Vaccinium macrocarpon L.) are particularly important characteristics that determine the harvests’ processing value and potential end-use products . However, cranberry fruit size and shape attributes can be difficult and time consuming for breeders and processors to measure, especially when relying on manual measurements and visual ratings. Therefore, in this study, we implemented image-based phenotyping techniques for gathering data regarding basic cranberry fruit parameters such as length, width, length-to-width ratio, and eccentricity. Additionally, we applied a persistent homology algorithm to better characterize complex shape parameters. Using this high-throughput artificial vision approach, we characterized fruit from 351 progeny from a full-sib cranberry population over three field seasons. Using a covariate analysis to maximize the identification of well-supported quantitative trait loci (QTL), we found 252 single QTL in a 3-year period for cranberry fruit size and shape descriptors from which 20% were consistently found in all years. The present study highlights the potential for the identified QTL and the image-based methods to serve as a basis for future explorations of the genetic architecture of fruit size and shape in cranberry and other fruit crops.Image-based phenotyping methodologies are powerful tools to determine quality parameters for fruit breeders and processors. The fruit size and shape of American cranberry ( Vaccinium macrocarpon L.) is a perennial fruit crop native to North America . The cranberry industry has used fruit sizers to separate large fruit, which are sold at a premium for SDC processing compared with small fruit, which are used for cranberry juices . Most cranberry breeding programs still use manual caliper measurements to gather data about basic cranberry shape and size attributes, and sometimes use visual assessments to categorize complex shapes of interest.The growing consumer demand for sweetened dried cranberries (SDC) has increased the need for new cranberry varieties that produce large, round, and uniformly shaped fruit  ratio), fruit size, and color have long been measured and used as major determinants of fruit quality in many crops . More reComputer vision methods, such as landmark-based methodologies  that desIn this study, we developed a massive phenotyping approach based on digital imaging to rapidly acquire data for basic cranberry fruit shape descriptors such as length, width, and area in breeding programs. We also implemented a newly developed persistent homology methodology to comprehensively quantify complex fruit shape features that are difficult to quantify with traditional descriptors. Moreover, we used data gathered using such computer-vision methodologies in a full-sib mapping population to map genetic regions governing fruit shape and size in cranberry.n = 351 individuals), which was previously used in recent cranberry genetic mapping studies  were exported to R for further statistical analysis and quantitative trait loci (QTL) mapping. The complete code for image analysis and persistent homology is provided , and u was a variance-covariance matrix (additive relationship matrix A). Genomic heritability (h2) was calculated for each trait within each year according to Using image analysis and persistent homology, we measured seven traits, three of them characterizing fruit size , and four characterizing fruit shape/elongation . For each trait on a per-year-basis, we averaged the repeated measurements per genotype  and proceeded to calculate best linear unbiased predictors (BLUP) by fitting a mixed model e sommer  where Y cross object with seven phenotypes was created in R using the package qtl  were calculated using the function scantwo with 1,000 permutations. In total, 21,000 permutations were required for the seven traits evaluated over the 3-year period. To speed up this process, we distributed the permutations among 1,000 jobs performed at the Center for High Throughput Computing of the University of Wisconsin-Madison using the software HTCondor  ; howeverPairwise correlations were computed for the genotype BLUP for each of the seven traits (two persistent homology-based PC and five basic descriptors) on a per-year basis. As expected, high correlations were observed among shape-related  and size-related  parameters . In parth2) on a per-year-basis ranged from 0.159  to 0.921  with a mean of 0.676  covering all traits  collected from cranberry fruit images. In total, we found more than 252 QTL for the 21 trait-year combinations of data; from these, more than 40% collocalized for the same trait in at least 2 of the 3 years and provided confidence the identified regions are involved in cranberry fruit shape and size expression. The remaining 60% that were unique within a specific trait/year combination may represent false-positives, or could represent genotype-by-environment interactions for the cranberry fruit traits.Collocalization of QTL from multiple traits also occurred, which was expected considering the high correlations observed among the shape and size related traits . To overCapsicum annuum and C. frutescens,  are genetically controlled by similar QTL, we searched for overlapping 1.5 LOD intervals between the yield related QTL discovered by tescens,  identifiFurther studies should investigate and validate the presence of acting genes and regulatory regions at the QTL locations discovered in this study. In this sense, in The process of domestication in many fruit crops initially focused in fruit size selection with subsequent efforts to select other agronomic and nutritional traits . AlthougThe GRGY population was chosen for this study because it has plentiful genotypic data available . In minoGiven that the population used here was developed for breeding and selection purposes, our measurements can be immediately used as criteria to select for materials of interest for growers and industry. Among the genotypes with potential for fruit size , genotypes P111, P148, P182, P194, P257, P275, P3, P330, P68, and P93, showed consistent values across years in the top 10%. Moreover, considering eccentricity and LW ratio (which measure fruit shape in the same direction), genotypes P104, P112, P121, P129, P136, P14 showed very elongated fruit. On other hand, if the goal is to select large and round fruit at the same time and based on all the traits combined, genotypes P116, P176, and P84 were among the most promising .To increase consumption and revenue, the cranberry industry has been developing new high value products based on fruit quality and the inherent cranberry nutritional properties. Therefore, fruit quality characteristics such as fruit color, firmness, size, and shape have become ever more important for cranberry breeding programs, particularly for the production of SDC. For example, the industry requires very specific fruit quality properties to allow efficient industrial processing of these type of products. Thus, varieties with high anthocyanin content and high yield coupled with large round and firm fruit are highly desirable for the industry. Besides the increased production, such ideotype is economically valuable for manufacturing SDC because only large and round cranberries make the sorting for the high value SDC processing lines.Commercial cranberry beds consist of very complex systems and infrastructure that provide the required soil, water, and management requirements of cranberry plants. These beds cannot be easily replicated or afforded at typical public agricultural research stations. Moreover, given the requirements for cranberry production, space availability is very limited for cranberry research and breeding programs. The GRYG population is a precious resource for cranberry breeding and genetics studies that is planted in an active commercial bed. Based on our study of this population, we discovered several linkage groups with promising marker-trait association and clustering areas with QTL collocated for multiple traits. Considering the number of QTL detected, the prevalence of QTL clustering, and the number of collocated QTL for multiple related traits, we found that the availability and use of genome-wide distributed markers to compute relationship/kinship matrices—combined with mixed model approaches—was a useful approach for obtaining accurate BLUP . This methodology considerably increased our observed genetic correlations among years and the genomic heritability of the evaluated traits. This strategy is useful in both breeding and genetic research purposes to correct for some of the micro-environmental variation not captured by the explicit design terms when suboptimal planting designs are all that is available or the only design possible.10.7717/peerj.5461/supp-1Supplemental Information 1Click here for additional data file.10.7717/peerj.5461/supp-2Supplemental Information 2Click here for additional data file.10.7717/peerj.5461/supp-3Supplemental Information 3Side views of the annulus kernel-isolated density features of three different fruit shapes. For the bell-shaped fruit (left panel), points a and b highlight the differences detected by the persistent homology method.Click here for additional data file.


