by a severe form of junctional epidermolysis bullosa, by means of autologous, transgenic epidermal cultures . Hassan'We will tell more about Hassan's story and scientific outcomes, but it is important to stress that this achievement did not come out of the blue. It was the culmination of decades of hard work.New England Journal of Medicine, where Howard Green  reported on life-saving regeneration of the epidermis in two severely burned children by means of autologous epidermal cultures  in Genova, Italy. Cancedda, knowing Michele's interest in epithelial cells, drew his attention to a paper just published on the cultures . Michelecultures , and torWe dedicated the first years in Genova to growing epidermal keratinocytes for the treatment of massive, life-threatening full-thickness skin burns. That was quite an exciting period; many patients were saved in collaboration with many Burn Units inside and outside Italy . HoweverWe soon realized that primary epidermal cultures contained melanocytes in close contact with growing keratinocyte colonies. We discovered that human keratinocytes strongly induce melanocyte proliferation, which requires keratinocyte contact and is highly regulated to maintain a physiological keratinocyte/melanocyte ratio. We found that only epidermal keratinocytes have all the information required for the proper physiological organization of melanocytes in the basal layer of the epidermis . These fMeanwhile, we developed cultures of urethral epithelium, which were successfully applied to regenerate the urethra of children carrying posterior hypospadias, a congenital defect in which the urethra terminates on the ventral surface of the penis .Even though neither Green nor us called cultured keratinocytes stem cells at that time, these human keratinocytes fit the definition of stem cells as we know them today. In those years, by clonal analysis of primary epidermal cultures, Yann Barrandon and Howard Green identified three types of clonogenic keratinocytes, giving rise to holoclones, meroclones, and paraclones . Over thWe applied this notion to a new cell therapy that we initially investigated in Genova at the Center of Advanced Biotechnology (CBA) and further developed first in Rome (IDI), then at the Veneto Eye Bank Foundation in Venice, and finally at the University of Modena and Reggio Emilia (Unimore), where we moved in 2007. We are referring to the use of limbal stem cells for the treatment of severe ocular burns.Stem cells of the limbus, the narrow zone between the cornea and the bulbar conjunctiva, underpin repair and renewal of the corneal epithelium . MassiveAn important step toward determining criteria for stem cell content of limbal cultures came from the discovery of p63  as a key+/C/EBPδ− limbal cells maintain their regenerative capability but have lost their self-renewal. ΔNp63α+/C/EBPδ− limbal cells still maintain essential stem cell features, inasmuch as enforced expression of C/EBPδ indefinitely sustains the self-renewal of ΔNp63α+ cells but cannot rescue self-renewal in clonogenic ΔNp63α− cells. Thus, ΔNp63α is essential for the proliferative/regenerative capacity of limbal stem cells, while C/EBPδ (and Bmi1) sustain their self-renewal in a ΔNp63α+ genetic background , our autologous limbal cultures were complying with the new standards of European regulation and became the first stem cell-based cell therapy to receive marketing authorization from the European Medicine Agency (Holoclar).ex vivo cell and gene therapy should be considered as advanced therapy medicinal products (ATMPs) and regulated as pharmaceutical drugs. To be approved, in addition to formal clinical trials, ATMPs needed to fulfill good manufacturing practice (GMP), good clinical practice (GCP)—globally referred to as GxPs—requirements, and deal with a variety of documents, including the Common Technical Document. We had to stop all our translational activities and we even thought about giving up: we did not have any GMP-certified laboratory and, more importantly, we realized that the pharmaceutical world with its rules was a different world, requiring a way of thinking and operating quite far from a scientist's mentality. We still remember a long phone call with Howard Green  who, at the end of the phone call, just told us: “you cannot afford to let people down just like that. You have quite a responsibility toward many people with untreatable diseases that you know you can at least try to tackle. You just have to keep going.” He was H , and we could not say “no” to H as he had been mentoring us for years.But this was quite a bumpy ride. Indeed, in 2007, while dealing with intense clinical application of limbal cultures  and our first clinical trial on gene therapy of epidermolysis bullosa, the new 1394 Regulation was issued by the European Community, stating that Fortunately, with the help of the “Fondazione Cassa di Risparmio di Modena” , our University, and Stefano Ferrari (the late Dean of our Faculty), we were able to build the new Center for Regenerative Medicine “Stefano Ferrari” (CMR) containing a large GMP facility. We linked up with Chiesi, a pharmaceutical company in nearby Parma that helped us to create a spin-off biotech, Holostem Terapie Avanzate (HTA). We can't thank enough Andrea and Paolo Chiesi for getting involved in this enterprise. HTA took on the regulatory challenges and made our product compliant with GMP rules. Slowly we came to understand what the European Medicines Agency and our national regulators (AIFA) were afraid of and demanding, and