School tobacco policies (STPs) that aim to achieve a tobacco-free environment require consistent enforcement by school staff. However, little is known about why staff choose whether or not to enforce STPs. Therefore, we investigated staff members’ responses to STPs that determine enforcement. Furthermore, we examined how these responses depend on contextual factors at the individual, interpersonal, school, implementation, and national levels.We performed a realist review (RR), which synthesizes existing primary evidence into a programme theory demonstrating key causal pathways through Context-Mechanism-Outcome configurations (CMOs). These CMOs link contextual factors to outcomes (i.e. staff enforcement) by explaining the underlying generative mechanisms . A systematic literature search for the period 2000–2016 was performed using Academic Search Premier, PsycInfo, and MEDLINE. Forty English-language articles were identified for the synthesis.Our programme theory demonstrated three CMOs: when contextual factors make staff members experience STP enforcement as part of their professional role and duties, it may lead to staff members showing responsibility for STP enforcement (CMO1); when contextual factors make staff members feel their contribution is leading to positive outcomes, it may lead to staff members showing motivation to enforce STPs (CMO2), and when contextual factors make staff members feel that they are able to deal with students’ responses, it may lead to staff members showing confidence in STP enforcement (CMO3). Moreover, the programme theory provided more precise insights into what contextual factors contribute to triggering the individual mechanisms and the consequent outcomes.By applying a realist approach, we have been able to detect three CMOs explaining staff members’ STP enforcement. The findings provide useful insights explaining how stakeholders can support staff members’ STP enforcement and consequently improve the impact of STPs on adolescent smoking.The online version of this article (10.1186/s13643-019-1086-5) contains supplementary material, which is available to authorized users. School tobacco policies (STPs) aim to decrease adolescent smoking behaviour and exposure to second-hand smoke by restricting smoking only to certain areas or banning smoking completely in the school buildings and outside premises during school hours. The rationale for STPs is based on research evidence showing that (i) the onset of smoking usually occurs in adolescence, (ii) schools have a major influence on adolescent smoking uptake, and (iii) schools are significant settings for health promotion . MoreoveResearch shows that STPs effectively decrease adolescents’ exposure to second-hand smoke –6, but eWhile staff enforcement is important for the effectiveness of STPs, there is only a limited understanding of what determines the consistency of staff members in terms of STP enforcement. Research has demonstrated a connection between staff members’ responses to STPs and the staff’s actual enforcement behaviour. For instance, Gordon and Turner’s  study shHow do contextual factors at the individual, interpersonal, school, implementation, and national levels (Context) contribute to triggering staff members’ cognitive, psychosocial, and behavioural responses (Mechanism) that may support their STP enforcement (Outcome)?Most of the current literature on STP enforcement by staff members report either on the context or on the responses, but how these factors are connected is rarely explained. Our realist review will contribute to this gap in the current understanding by explaining how staff members’ responses, which make up their STP enforcement, differ across contexts. The realist review is a suitable method, because it aims to explain how contextual factors  produce outcomes  by specifying the underlying generative mechanisms  . We aim A realist review is an explanatory method that aims to describe what works for whom, under what circumstances, and how. It synthesizes evidence into a programme theory explaining how differences in contexts may lead to outcomes by forming the enabling conditions that allow generative mechanisms to occur . The genThe initial programme theory Table —i.e. theNext, a systematic literature search was conducted to refine and substantiate the CMOs in the initial programme theory. The systematic search included two separate search strategies  because implementation and adoption are not categorically distinct processes.From the remaining 50 articles, we highlighted the relevant pieces of evidence for our study, and following the RAMESES publication standards for realist reviews, a quality appraisal for relevance and rigour was made for these selected pieces of evidence  Additio. The relThe rigour of the selected pieces of evidence was assessed by examining each article’s sample, data collection, and methods of analysis before determining how these features might affect the validity of the evidence. The quality appraisal of rigour was conducted as the last of all the steps; none of the remaining articles was excluded at this point. Two authors  worked together during the selection and appraisal of the studies, and all articles included in the final synthesis were examined and approved by both authors. In addition to the evidence found through the systematic search, seven articles published before or after the timeline of the search were included, as they provided valuable evidence for analysis. These articles were found through citation searching from the articles included and manual searches of the latest publications. The final number of articles was forty. Additional file The first author extracted the relevant pieces of evidence from the selected articles in order to refine or substantiate the initial programme theory. We began the synthesis with the “thick” evidence by studying how contexts, mechanisms, and the staff members’ enforcement are connected. Finally, the CMO configurations were compared to the thinner evidence to reveal further contextual refinements. The findings were reflected upon by the authors for a period of 1 month. All authors approved the final programme theory.We revised the initial programme theory into a refined programme theory. The refined programme theory revised the initial outcome “staff members’ STP enforcement” into three sub-outcomes: responsibility, motivation, and confidence in STP enforcement. In addition, the refined programme theory includes many new contextual factors ; when contextual factors make staff members feel their contribution is leading to positive outcomes, it may lead to staff members showing motivation for STP enforcement (CMO2); and when contextual factors make staff members feel that they are able to deal with students’ responses, it may lead to staff members showing confidence for STP enforcement (CMO3). The remainder of the “Staff members tend to commit to enforcement only when they know what is expected of them—i.e. they know what their duties are , 22–26. In addition to written policies, the senior management’s role in outlining the school values and policies and directing the enforcement is emphasized , 33, 34.Staff members who perceive that health promotion—e.g. protecting students from the harmful effects of smoking—is compatible with their professional identity, and values show more responsibility for STP enforcement , 23, 36.Staff members’ perceptions of whether their own smoking influences student smoking may have an impact on the staff members’ responsibility for STP enforcement. When staff members consider themselves non-smoking role models for students, they may also acknowledge STPs as part of the school’s core task –42: “We National legislation on STPs could be utilized to strengthen the staff’s responsibility for STP enforcement. When national legislation compels schools to enforce STPs, the mandatory nature of the laws may make staff members feel more responsible for enforcement , 43, 44.The staff’s perceptions of the influence of STP enforcement on staff-student relationships may affect feelings of responsibility for enforcement. If intervening in student smoking clashes with the type of relationship staff members wish to have with students, or which the staff perceive to be the basis for effective collaboration, the inconsistency may lead to prioritizing good relationships over enforcing STPs: “You don’t learn to manage them [pupils] by creating lots of rules and making sure that you enforce them. You manage them by establishing the relationship and working with the child, not against the child, and through that relationship to an understanding that there is a way of working together which is in both our interests. And that would be my attitude towards smoking.” .School working conditions, like overwork and smoking not being considered a priority health issue, may influence the staff’s responsibility for STP enforcement. For instance, perceptions of responsibility may decrease when the school is burdened with other tasks , 36, 43 When staff members believe that STP have positive outcomes for the school, staff, or students, it may trigger their motivation for STP enforcement , 51, 52.The behaviour of colleagues is one factor that may influence staff members’ perceptions of the ability of STPs to make an impact. If staff members witness their colleagues turning a blind eye to student smoking, their positive expectations of being able to make an impact on students—and thus their motivation to enforce STPs—may decrease , 23, 31.In addition, the characteristics of the smoking student may influence the staff members’ expectations on enforcing STPs. For instance, recognizing a student’s tobacco addiction may cause a contradiction with the staff members’ motivation to enforce STPs, because intervening could be considered “fire-fighting” rather than solving the smoking problem . The schPearson et al.’s  study shSTP enforcement may also have negative outcomes that influence the staff’s attitudes towards STPs and their motivation for enforcement , 51, 59.The national context may also play a part in smoking relocation in schools. Existing legislation rarely prohibits smoking in school surroundings, and thus it restricts and sets limits on the staff members’ jurisdiction , 22–26. Staff commit to enforcement when they feel confident enough to intervene in student smoking , 22–26. The staff members’ own personal smoking habits may also decrease their ability—e.g. authority—to intervene in student smoking. Staff members who smoke may feel that they are not fully entitled to take action against student smoking, and students may use the staff member’s smoking as an argument against enforcement , 29, 31.At the national level, legislation compelling schools to implement STP strengthens staff’s abilities to intervene in student smoking, because government rules stand as a backbone and give staff authority for enforcing with criticizing students , 29, 43.The purpose of our realist review was to improve our understanding of why staff members in some schools enforce STPs more consistently than others by explicating how contextual factors at the individual, interpersonal, school, implementation, and national levels contribute to triggering school staff members’ cognitive, psychosocial, and behavioural responses (mechanism), which may in turn influence their enforcement behaviour (outcome). We discovered three generative mechanisms, which we integrated into a programme theory.CMO1: When contextual factors make staff experience STP as part of their professional role and duties, it may lead staff members’ responsibility for STP enforcement. Key contextual factors that may trigger responsibility are the staff members’ professional identity and values  and perceptions that enforcement does not considerably burden them or negatively influence staff-student relationships.CMO2: When contextual factors make staff perceive that their contribution is leading to positive outcomes, it may lead to staff’s motivation for STP enforcement. Key contextual factors that may trigger motivation are the staff members’ perception that schools can compensate for negative peer and family influences and their perception that all colleagues are doing their part and participating in enforcement.CMO3: When contextual factors make staff feel that they are able to deal with students’ responses, it may lead to staff’s confidence for STP enforcement. Key contextual factors are the staff members’ own smoking status, non-familiarity with students, and the expectation that students will respond aggressively. Although the programme theory presents the CMOs separately, they are interconnected, as the staff’s responsibility (CMO1) and confidence in STP enforcement (CMO3) influence the consistency of all staff members in enforcing STPs. This further triggers the staff’s outcome expectations and motivation for STP enforcement (CMO2).This was the second realist review looking at how to facilitate staff members’ implementation of health promotion policies/programmes in the school context. Pearson et al.’s  review sPrior studies examining programme implementation in schools have pointed out that support from senior management is a key element in successful implementation, yet they did not explicate in detail why this is the case , 60. OurA novel finding was the importance of staff members’ collective STP enforcement for individual staff members’ expectations of a positive outcome. Earlier research on STPs had already demonstrated that the consistency of staff members’ enforcement influences the impact of STPs on adolescent smoking , 8, 10, The results show that staff members’ positive outcomes may decrease if implementing and enforcing smoking bans on the school premises leads to smoking outside the school’s boundaries and increased smoking visibility. A solution at the school level could be to prohibit students from leaving the grounds during school hours—that is, making the school hours a smoke-free time for all adolescents. However, one may question whether such a rule would not lead to adverse effects for the most vulnerable students. A more feasible solution may be to adopt a government policy that permits schools to enforce the smoking rules during school hours outside the areas that fall under schools’ formal jurisdiction.The results also demonstrate the significance of staff members’ collective STP enforcement, highlighting the importance for schools to engage all staff members in the enforcement of STPs. There were many reasons explaining why individual staff members may not enforce the rules, but one important reason was that staff members question the impact of punitive sanctions for nicotine dependent students. Therefore, it is important for schools to find ways to support nicotine-dependent adolescents; otherwise, staff members will remain reluctant to enforce the rules, in turn, decreasing the overall impact of the STP .Schools should be motivated not only to aim at promoting adolescents’ academic outcomes, but also to contribute to the students’ overall health and well-being. The results indicate that national policies have an important role to play in making staff members feel that STP enforcement—and health promotion more generally—is part of their professional role. Finland is an example of a country where national laws on education and health presume co-operation between sectors in the education and welfare activities of schools. A basic education law  also aimThe programme theory explains under what conditions staff members feel responsible, motivated, or confident (i.e. generative mechanisms) to enforce STPs. However, the main limitation is that the programme theory is unable to differentiate the relative influence of the contextual factors and generative mechanisms on actual staff members’ enforcement behaviour. Such questions of relative influence are best addressed in future studies using quantitative methodologies.Another limitation is that evidence on contextual factors at the school and intrapersonal levels was scarce. Future research should focus in more detail on these school and intrapersonal level factors, because they are likely easier to tackle by schools and local stakeholders compared to national-level factors. For instance, our results show that staff experience difficulties in enforcing STPs when they know students are addicted to nicotine, yet evidence on possible solutions to this problem remains absent.By applying a realist approach, we have been able to detect three CMOs that explain school staff members’ STP enforcement. We have extended the contemporary understanding of the complexity of implementation in the school context by thoroughly specifying how contextual factors at different levels  may influence staff members’ STP enforcement. The study offers insights for policymakers and stakeholders on how to support staff members’ STP enforcement and thereby the effectiveness of STPs on adolescent smoking.Additional file 1:Search strategy. (DOCX 155 kb)Additional file 2:Main characteristics of the included studies. (DOCX 36 kb)Additional file 3:RAMESES publication standards: realist syntheses. (DOCX 15 kb)


Diabetic retinal neuropathy refers to retinal neural tissue damage occurring before the structural retinal changes of diabetic retinopathy and fulfils many of the criteria for causality for the subsequent vasculopathy. Developing reliable means of measuring neuronal damage in diabetes may be important in efforts to prevent retinopathy of a clinically significant and irreversible stage. This study aimed at systematically assessing current clinical measurements of diabetic retinal neuropathy so that future studies may utilise a consensual battery of tests in studying this poorly understood disease state between a healthy retina and one that is retinopathic.  A systematic search of the medical literature since 1984 was performed on PUBMED and EMBASE, and the evidence supporting each identified method as an indicator for clinically important diabetic retinal neuropathy was graded relatively as compelling, medium, or weak according to criteria assessing its relationship to subsequent diabetic retinopathy, quality of supporting studies, and published reproducibility.  The systematic search yielded 6432 results. Subsequent assessment by two independent investigators identified 601 multiple subject studies in humans assessing clinical aspects of the retinal structure, function, or psychophysics in the prediabetic retina. The 933 separate instances of clinical methods assessed as being supported by relatively “compelling” evidence included colour vision changes, flash ERG b-wave latency, flash multifocal b-wave latency, scotopic b-wave and oscillatory potentials in ERG, and contrast sensitivity.  The results showed moderately poor quality of extant evidence and indicate the best clinical methods for assessing diabetic retinal neuropathy that remain to be confirmed. This is the first systematic assessment of the medical literature aiming at assessing the breadth and validity of these methods and represents an early step in identifying and developing clinical endpoints for use in trials designed to identify at-risk patients or prevent diabetic retinopathy. Diabetic retinopathy is a significant and progressive cause of blindness and visual impairment worldwide . DiabeteDue to its high metabolism, the retina is particularly vulnerable to the many metabolic changes that result from diabetes , 9. IrreIf the processes leading to this neurodegenerative precursor of clinical diabetic retinopathy could be clearly defined clinically using currently established or easily adopted testing procedures, it could facilitate further studies on potential treatments or preventative therapies against the development of diabetes-induced visual loss. Based on a systematic study of the body of the scientific literature using results from over 6400 papers to identify trends in the most useful clinical tests, this study provides an initial attempt to provide a meaningful clinical definition of diabetic retinal neuropathy according to easily performed clinical tests. Describing and quantifying a disease state that may be modifiable but not currently measurable in terms of the clinical tests that may be most useful in identifying the pattern of disease progression may allow further research into this disease process on a larger scale.Investigation of retinal vasculopathy in diabetic retinopathy has remained the dominant scientific paradigm for many decades, and as such, the role and context of diabetic retinal neuropathy in the wider clinical problem of diabetes-induced blindness is less understood. Whilst the phenomenon is widely acknowledged, the field remains controversial: no one test has been shown to be the gold standard in diagnosing retinal neuropathy in diabetes. This study assumed