we began planning experiments to give them the reassurances they needed. Overall, however, we lost many years during which also our scientific production decreased substantially, due to the regulatory-type activities we had to perform. Were these requirements appropriate? Yes, because of the improper use of stem cells. While we were working on the construction and certification of the CMR, we were fighting the “Stamina case” in Italy, as worried members of our scientific community . The Staex vivo cell and gene therapy. The first successful attempt to introduce and express foreign genes into primary human keratinocytes dates back to 1987 , the most common form of EB  of anchoring fibrils induces blister formation at the level of the lamina densa and is characterized by severe scarring. Kindler syndrome is due to mutations in the gene encoding kindling-1, a focal contact protein expressed in basal keratinocytes. We decided to tackle generalized junctional EB (JEB). In JEB, blisters and erosions of the skin and mucosa occur within the lamina lucida of the basement membrane in response to minor trauma. Massive chronic skin wounds greatly impair patients’ quality of life, lead to recurrent infections, and predispose patients to skin cancer. JEB is caused by mutations in three genes—LAMA3, LAMB3, or LAMC2—that jointly encode laminin-332  and in genes encoding collagen XVII and α6β4 integrins. More than 40% of patients die before adolescence  correction of JEB skin lesions  was concentrated on this enterprise. We generated almost 1 m2 of transgenic epidermal cultures and flew to Bochum, where these grafts were applied in collaboration with the German clinicians, with two big surgical procedures in 2 months.Now we can return to Hassan, who allowed a big leap forward for the development of EB gene therapy. The story of Hassan is touching. He suffers from a severe form of JEB, which could not be controlled in Syria because of the civil war. After a period in Lebanon, his family escaped from that difficult situation and was welcomed in Germany. For a number of reasons, it was too late to control Hassan's disease, which progressively worsened. Due to massive generalized infection from ex vivo cell and gene therapy has proved to be life saving, inasmuch as it was able to regenerate virtually the entire epidermis of Hassan (ex vivo gene therapy clinical trials trying to tackle different forms of EB (Such combined f Hassan . At the f Hassan . Hassan'ms of EB .in vitro and in vivo. Indeed, Hassan received ∼4 × 108 transgenic clonogenic keratinocytes and did not manifest tumor development or other related adverse events (bright holoclones (Genome-wide integration profile of his transgenic epidermis confirmed the absence of clonal selection both e events . The trae events . Until te events , includiloclones . This laloclones .This is the essence of our scientific career, which led us to be chosen to receive the 2018 ISSCR Award for Innovation. There is no greater honor for us than to be recognized by top scientists working in our same field, scientists for whom we have enormous respect and esteem; scientists who stated that this prestigious award was motivated by our perseverance in trying to combine basic science and highly controlled translation medicine to help people with virtually untreatable disease. While struggling with regulations and climbing the steep, long, and winding road toward clinical translation of such advanced therapies, we also had to fight quacks selling unproven “stem” cell therapies. As our colleagues told us while congratulating us for this award, we also hope that our work could provide young scientists with a blueprint that can lead them to successfully develop other fields of regenerative medicine. The past decade has been marked by other stem cell-based therapies producing remarkable clinical results on incurable diseases, such as hematopoietic stem cell gene therapy of immunodeficiencies, Wiskott-Aldrich syndrome, or metachromatic leukodystrophy . In 2016We could not imagine focusing on any science not involving our beloved keratinocytes and their use in regenerative medicine. Thus, our heartfelt thanks go to our Chiesi/Holostem industrial partners, who are trying to turn our science into real therapies for all people suffering from such severe diseases, and to the many clinicians collaborating in the development of different fields of regenerative medicine. Our last thought, however, goes to the numerous BSc and PhD students, postdocs, technicians, and staff we had the honor to mentor in these years. They were and are our victims, since they too had to love keratinocytes before being allowed to work with them. They are too many to be named, but without them all this work would not have been possible. It would be hypocritical to deny that some of them have been and are special.


Dementia is a syndrome, with a wide range of symptoms. It is important to have a timely diagnosis during the disease course to reduce the risk of medication errors, enable future care planning for the patient and their relatives thereby optimizing quality of life (QoL). For this reason, it is important to avoid a diagnosis of dementia not otherwise specified (DNOS) and instead obtain a diagnosis that reflects the underlying pathology. The aim of this study was to investigate the prevalence and associated factors of DNOS in persons with dementia living at home or in a nursing home.n = 1223) or in a nursing home (n = 790) were included. Data were collected through personal interviews with questionnaires based on standardised instruments. Specific factors investigated were sociodemographic factors, cognitive function, and mental health, physical health, QoL, resource utilization and medication. Bivariate and backward stepwise multivariate regression analyses were performed.This is a cross-sectional cohort study performed in eight European countries. Persons with dementia aged ≥65 years living at home  in persons living at home and 21% (range 1–43%) in persons living in a nursing home. These people are more often older compared to those with a specific dementia diagnosis. In both persons living at home and persons living in a nursing home, DNOS was associated with more severe neuropsychiatric symptoms and less use of anti-dementia medication. In addition, persons with DNOS living at home had more symptoms of depression and less use of antidepressant medication.The prevalence of DNOS diagnosis is common and seems to vary between European countries. People with DNOS are more often older with more severe neuropsychiatric symptoms and receive fewer anti-dementia medication, anxiolytics and antidepressants. This would support the suggestion that a proper and specific diagnosis of dementia could help the management of their disease. The code “dementia not otherwise specified (DNOS)” is used when symptoms and findings of cognitive dysfunction do not meet the criteria for a specific type of dementia. It may be used when the cause of dementia is unknown despite investigation  or when The most common dementia diagnosis worldwide is AD (50–70%), followed by vascular dementia (VaD) (20–30%), FTD 5–10%) and LBD (5%). It is also common for AD to occur together with VaD % and LBD. The diaFactors contributing to diagnosis of dementia involve health care providers, and patient, caregiver and system factors . Bond etThere is no cure to dementia diseases and pharmacological and non-pharmacological treatments are symptomatic and aim to maintain functional ability and independence of the person, as well as QoL and well-being , 19. AceA timely dementia diagnosis is the key to medical treatment, care and support , 24 and This study was a cross-sectional cohort study performed 2010–2013 in eight European countries within the European project RightTimePlaceCare (RTPC) . Participating countries were Estonia, Finland, France, Germany, the Netherlands, Spain, Sweden and the United Kingdom . The eigThe main variable for this study, DNOS, was obtained from the questionnaire on which the interviewer entered type of dementia as AD, AD/VaD, VaD, FTD, LBD, unknown or other diagnosis. Unknown diagnosis was considered as DNOS. Comorbidity was measured with the Charlson Comorbidity Index (CCI) . To measp = ≤0.05 was regarded as significant. All variables used in the bivariate regression analysis were also used for the multivariate regression analysis. For the analysis, SPSS version 25.0 of was used .For the association analysis in the RTPC study, inclusion of 785 participants was needed and for mean differences, 393 participants was needed to demonstrate effect size with a power of 80% (α = 0.05). In home care, drop-out rate was expected to be 15% and consequently 175 informal caregivers and persons with dementia dyads per country were planned to be included with a total of 1400 dyads. In this study, the following characteristics of participants with DNOS in eight European countries are described: demographics, comorbidity, cognitive function and QoL. Furthermore, the study includes ADLs, depression, resource utilization, BPSD and medical treatment. For missing data in both the SMMSE and the CCI, handling of missing data was not applicable, i.e. no summary score was calculated. For QoL-AD, a maximum of two missing items were replaced with the mean score. For the NPI and the Katz ADL, no missing values were imputed. For the Katz ADL, no total score was calculated if one item was missing. Mean score was imputed in the CSDD with a maximum of three missing items. No total score was calculated if more than three items were missing. The answer option “unable to evaluate” was treated as a missing value. For regression analysis, the dependent variable type of dementia was dichotomized into “DNOS” =1 and other dementia diagnosis = 0 . For the independent variables  bivariate regression analysis was performed for DNOS when living at home or in a nursing home. To analyse the association between DNOS and the independent variables, backward stepwise multivariate regression analyses (living at home/living in a nursing home) were performed and The prevalence of DNOS in the eight participating European countries was 16% in persons living at home and 21% in persons living in a nursing home Table . The mosThe age of persons with DNOS living at home varied between 82 and 90 years and these persons were more often female  or in a nursing home (n = 790). In the bivariate regression the single factors  showed significance (p ≤ 0.05) with a small 95% confidence interval (CI) in most variables, suggesting that the sample was large enough. However, when investigating each country separately, some countries , had very few participants with a DNOS and a large 95% CI which probably make the results less reliable in this respect. Therefore, only the results for the whole cohort are presented here.One limitation of the study is that this is a secondary analysis of a more global study (RTPC) which was not aiming to study DNOS. The variable DNOS was determined when the type of dementia was “unknown”. Therefore, this category could include cases where, despite a thorough diagnostic procedure, the specialists could not define the type of dementia, as well as cases where no proper diagnosis procedure was applied. Therefore, the group of participants classified as “DNOS” may be heterogeneous. We investigated a large group of persons with dementia living at home  and were judged to be at risk of institutional care within 6 months. This means that the participants may not be representative for persons with dementia in general.A diagnosis of DNOS is common but vary between countries. People with dementia who are older more often appear to have a DNOS diagnosis. They seem to be cared for more often by a GP, especially in home care, and receive fewer anxiolytics and antidepressant medications. Results of the bivariate analysis in the present study suggest that people with DNOS suffer from more severe neuropsychiatric symptoms, which would support the idea that a proper and specific diagnosis of dementia could help the management of their disease.


Restricting alcohol advertising and marketing is a cost-effective intervention for reducing alcohol harms. However, the alcohol industry maintains that advertising does not affect consumption, claiming that its purpose is to help consumers choose brands, it is not aimed at young people, it only promotes “responsible consumption”, and any relationships with consumption are not causal. We reviewed 39 case studies (1981–2016) published by the advertising industry, which evaluate the effects of alcohol advertising campaigns. We used these to examine these industry claims. 30/39 (77%) of the case studies mentioned increasing/maintaining market share as an objective, or used this to assess the effectiveness of advertising campaigns. Most  found that campaigns increased consumption-related outcomes. Some campaigns targeted women, and heavy drinkers . Campaigns often  targeted younger drinkers. These data show that advertising does influence market share. Other effects reported in the case studies include changing the consumer profile towards: younger drinkers, women, new/lapsed drinkers, and heavy drinkers. They also present evidence of a causal relationship between advertising and consumption. In conclusion, this analysis, based on industry data, presents significant new evidence on (i) the effects of alcohol advertising on consumption-related outcomes, and (ii) the mechanisms by which it achieves those effects. Alcohol advertising is an important influence on alcohol consumption, and the evidence supports the restriction of advertising and marketing as a cost-effective intervention for reducing alcohol harms . AlcoholThe mechanisms through which this influence is exerted have been well-documented. Alcohol marketing may result in an affective or cognitive response among consumers, through which they become receptive to marketing, and develop an interactive relationship with the specific brand. Further, perceived peer norms on drinking are related to heavy drinking and problem drinking in late adolescence and young adulthood ,4. It ishow it works. For example, the authors note that brand recognition, including identifying oneself as a ‘brand drinker’, is a significant mediator [The effects on consumption in general are well-evidenced, though much of the evidence is associational and cross-sectional. However, a 2016 systematic review of longitudinal studies found positive associations between level of marketing exposure and level of youth alcohol consumption in twelve such studies published since 2008 [mediator . Such seWe have identified a significant new source of evidence on the effects of alcohol advertising which does not appear to have been included in previous systematic reviews. This source is a series of evaluative advertising industry case studies, which report on the effectiveness of advertising campaigns. These case studies have been published by the Institute of Practitioners in Advertising in 23 volumes from 1981 until the most recent we identified in 2016 .(i)to use these data to test five common alcohol and advertising industry claims about the purpose, and effects (or lack of effects) of alcohol advertising see , and(ii)to identify the main mechanisms by which alcohol advertising works, as reported in these case studies.This study presents the first analysis of the content and findings of these case studies. The main aims of the study were: We first identified five common industry claims about the direct and indirect effects of advertising on consumption , above. n = 20 (51.3%). Spirits  and similar drinks accounted for fourteen case studies (35.9%), and wine and sherry accounted for five case studies (12.8%). We identified these by obtaining all volumes of the IPA series, and selecting the alcohol case studies, excluding other products . The volumes were identified from the IPA website (https://ipa.co.uk/), and from the reference lists of the volumes themselves.Second, we identified a total of 39 alcohol case studies published by the Institute of Practitioners in Advertising (IPA), and the Scottish Institute of Practitioners in Advertising  20,21,,21,22. TThe case studies present mainly quantitative data on the effects of advertising campaigns on a range of sales and other outcomes. The data  data) are commonly analysed using regression models to control for other possible explanations for any effects, such as seasonality. Many of the analyses use control groups or areas , some of the studies also present