that a system of assessments could better provide a scientifically based initial platform for identifying the condition and monitoring for both early disease progression and potential therapeutic effects in the interval before the traditional retinopathic stage of the disease.This study therefore aimed first at systematically assessing the current best evidence behind commonly available clinical measurements of impaired neuronal structure or function in the retina in early diabetes. Secondarily, it aimed at analysing these results in the context of current clinical practice to inform the utility of commonly available functional indicators and tests of diabetic retinal neuropathy available to practicing ophthalmologists.To maximize the characterisation of the current knowledge regarding clinically measurable early diabetic retinal changes, a critical analysis of known scientific evidence behind widely available clinical investigations of pre-retinopathic diabetic damage was conducted. However, further analysis to differentiate between the quality of evidence, clinical practicalities, and the risks and benefits of any proposed clinical test in the context of this systematic review of the literature was also considered in providing a framework to determine a justifiable appraisal of the available evidence for clinical assessment of the condition. Determining the baseline benefit of an investigation in the context of this immature field must be explicit and defensible. The internationally recognised GRADE system of evidence measurement satisfies all these criteria , and it This article is the first to apply a system of assessing strength of evidence as a means of critically evaluating the large body of research on preclinical diabetic changes. This approach serves to define initial potential endpoints in diabetic retinal neuropathy for use within the context of other more established retinopathy grading systems, as there is currently no clear unequivocal measure of diabetic retinal neuropathy for use in a clinical or clinical trial setting.This study uses a systematic review performed within a specific time frame. It uses the described search strategy and weighting system to sample the literature on this broad topic and proposes a framework of clinical tests to base further scholarship into this field upon. It is intended to be updated and refined in future, and because of its systematically collected nature, is necessarily is not exhaustive or comprehensive.in vivo at a stage where patients were diabetic and did not demonstrate retinopathic changes. Studies which did not distinguish between patients with diabetes graded as nonretinopathic and early  retinopathic grades were included. The evidence supporting each tested method likely to be clinically relevant for identifying diabetic retinal neuropathy was graded relatively as compelling, moderate, medium, or weak according to the GRADE criteria-based table   24, 35––35–37. MThis study included methods of visualising diabetic changes in the retina. The limitations of these tests, though they are frequently cited in the literature, are that while they are a useful means of identifying end-stage damage to the neural retina vis-à-vis diabetic retinopathy, they give less useful insights into functional deficits of the neural retina at potentially reversible early stages, although relatively large numbers of results are reported at this stage. Additionally, significant disagreement over guidelines for imaging modalities and classification systems was found .Contrast sensitivity and dark adaptation have more compelling evidence in the literature than clinical colour vision tests (the clear majority of which were performed with FM-100 colour tests) or best-corrected visual acuity (BCVA) for detecting early diabetic changes . As can Perimetry has a well-established clinical role in monitoring subtle visual-field loss. Despite the relative paucity of studies, the significance of SWAP, a clinically archaic modality for glaucoma detection, proved to be interesting as a means of detecting early blue-yellow colour vision loss from reduced blue cone sensitivity in the diabetic retina , especiaAfter weighting the strength of evidence being examined, the second aspect of the GRADE system of assessment is the proposal of recommendations based upon the strength of evidence. For the purposes of this study, the clinical tests with the greatest proportion of compelling studies and the highest prevalence in the literature would be recommended in a battery of investigations to assess patients at risk of developing diabetic retinal neuropathy and, possibly, retinopathy.Electrophysiology proved to have a relatively strong evidence base, with 69 cases of compelling evidence of detection of pre-retinopathic neuropathy. This included 27 cases of compelling evidence for mfERGs , 25 for implicit times, both b-wave and 30 Hz flicker (86%), 23 for the magnitude of various combinations of oscillatory potentials (77%), and 16 for PERG and VEPs . There were only four cases compelling studies for scotopic threshold response, compared with two moderate and one case of no evidence (57%), but the small number of studies indicates further studies should be conducted rather than that this test does not have a value as a modality.Ophthalmology is relatively unique amongst medical specialties in which pathology can be routinely visualised with the observer's own eyes in a routine clinical exam. Modalities include a simple retinal exam, OCT, and more advanced pattern recognition and processing software that mimics and seeks to improve upon a clinician's capacity for diabetic retinopathic pattern recognition. Great strides have been made in developing algorithms for analysing large numbers of diabetic retinas for frank retinopathy using the superior resolution capabilities of machines to detect diabetic changes such as microaneurysms or cotton-wool spots, but there is currently no consensus due to the proprietary nature of these technologies. Many studies showed compelling evidence for retinal imaging and computer processing software to detect early neuropathic changes as well, but as most were proprietary and not widely available, no analysis on widespread clinical utility could be made at this time, although the possibilities for development of this field are promising. Other imaging modalities, which showed good evidence of early diabetic changes, included vessel calibre changes , capillary density in perifoveal intercapillary space , and optic nerve head shape . OCT, obviously so useful in other fields including actual diabetic retinopathy, did not show a strong evidence base in this field, with retinal thickness measures  being a relatively a poor metric for identifying or predicting retinal neuropathy. It is a possible new OCT, and adaptive optics technology could be more useful for this purpose in the future.Several of the functional tests identified in this investigation are perhaps the most relevant to general clinical and clinical trial recommendations at the current stage of knowledge as they can be applied in any clinical setting, including general practice clinics and rural settings. The functional test with the most compelling evidence in the literature was contrast sensitivity , which demonstrates early diabetic retinal changes, especially in young type 1 diabetics , 43. ColPerimetry also showed potential as a field of clinical investigation for detection of early diabetic changes and as a widely available test and a potentially clinically practical one. Perimetry  had 18 cases of compelling evidence, 10 moderate, two weak, and only one study where evidence was not statistically significant. Short-wavelength automated perimetry (SWAP), despite its recently disappointing results in the glaucoma literature, has relatively strong scientific basis in detecting early diabetic changes . As young, type 1 diabetic patients theoretically have much longer to live with the disability of diabetic retinopathy, this modality's efficacy in early detection of retinal neuropathy merits revisiting it in a research and ultimately clinical setting as a possible valuable early therapeutic endpoint.These findings are systematic, comprehensive, and allow the authors to make a series of recommendations for patients who are being assessed in clinical, clinical trial, and research settings for diabetic retinal neuropathy. As this is a developing field, during this investigation's inclusion period, several included studies were not specifically testing subjects for pre-retinopathic diabetic retinal neuropathy and patients with the early stages of diabetic retinopathy were included. The effect of this necessary methodological decision will likely become clearer once established protocols for quantifying diabetic retinal neuropathy in the absence of retinopathy are established, and more studies of retinal function are performed to specifically target the pre-retinopathic diabetic retina.Patients at risk of diabetic retinopathy should receive the gold standard of diabetic retinopathy assessment according to local authority guidelines. In addition to a baseline BCVA being taken, patients should undergo contrast sensitivity and colour vision testing . Where It must be stressed that the study of diabetic retinal neuropathy is still an immature field. This initial attempt to categorically rate the strength of evidence of this disease process using a formal GRADE system is a systematic demonstration of current knowledge on the topic with a view to demonstrating the validity and usefulness of further study, as well as a providing a methodological framework for doing so. The data and conclusions found here will necessarily change with time and new data.This exciting field of study is clearly in its infancy. Acknowledging the realities of clinical practice, modalities were selected that could make a real-world difference. Some of the decisions regarding the compelling nature of the literature were made selectively in the context of the entire literature review, comparing studies with one another. This comparative approach would not have been possible without an exhaustive and systematic review of the literature. This study reinforces many practices already employed by clinical ophthalmologists and codes a set of investigations that should be conducted at minimum in assessing diabetic patients for early neuropathic changes in the retina.