evidence on dose-response effects. Qualitative data  is sometimes reported. These case studies represent a key overlooked source of evidence on the primary and secondary effects of alcohol advertising, and have the potential to shed further light on the aims, effects, and mediators of alcohol advertising.In many instances, the case studies also provide detailed descriptions of the mechanisms by which the campaigns are intended to work. These include psychological and attitudinal mechanisms , as well as social mechanisms (for example through influencing the drinker through their peers and friends). These case studies therefore provide an important source of industry data on the intended and actual effects of alcohol advertising, and its mechanisms.Title of case study The stated advertising objectivesThe stated effects of the campaignThe reported methods used by the case study to show impact , andAny other reported effects of the campaign .Data extraction and analysis: We developed and piloted a data extraction template and used it to extract the following data from each case study as free text:A codebook was developed to systematically code and categorise the data within the main themes, and to help maintain uniformity of coding during analysis. This was done by multiple authors reading and re-reading the text of all case studies and generating a list of codes relating to the main industry claims. Coding was completed initially by two authors for the first five case studies, and then each case study was coded, and data was extracted by one author, who cross-checked codes as necessary with other authors. By this means, all text relating to any consumption-related claim was identified and extracted to tables. Initially, a longer set of nine claims was identified, but to produce a focused paper, the analysis concentrates only on the five most common claims . ExampleA total of 41 objectives and related effects of advertising were reported in these case studies. These are summarised in the The data from the case studies are used below to examine the five industry claims, in turn.“Stella’s fortunes were transformed. It outperformed every other premium lager brand, with sales increasing five-fold in just seven years, its growth outpaced the market, and as a consequence its share almost doubled…whilst commanding a significant price premium over every other comparable brand”.  and distribution…and hence its market share” .There is consistent evidence from these case studies to support the industry claim that growing or defending market share is an important advertising objective. However, to determine whether this is the ‘primary’ effect requires consideration of its other effects (below), as it is unlikely that advertising has one effect only, and indeed there is evidence that this is not the case . OverallNot only did we achieve our objective of maintaining share…”  [“Marketing objectives: 1. Increase awareness and share…”  [“r, 2002) , and “May, 2003) . (1)stimulating trial of the product,(2)increasing drinking frequency,(3)extending the type and number of occasions on which the product can be drunk,(4)targeting heavy drinkers,(5)recruiting new drinkers, and/or(6)increasing claimed usage.If sales and volume sales can be taken as a proxy for consumption, then all of the 39 case studies present evidence that advertising affects this outcome. However, the claim was also tested using a narrower definition of consumption-related outcomes: if a case study reported that the campaign was aimed at or effective in one of the following ways, then it was taken as evidence that advertising either aimed to, or succeeded in, increasing consumption: “We did not want to just sell Magners in the warm summer months: we wanted it to be drunk throughout the year”. Most  of the case studies report changes in at least one of these six outcomes. This is sometimes an explicit aim of the campaign. For example, in the case of a Magners cider campaign:“…amplified Magner’s relaxed timeless brand values and drove winter consumption” [The same campaign also: umption” . “…gave permission for a ‘drinking occasion’… Blokes were lapping up the ads, but most importantly, they were lapping up Foster’s lager too…as the ads ran, sales rose, and they have continued to do so”.Arguably, these examples show attempts to increase market share, rather than overall consumption. Other examples are more likely to reflect increases in consumption, such as this example where Foster’s lager used a humour-based campaign. The evaluation describes how it“… was to be a large profitable brand we had to attract these young heavy drinkers” [Campaigns which target heavy drinkers also appear to be more clearly aimed at consumption outcomes. For example, in the case of Miller Lite, which if it rinkers” .