Methods: Using a human‐centered design approach, we created prototypes employing a broad range of methods to iteratively develop EtD framework content and iEtD tool functionality. Results: We developed tailored EtD frameworks for making evidence‐informed decisions and recommendations about clinical practice interventions, diagnostic and screening tests, coverage, and health system and public health options. The iEtD tool provides functionality for preparing frameworks, using them in group discussions, and publishing output for implementation or adaption. EtD and iEtD are intuitive and useful for producers and users of frameworks, and flexible for use across different types of topics, decisions, and organizations. They bring valued structure to panel discussions and transparency to published output. Conclusion: EtD and iEtD can resolve some of the challenges inherent in multicriteria, multistakeholder decision systems. They are freely available online for all to use at https://ietd.epistemonikos.org/ and https://gradepro.org.Evidence‐informed health care decisions and recommendations need to be made systematically and transparently. Mediating technology can help manage boundaries between groups making decisions and target audiences, enhancing salience, credibility, and legitimacy for all. This article describes the development of the Evidence to Decision (EtD) framework and an interactive tool to create and use frameworks (iEtD) to support communication in decision making.  The collection focuses on two chief actors and their relationship: the SAC  and the target users of their advice. In this article, we draw attention to a third technological “actor:” mediating technology. The Evidence to Decision (EtD) framework and the interactive Evidence to Decision (iEtD) tool are technologies designed to be used by SACs, advising about treatment or intervention options in the health sector or by other groups, including target audiences, using that advice for decision making. The purpose of these technologies is to support systematic and transparent use of evidence in decision making, as well as mediate and manage information boundaries between multiple stakeholders with diverging perspectives and information needs. Here, we describe the methods we used to develop the framework and the interactive tool, their primary features and functions, what insights during development contributed to their evolution, and what lessons from this work might inform others designing technology to link knowledge to action.Decisions and recommendations about health and health care for a population are often made by groups of stakeholders, brought together by organizations  that publish output for targeted audiences . These processes are often complex, requiring judgments about multiple factors, such as whether the balance of benefits and harms favor one of the management options. Using a systematic approach can help ensure that people making judgments have considered all the important factors (criteria) and that these judgments are informed by the best available evidence.In addition, transparency is necessary to help ensure that people who are affected  know which criteria and supporting evidence were considered, what judgments were made, and the applicability of the decision or recommendation to themselves or their context. Transparency can also increase credibility, enabling people to make an assessment of how much confidence they can have in the result.However, transparency alone is not sufficient. Effective dissemination of health care decisions or guideline recommendations relies on many other factors, some of which relate to how the information is presented. A systematic review of features that could improve guideline dissemination suggests that presentation strategies, such as increasing usability (ease of use), understandability, and communicability, are among those likely to be important;Dealing with uncertainties is a challenge for any SAC. In 2000, the GRADE Working Group began developing a systematic and transparent approach for making recommendations about health care and health system interventions that included strategies for incorporating and communicating uncertainties. The GRADE approach involves systematically assessing four key evidence‐to‐decision criteria: (1) the balance between desirable and undesirable effects, (2) quality (certainty) of the evidence, 3) variability in people's values and preferences, and 4) resource use, to grade recommendations according to their strength . variabil resourceIn 2011, the GRADE working group established the DECIDE project, a European Union funded initiative that aimed to develop targeted dissemination strategies for improving communication of evidence‐based guidelines to decision makers, policy makers, health professionals, patients, and the general public.The concept of an EtD grew out of these discussions and earlier work by the GRADE Working Group on evidence to decision criteria.Our overarching purpose was to support three different types of decisions: moving from evidence to recommendations , moving from evidence to decisions , and moving from recommendations to decisions . We also aimed to support communication to people who would use these decisions in some way (for implementation or adaptation) or people whom these decisions affected, such as regional managers, health professionals, and their patients.(1)Help guideline panels or other decision makers use evidence in a systematic and transparent way to inform their deliberations when making recommendations and decisions by:Ensuring transparent consideration of the most important criteria for making a recommendation or decision;Presenting a concise understandable summary of the best available evidence to inform judgments about each criterion;Helping structure discussion and identify reasons for disagreements;Facilitating later adaptation of recommendations and decisions to specific contexts other than the ones for which they were developed originally.(2)Support people affected by a decision or recommendation by:Enabling them to understand the criteria, evidence, and judgments that led to the conclusions;Helping them decide whether recommendations can and should be implemented in their own setting.Our work was informed by Daniels' framework of accountability for reasonableness, a “fair process” approach to priority setting with three key elements: “transparency,” “buy‐in from key stakeholders,” and “revisability in light of new evidence or judgments.”In this article, we describe how we developed the EtD framework and the iEtD tool, an online solution for creating and using frameworks.2TableAlthough the framework and tool name is “Evidence to Decision,” these have a broader context of use including both recommendations and decisions. From now on, we use “decision” to mean both decisions and recommendations. See 2.1FigureThe project evolved in two phases over five years Figure1. FourIn Phase 1, the teams focused on developing EtD framework content for their respective topic areas. In Phase 2, teams continued to refine content and test frameworks in real‐life guideline panels,FigureThe project teams' development efforts were grounded in a human‐centered design approach.Below is a summarized description of our approach. See Additional files S1 and S2 (Supporting Information) for more details about the methods and participants that informed development cycles.2.2Following a consultation of existing systematic reviews of decision making frameworks,2.3We aimed to learn about the needs and concerns of multiple types of users and stakeholders: people in organizations involved in decision making and dissemination  as well as people who would use this information . Guided largely by themes from a framework of user experience,2.4We analyzed data as it were collected. The aim of our analysis was to draw out findings that could inform content and improve design from the perspective of users and stakeholders. Drawing from the user experience framework, we sought in particular to identify issues regarding usefulness, usability (ease of use), and understandability.The teams shared a common approach to processing data from piloting and feedback collection, based on the detailed method description in the project protocolWe iterated continuously, making small, frequent incremental adjustments more often than major changes. In Phase 1, teams experimented with diverse approaches to content and format, but recognized early in the process the strengths of establishing a common core. When teams reached consensus regarding EtD content and structure, we created a common prototype to be used by all teams and that formed the basis of the remaining development. In Phase 2, the cycles of feedback and prototyping of the iEtD tool was coordinated and carried out by the iEtD tool team. Additionally, all four teams continued to test and collect feedback on the paper‐based EtD frameworks, passing relevant findings on to the iEtD tool team.33.13.1.1Following some early prototyping and testing of example content, we observed actual decision making panels to better understand the context of use . Chairs, for instance, faced challenges in managing time, dealing with domineering participants and ensuring information is introduced and discussed in an unbiased way. Panel participants displayed different levels of skills in understanding numerical data and other aspects of research evidence. The large amounts of information appeared to be overwhelming for some, and some panel members were seen to be reading written material rather than following central discussions. Drawing on these observations in addition to findings from earlier work on making evidence understandable and useful in decision making,3.1.1.1(1)Present the evidence and judgments in a way that is understandable to people without technical expertise;(2)Have a coherent, logical, visible structure;(3)Not be longer or more complex than necessary;(4)Keep relevant information collected close together on the same page;(5)Present content using a layered approach, with summary/key points in the top layer and more details on demand.The EtD frameworks need to:(1)Separate judgments about evidence from the evidence itself, and make both explicit;(2)Keep evidence summaries very compact so they are not overwhelming and provide links to more detailed information;(3)Be able to consider multiple intervention options;(4)Be flexible in use ;(5)Be able to adapt output for different end users, such as decision makers at a local level or health professionals.We entered different types of content into prototypes (“example testing”), to test their flexibility and suitability for different kinds of questions. Our experiences and stakeholder feedback to early prototypes led to a better understanding of some key formatting considerations, including the need to:We carried out prototyping of content and structure for approximately two years Figure .3.1.2FigureBy the end of Phase 1 teams had reached consensus on a basic EtD structure Figure3 and c3.1.3Question: The Population, Intervention, Comparison, and Main outcomes (PICO) that the recommendation will address as well as Setting, Perspective, Subgroups, and Background.Criteria: Criteria are the factors that should be considered when making a decision . For each criterion, the framework offers an opportunity to fill in the following information:(1)Judgment—the option chosen by the panel that reflects their judgment with regards to the specific criterion;(2)Research evidence—evidence that is collected in a preplanned and rigorous fashion to inform a judgment, e.g., evidence from systematic reviews;(3)Additional considerations—other information and considerations to inform or justify each judgment, e.g., practical experience.Conclusion: This includes the summary of judgments, strength of recommendation, recommendation text, justification, implementation considerations, monitoring and evaluation, and research needs.3.1.4Problem – Is the problem a priority?Desirable effects – How substantial are the desirable anticipated effects?Undesirable effects – How substantial are the undesirable anticipated effects?Certainty of the evidence of effects – What is the overall certainty of the evidence of effects?Values – Is there important uncertainty about or variability in how much people value the main outcomes?Balance of effects – Does the balance between desirable and undesirable effects favor the option or the comparison ?Resources required – How large are the resource requirements (costs)?Certainty of evidence of required resources – What is the certainty of the evidence of resource requirements (costs)?Cost‐effectiveness – Does the cost‐effectiveness of the option favor the option or the comparison?Equity – What would be the impact on health equity?Acceptability – Is the option acceptable to key stakeholders?Feasibility – Is the option feasible to implement?This is the core list from which frameworks for different topics and perspectives are tailored:3.2The following are the main thematic findings from Phase 1. These are loosely organized according to three central user experience themes of usefulness, understandability, and usability for different types of users and stakeholders. The findings we have chosen to report here have either been important for development in Phase 1, formed a basis for the work in Phase 2, or are potentially relevant for organizations considering use of the frameworks.3.2.1The most consistent response across the broad range of users and stakeholders who gave feedback was that the framework was perceived as useful and relevant.“It is logically organized and puts the key evidence into the context of a decision problem. This is much more relevant and engaging than simply presenting summaries of effect sizes, ICERs, etc.” (Member of stakeholder network)Panel chairs valued the EtD framework as a useful tool for managing discussions, teasing out complex issues, and ensuring conclusions were grounded in available evidence. The structure helped them to keep panels on track and limit digressions.“It helps … keep to the agenda… (I) have a good excuse to cut people off then, without being impolite” (Guideline developer ‐ chair)Chairs reported that use of the EtD helped them limit panel requests to add new evidence to the discussion, and allowed them to “land” judgment discussions or “park” comments as pertaining to criteria other than the one under discussion. Several people emphasized that the key factor for successful use of the framework was a knowledgeable trained chair (or facilitator) familiar with GRADE and with the EtD framework.“…if you have a strong chair you can structure the conversation. You can park things where they belong and make the distinction between evidence versus anecdote and make the distinction between effectiveness versus resource use versus acceptability…” Panel and workshop participants reported that the separation and organization of judgments and evidence was useful, since it made the relation between these clearer and more explicit. They also appreciated the physical placement of short summaries of evidence on the same page next to the judgment options.“I love the formatting… the way evidence to support the answer runs parallel to it.” (User test participant ‐ physician)People were positive about an approach that considered both evidence on health effect and evidence on other factors .“For Resource use, the panel will only have ‘additional information' as opposed to direct evidence. The panel then needs to decide how much weight to put on this information.” Even when no evidence was provided for some of the criteria, participants perceived the framework to be helpful as a checklist to structure meeting discussions.3.2.2FigureWe know from previous work that understandability of evidence is helped by presenting main findings in a concise format, with access to more details elsewhere.“To try to encourage people who are quiet to speak up… is also tied to the way that you present the evidence ‐ have you presented it in a way that is not intimidating?…A lot of the discussions we had were around sort of crash course in how to present evidence in a very small space.” People participating in panels also needed explanations of less familiar elements, such as interpreting the “Values” criterion or judgment options. Linked explanations could resolve some misunderstanding or confusion, but groups also relied heavily on discussions and the knowledge of chair and technical team.3.2.3Frameworks were not necessarily easy for technical teams to use. There were many practical implications related to gathering evidence for several criteria. Some were uncertain about where to search for or synthesize “new” types of evidence or what to do when there was no evidence. Guideline producers who used the framework noted that filling in evidence for all the criteria demanded a lot of extra resources and new skills, and emphasized the need for guidance and training.“The framework adds another layer of work… in addition to doing the reviews you kind of have to condense the information and put it into this thing in a way that makes sense to other people to use in the guideline process.” Some technical teams experienced trouble deciding what criterion an issue belonged to. Others pointed out that placement was less important as long as the issue was covered somewhere.Though the structure and purpose appeared to be intuitive to panel members, they did not always experience it as easy to use. For instance, choosing among a set of given judgment options  could be challenging, and led to much careful consideration of options and wording by the development teams.Feedback indicated that people were divided in their views about how much detail was desirable. Although the prevailing view was that the framework accurately reflected the complexity of decision making, some wanted a simpler solution, while others requested more complexity.3.2.4Several guideline producers expressed a desire to tailor the frameworks to meet their mandate and perceived needs by adding or deleting criteria. For instance, in an evaluation of the framework, the Swedish Institute of Public Health suggested including Sustainability (which we included as a detailed consideration under “Feasibility”) and Autonomy (which we included as a detailed consideration under “Acceptability”) as separate criteria.We also observed that guideline producers used EtD frameworks in very different ways. In one project, the technical team filled out entire frameworks for a large set of questions beforehand, including tentative judgments and draft recommendations, saving the panel meeting time to focus on areas of disagreement. In other projects with fewer questions, panels filled in all the judgments during the panel meeting. In yet another organization, the chair used the list of criteria as a checklist for discussion, without filling in each criterion's judgments explicitly.3.3In Phase 2, the iEtD tool team turned their attention to the question of how we might facilitate preparation and use of EtD frameworks with an online tool.FigureThe tool should support three types of guideline and decision making processes: moving from (1) Recommendations to Decisions, (2) Evidence to Recommendations, or (3) Evidence to Decisions Figure5.3.3.1We supplemented the design principles established in Phase 1 for EtD development with principles grounded in guidelines for web usability3.3.1.1(1)Simple intuitive “what you see is what you get” text entry;(2)Minimal need for training;(3)Full user control ;(4)Suitable for use in groups ;(5)Suitable for screen projection, computer viewing, or printing on paper;(6)Maximal flexibility, for use by different people, for different target audiences, and in different organizations or work flows;(7)Open access.Although frameworks can be used many types of groups making various kinds of decisions, supporting guideline development was a central focus in the DECIDE project. Therefore, in defining user roles and tasks in order to specify iEtD functionality, we modeled use of the tool on our knowledge of evidence‐informed guideline processes, drawing on experience from DECIDE partners.3.3.2FigureTo maintain framework consistency across multiple users, we determined that people preparing frameworks would choose from a list of standardized templates and enter content in fixed text fields. Creating and using EtD templates in a guideline process therefore involved five basic steps: selecting (or tailoring) a template, filling in a template, making judgments and a recommendation, publishing a recommendation, and using the recommendation Figure6.We also defined a set of roles that represent people who either produce or use guidelines: the organization , technical team , panel chairperson, panel, and end users (people who read the published recommendation or use it as a basis for a decision).Starting with these five steps and roles, and drawing on our teams' experience in guideline development processes and on feedback from Phase 1, we generated ideas about what kind of detailed tasks people in these different roles would need to be able to do during the different steps. This led to a list of desired functionality that formed the basis of our design .3.3.3FigureThe iEtD tool includes all the content from EtD frameworks, in addition to interactive