“To build awareness of the brand, on the assumption (based on the development research) that this would ‘naturally stimulate’ trial. Objectives were set for post-advertising brand awareness levels of 30% spontaneous and 45% prompted, and for trial levels by end of first year of 10% of all adults, 15% in 18–34 age group.”One example is from the Shakers Cocktails  (1985) c“Served blind, Stella was not significantly preferred to other draught lager brands, indeed it frequently lost to them. The reason is that Stella is one of the most bitter tasting of all lagers, and many people find a fuller, sweeter taste more to their liking. So, despite the expensive Czechoslovakian female hops, Stella is not a significantly preferred pint…until of course you put the name back on it.”An experiment reported in a Stella Artois case study also showed the effect of advertising to stimulate consumption among drinkers who did not normally like the product:“The most concrete measure of increased consumer demand is rate of purchase. Grolsch’s rate has more than trebled since campaign launch…Put simply, consumers are demanding the brand more than ever”.As noted above, the fact that all campaigns had increasing sales as an objective and/or main outcome is also an indirect indicator of the intended effects on consumption. There is also a possible feedback loop, so that consumer demand itself stimulates advertising. But it seems clear from the case study data that the purpose of advertising is to stimulate demand, and one common way of measuring the effectiveness of the campaigns is in terms of willingness to purchase. The Grolsch lager campaign provides one example of this:The use of advertising to target heavy drinkers (see below) is also indicative of the intended effect of advertising on consumption. In evaluations, inferences are strengthened if longitudinal data are available, showing effects before and after the intervention, and by using data across multiple time points. They are further strengthened by the use of concurrent control or comparison groups or areas  and by the control for potential confounders . Such meAlternative explanations are often controlled for using econometric modelling “Confidence levels are over 99% that there is a causal relationship between cumulative advertising weight and penetration”.(Penetration = proportion of a target audience reached ) The various causal paths and mechanisms from advertising through to sales and consumption are also clearly described in many case studies. One pathway from building a relationship with drinkers through to sales is clearly articulated in the case of a Stella Artois advertising campaign:In summary, most of the case studies present detailed evidence for a causal relationship between advertising and consumption-related outcomes  through the use of controlled, ITS data, while controlling for other possible explanations. This does not rule out a significant effect of advertising on market share (as per Claim #1), as opposed to consumption. Claims about effects on consumption may come from other data .“If Miller Lite was to be a large profitable brand we had to attract these young heavy drinkers”.“…Campari needed to achieve a more stable and democratic base. This meant recruiting new, younger, mass market trialists from among the socially mobile, high-spending, heavier drinkers with the discretionary income to spend drinking in pubs in the evenings.”“Television was chosen as the sole medium. This was not only for reasons of cost-efficiency , but because of the nature of the advertising task”.It has been shown that the alcohol industry is dependent on harmful drinking to protect its profits, and targets heavier consumers ,43. Ther“A quality lager to a “Headbanger” is one which is stronger…The clever thing about this line  was that each user group could appropriate it for their own ends. The original ‘Connoisseurs’ could use it with the ingredients story to reassure themselves that the product had a distinctive flavour, the ‘Headbangers’ who knew that the duty levied on alcohol made up a large chunk of the price, could use it to reassure themselves that because it cost more it was stronger”.However, this is most clearly shown in a Stella Artois lager case study, where the market segmentation claimed to identify three types of drinker which it was aimed at: ‘Connoisseurs’, ‘Style-seekers’ and ‘Headbangers’. For the latter group, the strength of Stella Artois is its key selling point:“A cluster analysis …isolated a group of late 20s/early 30s up-market drinkers with clearly affluent quality-oriented tastes (Connoisseurs), a group of younger middle-market heavy drinkers with clearly hedonistic tastes (‘Headbangers’) and a group of younger up-market drinkers, highly experimental and with fashion-oriented tastes (Style –seekers’)…the only premium brand they all consume above average is Stella Artois”. The Stella Artois advertising campaign was reported to successfully appeal to these three groups of drinkers:“As is the case in many post-mature markets, whisky brands are very reliant on a small number of heavy, and increasingly ageing, consumers, to provide the majority of volume. The Famous Grouse was no exception. Our first advertising task was to protect and build this core drinker base by persuading existing consumers and drinkers of competitive blends to choose The Famous Grouse more often. In the longer term we had to attract more younger drinkers – the heavy-using loyalists of tomorrow”.“The potentially disastrous implications of losing heavy drinkers had locked whisky advertising into a creative paradigm defined by past executions, the so-called ‘whisky cage’. To achieve our objectives, we needed to break out of this cage.”. The need to recruit heavy drinkers appears to be particularly strong for whisky, as these consumers are their main consumer base, as shown in the Famous Grouse whisky case study. This case study highlighted the need to recruit younger drinkers who will become future heavy drinkers:“Blended whisky suffers from an ageing customer profile. Figure 1 shows that 62% of heavy users are aged 55+ and 39% over retirement age. Parts of the market are literally dying off, whisky tumbler in hand….”