functionality for tailoring, preparing, administrating, or using the content Figure7. It iIn addition to the main parts of the EtD , we added new sections for more detail . We added two new fields under each criterion: Detailed judgments and Panel discussion. Detailed judgments are topic‐specific sets of questions that can help panels unpack the issues underlying a judgment when there is disagreement or when the judgment is difficult to make. We added Panel discussion based on concerns from one organization reporting that some panels felt their role was reduced to mechanically approving prechecked judgment option boxes, and that the framework lacked a space for recording panel discussions they considered important.We created guidance for producers of EtD frameworksWe established anonymous, optional voting functionality in the judgments and conclusions sections. We created a toolbar with functionality for managing different viewing options , finding contextually relevant guidance, making comments, and exporting. We created a top menu with administrative functionality, such as organizing projects, templates, and users and version control . This included both templates for draft reports and for final publications aimed at end users. For the latter, we achieved a layered approach by reordering the framework sections so that the conclusion came first. We also created templates for “Recommendations to Decisions” for people making decisions based on recommendations .We implemented several features that enable organizations to tailor the iEtD. Templates for creating or exporting EtD frameworks are editable: criteria can be added or removed, response options (the range of answers provided for making judgments and detailed judgments) can be changed, text in the guidance section can be edited (so that organizations can create tailored instructions), and all template text can be rewritten in another language. Organizations can also add their logo. People who are registered as an organization administrator can accept members to their projects and assign them any functionality .3.4Much of the feedback described in Phase 1 is applicable to use and preparation of EtD frameworks regardless of whether they are in a paper or digital format. Here, we present feedback and observations that are specifically relevant to preparation and use of frameworks in a digital format created with the iEtD tool.3.4.1Most workshop or training attendees found the iEtD intuitive and easy to learn. However, others felt more comfortable using the paper‐based framework prototypes from Phase 1. Some technical teams felt that learning to use unfamiliar technology placed an unnecessary extra stress on their already overloaded agendas.“Everything that is digital is a barrier ‐ learning to use it takes time.” (Guideline program manager)One guideline program manager noted that they constantly had newcomers joining their teams who needed to learn many other things at the same time, such as GRADE methodology. This lowered their ability or desire to engage with new technology at the same time.Some feedback also indicated that people had mistaken expectations that the digital tool would produce automatically calculated conclusions.3.4.2Some people had concerns related to IT security and ownership. People who were unfamiliar with the system host (Epistemonikos) were uncertain whether they could trust that their data were backed up and secure. Some said their organization would not permit them to use a system that was hosted on an external server. There was concern about the need for a stable internet connection or making sure nothing technical would go wrong when running time‐pressed panel meetings.3.4.3Interactive, anonymous voting appeared to provide a useful method of charting the groups' distribution of differing judgments without identifying the views of specific individuals. In workshops, we observed groups using voting to spark discussion rather than to just finalize conclusions, providing a starting point for presenting different opinions and clarifying misinterpretations of the evidence.4Using a human‐centered design approach, we created a common core structure and terminology for EtD frameworks and developed topic‐specific variations of frameworks for decisions about clinical interventions (treatments) and tests, coverage, and health system or public health interventions. We developed a flexible iEtD tool for producing, using, and adapting transparent frameworks in decision making and communication. Stakeholders and users experienced the EtD frameworks as a useful reminder of the most important criteria for making decisions and for bringing evidence into the decision making in a systematic way that helped bring clarity and structure to their thinking, discussion, and dissemination. The layered format, which entails use of highly condensed evidence, was key to understanding of evidence and to ease of use in discussions, but requires skill to prepare. Populating frameworks, learning to use the digital tool, and helping panels demanded extra resources and skills that organizations may lack. The iEtD tool has several unique features, such as interactive voting that help groups identify reasons for disagreement, and export formats that are tailored for different end users and that can facilitate understanding, implementation, revision, or adaption.4.1The strength of this work was the large amount of feedback provided throughout the project, by a wide range of stakeholders and users from multiple perspectives and for several types of decision making. Frameworks underwent rigorous user‐testing and iterative development, as well as real‐life testing with guideline panels. The multidisciplinary team brought a rich set of skills and perspectives to the development.One limitation was fewer cycles of prototyping and feedback in Phase 2 due to the time needed for software development. Lack of time at the end of the project also limited the number of export format iterations and amount of end user feedback about these that we could carry out. However, we drew heavily on earlier work exploring effective ways to support both health professionals' and consumers' understanding of evidence,4.2“Efforts to mobilize S&T (science and technology) for sustainability are more likely to be effective when they manage boundaries between knowledge and action in ways that simultaneously enhance the salience, credibility, and legitimacy of the information they produce.”The EtD framework and iEtD tool are examples of technologies built to help link knowledge to action. Technologies are likely to be effective when the information they produce is salient, credible, and legitimate.4.3In implementation science, including guideline dissemination, communication is commonly conceptualized as “information transfer” – packaging information (such as recommendations and evidence) in ways that make it clear and understandable for a target audience.(1)Within technical teams while they are creating and editing framework content;(2)Within SAC panels while they are discussing framework content;(3)Between organizations, technical teams, and SAC panels;(4)Between organizations and end users of framework output.In this project, we worked along both of these dimensions. Some of our design efforts concentrated on enabling successful “information transfer” by improving the individual user's experience of the information . But, we also worked to enhance group communication and “shared understanding” within SACs and between many groups, by working to create transparent solutions that could support discussion, participation, and mediation. The EtD and iEtD can support improved communication:4.4Many organizations still struggle with overdependence on “expert opinion,” often resulting in recommendations or decisions that are unbalanced and not possible to retroactively unpack and inspect. Although the EtD and iEtD have been designed specifically for decisions about health care intervention options, they provide an example for any sector of how evidence can be brought to decision making in a transparent and systematic manner and how experts might assume a more balanced role in SACs together with other stakeholders. EtD and iEtD can also be tailored for use in other sectors to answer intervention questions that have a PICO structure .At first glance, use of EtD and iEtD may appear suitable only for use in projects with ample time and resources for producing comprehensive systematic reviews of evidence for each criterion. However, they can also be used in contexts even where there is little or no evidence. Using the framework, the lack of evidence can be made apparent, allowing readers to see which other considerations informed the judgments and conclusions. The iEtD may be more useful in organizations where there is a stable pool of technical team staff, who can develop the skills needed to use the technology.EtD and iEtD also have the potential to be used as teaching tools, for instance, to train medical students or other groups in systematic approaches to collaborative decision making or prepare them for participation in civil society. We are planning to use iEtD in future work as part of an ongoing effort to teach young people how to make informed health choices.4.5Exploring how best to link knowledge to action across multiple stakeholders requires a research approach that looks at a wider set of issues than individual users' interactions with a piece of information or technology interface. Future development of the EtD and iEtD should be accompanied by research questions and methods that more specifically explore how the technology can best support communication between producers, panels, and users. Work should also be carried out to explore how use affects the participation of panel members, their conclusions, the transparency of reports for end users, and the usefulness of that output for those audiences. The potential for adaptation of this approach to multistakeholder decision making for other sectors as well as across sectors – an important consideration in relation to the recently agreed Sustainable Development Goals4.6According to recent estimates, there are currently over 7000 users of the static and interactive versions of the EtD frameworks. More detail about each type of EtD framework and links to other relevant tools can be found in Additional file S4 (Supporting Information).https://ietd.epistemonikos.org.The stand‐alone, open access iEtD toolhttps://gradepro.org (www.gradepro.org).EtD frameworks are also accessible through GRADEpro Guideline Development ToolThe authors declare no conflict of interest.SupplementaryClick here for additional data file.