“The increased volume and rate of sale, despite the diminished distribution, indicates that where the brand was available, purchase was also hugely increased – not only from existing customers buying more”. As with many other markets, the Pareto principle applies: 20% of drinkers account for 80% of sales. So, rather than struggle to make whisky appeal to younger consumers like the premium brands, we chose to focus on the core audience of heavy users. We knew that they were older. We knew they were primarily male. We knew that unlike malt users they tended to be downmarket”.The Scottish Leader whisky campaign (2003) also had a target market of heavy drinkers:“…young people in the early 1990’s turned away from “routine heavy drinking” (see p 409). Around 1995 however the % of daily drinkers went back up to 62%, including the rise of a ‘feminine session culture’, which facilitated a new drinks sector, ‘Premium Packaged Spirits’. . ‘A great deal of this is amongst Archers’ core target”.The Archers schnapps case study describes how a new drinks category arose to exploit session drinking in women:Other examples of this are reported in the Miller Lite (1990)  and Campheavy-using loyalists of tomorrow”. Many other case studies refer to the need to recruit young drinkers. There is therefore clear evidence from these case studies that advertising often targets younger drinkers, however this is not the right dataset to examine effects in underage drinkers.These case studies do not mention effects on underage drinking – it is unlikely that they would put forward data on such adverse impacts, even though it is well-documented elsewhere that advertising aims to, and is successful in, recruiting underage drinkers . However“By 2014, Guinness started to see significant drops in price elasticity in Great Britain and Ireland…The reduction in price sensitivity also helped us to stem long-term decline in volume in GB, and we saw an upturn in fortunes in Ireland”.Finally, a number of other effects were identified in the case studies (other than those which we tested against the five industry claims). These other effects include positive effects on the parent company’s share price, and organisational effects. These effects are listed in “The premium price ideally pays for the advertising which tells the consumer the product costs more in the first place”. Several case studies also describe the mechanisms by which higher prices are maintained, e.g.,The full list of effects of advertising which are described in these case studies, and a summary of the mechanisms through which it works, are summarised in “The in-depth interviews supported the earlier qualitative research in suggesting that Hofmeister’s new appeal lay in drinkers’ perceptions of it as a popular, fashionable lager, thus, the link between the brand’s advertising-born saliency and its sales increase was confirmed” [“That promotions have worked so well is attributable in a large part to the role that advertising plays before consumers even step into the supermarket” : nfirmed” . Advertiis, 2003 ).“Buyers want to feel that they are making a sensible, defensible choice that reflects well upon them as knowledgeable beer drinkers. This can override actual taste preference, the brewery adage that ‘people drink with their eyes’ has been repeatedly confirmed by blind and branded product tests, where the brand-names can reverse the preferences expressed ‘blind’” . “In its Belgian homeland, Stella is a swilling lager lacking in premium credentials, in blind taste tests in the UK, the product regularly finishes bottom of the league (being too bitter for many). However, add the Stella name and the perspective of British lager drinkers changes radically… This phenomenon, where brand potency overcomes product reality, is also seen quantitatively. Stella outperforms its key competitors on almost every image dimension”.The Stella Artois  case study provides another clear example:These data suggest that advertising both aims to change attitudes, expectancies and consumption behaviour, and is effective in doing so.“However, the effect of advertising does not cease at this last data point. Not because we continued advertising after that period (even though we did) but because there would be residual effect from the advertising up to that period… advertising was responsible for an extra 62,618 barrels (excluding adstock) and 94,341 barrels (including adstock)”.There is also interesting data in these case studies on the continuing effects of campaigns even after they have finished. This is described in the case of Boddington’s (1995) beer:the additional effect of advertising appears to continue for at least 6 years”—Murphy’s stout (1993-5) [“The analysis shows that, although the ads were only on air for a two and half year period, they ‘continue to generate a further 72 million bottles and £77, of extra revenue over the next six years’”“The result has been accelerated growth that even now, eight years later, remains very strong and continues to outpace the category significantly”.This period can be considerable (“(1993-5) . For exaThese lagged effects have implications for future evaluations and systematic reviews of the effects of advertising (see below).every £1 spent on advertising since 2010 has generated £32 in sales revenue”) [Some of the case studies also report some quantitative measure of the Return on Investment (ROI) of advertising. The ROI ratios where reported range from 2–3, though in some cases are much higher : “evenue”) .These findings show firstly that advertising does, as the alcohol and advertising industries claim, influence share of the market. Whether this is its primary effect is difficult to ascertain, but it appears clear from these evaluations that advertising does considerably more than this, with evidence that it is used to effectively change the consumer profile, for example, towards younger drinkers, women drinkers, new or lapsed drinkers, and heavy drinkers. It appears to do this through a wide range of psychological, behavioural and social mechanisms , by inflThe case studies also provide consistent evidence that advertising increases both brand sales and indirect consumption measures and that this relationship is causal, with most of the studies using appropriate quasi-experimental methods and longitudinal data  to support their claims of effectiveness. While the current dataset is not sufficient to draw firm conclusions on advertising’s effects on individual consumption, as distinct from shifting brand choices within a particular category, there appears to be strong evidence of its effects on consumption within specific categories of drinker. Moreover, all this is consistent with the existing evidence . A recen“We targeted the influential drinkers who had a high degree of interest and were well connected…the on-trade teams targeted influential bars for initial distribution, and we undertook an extensive sampling campaign to accelerate trial”.These analyses of the advertising campaigns also provide insights into the causal pathways and mechanisms through which advertising works ‘Advertising is a progress through various stages. Behaviours are only influenced by advertising at the end of a 9-step process, beginning with exposure to the ad, and moving through paying attention to it, reacting favourably, comprehending it, agreeing with it, sorting and retaining its content, remembering it, deciding upon it and behaving in accordance with this decision. At any step of this tenuous process the causal chain can be broken. Most available literature is unable to demonstrate a direct causality throughout these 9 steps.’The findings on the lagged effects of advertising are particularly important. They have significant implications for evaluations of marketing restrictions, as it means that null findings from any such studies can potentially be explained by the fact that the advertising clearly affects consumption for a considerable period after it is withdrawn. The implication is that the lengths of follow-up needed for evaluative studies may be much longer than anticipated, if any effect of marketing restrictions in reducing consumption are to be identified. For comparison, the lengths of follow-up in previous such evaluations ranged from 1 to 3.5 years . The recA significant strength of the study is that it uses a hitherto overlooked source of industry evidence that triangulates well with current scientific evidence, particularly recent evidence reviews that show the impact of alcohol advertising on consumption ,2. The kIt should also be noted that the case studies span a long time period. One potential criticism which may be levelled at the findings is that they represent old campaigns, and do not reflect current practice. Certainly, there are few alcohol case studies dating from after the tightening of Ofcom (UK communications regulator) regulations in 2004/2005: only 2/39 case studies date from 2005 onwards. It is not possible to determine from these data alone whether subsequently revised Ofcom regulations did affect advertising, or whether they meant that advertising companies were subsequently less likely to submit alcohol case studies after 2005, and/or were less likely to report promotion of harmful/heavy drinking after this date. However, our analysis of the importance of heavy drinkers to the alcohol industry used data from 2013/14, so this dependence clearly continues . MoreoveThese findings show the role that alcohol advertising has in promoting alcohol consumption and heavy drinking. This appears to extend well beyond its effects on market share—what the industry claims is its “primary” effect—and suggests that future evaluations and systematic reviews need to include evidence on the wider psychological, behavioural and social and societal mechanisms and effects of alcohol advertising – for example, by ensuring that any evaluations examine these processes and mechanisms (as well as consumption outcomes).harmful consumption. Our findings clearly do not support this interpretation. The study provides clear evidence, based on industry data, of the mechanisms by which advertising affects consumption, and shows its emphasis on recruiting drinkers, and particularly younger drinkers, as well as its emphasis on encouraging more drinking occasions, and, in some cases, targeting heavy drinkers. The reliance on heavy drinkers also requires a constant search for new groups of heavier consumers, to replace those that die in no small part due to that consumption; As one whiskey producer put it, “Parts of the market are literally dying off, whisky tumbler in hand….” These findings should be used to inform future evaluations and systematic reviews of the effects of alcohol advertising, and future assessments of the potential effects of regulatory interventions.Finally, the claims that we examined are used by the alcohol industry to argue that tighter restriction on advertising is unnecessary because advertising does not ‘work’ to promote consumption, and, they claim, even if it did, that advertising does not promote