This study aims to assess the possible association of the most frequent BAs with EMSs in a large group of late adolescents and young adults and to evaluate their self-perceived quality of life (QoL).Behavioral addiction (BA) is a recent concept in psychiatry. Few studies have investigated the relationship between BA and early maladaptive schemas (EMSs). EMS is the core of Schema Therapy (ST). According to the ST model, psychiatric disorders result from the development of EMSs in response to unmet emotional needs in childhood. N = 637; 59.3% women). A forward-stepwise logistic regression model was run to identify which variables were associated with BAs.A battery of psychological tests assessing food addiction (FA), gambling disorder (GD), internet addiction (IA), and QoL was administered to 1,075 late adolescents and young adults  and Mental Component Summary (MCS) scores. Finally, specific EMS domains and demographic variables were associated with each BA.Food addiction was more frequent among women and GD among men, while IA was equally distributed. Regarding the EMSs, participants with FA or IA showed significantly higher scores on all four-schema domains, whereas those with GD exhibited higher scores on disconnection and rejection schema domain, IA with all the schema domains (except for impaired autonomy and performance), and GD with impaired autonomy and performance schema domain. In conclusion, our findings suggest that EMS should be systematically assessed during psychotherapy of patients with BAs.Late adolescents and young adults with FA or IA have a lower perception of their mental and physical health. The most striking result is that FA appears to be associated with the  The construct of behavioral addictions (BAs) is a recent concept in psychiatry. In fact, it was first included in 2013 in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) as an official psychiatric diagnosis. So, in clinical practice, it is necessary to distinguish between substance and BAs. In fact, even if BAs do not appear in the DSM-5, except for gambling disorder (GD) and Internet gaming disorder , they share the following characteristics with substances addiction: the age of onset in adolescence and early adulthood, the specific features , and the clinical course .Other problematic behaviors, such as food addiction (FA) and Internet addiction (IA), have aroused interest in recent years . AlthougAll of these addictions, however, are associated with a pattern of emotional dysregulation and cognitive distortions, which are typical of behaviors that people use to seek immediate gratification. It has been hypothesized that dysfunctional behavior could be a maladaptive strategy for dealing with negative emotions and feelings, such as frustration, inadequacy, and isolation . FurtherPerhaps the most relevant point to highlight is that research has mainly focused on the presence/absence of symptoms of BAs, whereas the etiological processes and peculiar characteristics of BAs have rarely been investigated. Moreover, some of these symptoms, such as withdrawal and tolerance, are difficult to apply and measure in relation to behaviors .disconnection and rejection: All the schemas of this domain are associated with a lack of security, safety, and stability in interpersonal relationships; (2) impaired autonomy and performance: People with schemas of this domain perceive themselves as insecure and suffer from a lack of autonomy, i.e., they are afraid that autonomous decisions may damage important relationships, or they expect to fail in situations where they must provide a performance; (3) excessive responsibility and standards: People with patterns in this domain typically put the needs, desires and wishes of others before their own, and, as a result, many of their efforts are directed toward satisfying the wishes of others; and (4) impaired limits: A lack of internal limits, an inability to form long-term goals, and a lack of responsibility to others.According to the theoretical model of Schema Therapy (ST), psychiatric disorders might result from the formation of early maladaptive schemas (EMSs) in response to unmet needs in childhood. EMSs are defined as “extremely stable and enduring themes, comprised of memories, emotions, cognitions, and bodily sensations regarding oneself and one’s relationship with others, that develop during childhood and are elaborated on throughout the individual’s lifetime, and that are dysfunctional to a significant degree” . The newimpaired autonomy and performance disconnection and rejection schema domain; IA associated with all the schema domains; and, GD associated with impaired autonomy and performance schema domain. Regarding the possible role of gender in the development of BAs, we suppose to find the male gender associated with GD, the female gender with FA, and no gender difference on IA.To assess the possible association of specific BAs  with EMSs and gender in a large group of late adolescents and young adults. More in detail, according to the previous research, we expect to find: FA associated with the (2)To evaluate their self-perceived QoL; in particular, we expect to find a worse QoL among participants with any BAs.First- and third-year university students and senior high school students from the same catchment area in southern Italy participated in the research.Through an anonymous online survey, the participants completed an informed consent form and the questionnaires, and they also provided their heights and weights. Answers of participants who did not complete all items were dropped from the electronic database automatically. Anonymity was guaranteed through the use of nicknames . No grant or economic compensation was offered to participants.N = 637; 59.3% women) with a mean age of 19.69 ± 1.7 (17–24) years old; 810 (80.5%) participants had middle school diplomas while 210 (19.5%) had high school diplomas. All participants were Caucasian. The present study was carried out in accordance with the latest version of the Declaration of Helsinki and was approved by the local Ethical Committee. All participants provided informed consent before participating and parental consent was sought for those younger than 18 years of age.The final sample consisted of 1,075 participants (The Young Schema Questionnaire Short Form-3 (YSQ-S3) is a self-report instrument that consists of 90 items rated on a six-point scale (from “completely untrue of me” to “describes me perfectly”) that accounts for 18 EMSs . Differedisconnection and rejection, excessive responsibility and standards, impaired autonomy and performance, and impaired limits  is a self-report test that assesses problematic Internet use and consists of 20 items on 5-point Likert-type . The totSouth Oaks Gambling Screen (SOGS) is the most widely known and used questionnaire for the screening of GDs and is composed of 16 questions, including 37 items, which ask the subjects about their gambling activity and associated behaviors throughout their lifetime. There are 20 scoring items, all equally weighed, requiring a “yes” or “no” answer, so scores range from 0 to 20 . Scores The Yale Food Addiction Scale 2.0 (YFAS 2.0) evaluates addiction-like eating behavior over the preceding 12 months . It cons1 Two types of scoring are possible: (1) a final symptom-count score can be calculated by adding up all of the endorsed symptoms; (2) the severity level is described according to the diagnostic thresholds for SRAD in DSM-5: mild FA (2–3 symptoms), moderate FA (4–5 symptoms), and severe FA (≥6 symptoms). Finally, every FA “diagnosis” requires the presence of the distress or impairment criteria. In this study, we used the cut-off≥6 symptoms (severe FA) to diagnose FA. Kuder–Richardson’s alpha for dichotomous variables was run and in this study was 0.880.Each of the 11 diagnostic criteria was considered present if one or more of the relevant questions for each criterion reached the threshold. For the specific threshold of each item, it is possible recover them in the validation of the scaleThe Short Form-12 Health Survey (SF-12) is a widely used instrument for assessing QoL and consists of 12 items derived from the SF-36 . These it-tests or ANOVA for continuous data, as appropriate. Additionally, Cohen’s d or η2 were, respectively, calculated for significant results in t-tests or ANOVA as measures of effect size (ES). Values of 0.2, 0.6, 1.2, and >1.2 can be, respectively, categorized into slight, small, moderate, and large ES for Cohen’s d  version 21.0 . Descriptive statistics included frequencies and percentages, and means and standard deviations, as appropriate. Differences between groups were assessed with chi-squared for categorical variables and ohen’s d . In the large ES . A forwaimpaired autonomy and performance and impaired limits schema domains. As displayed on the last row of the table, average scores of all domains increased with the association of two or more comorbid BAs.disconnection and rejection schema domain scores were associated with YFAS 2.0 positivity. Younger age and higher scores in the disconnection and rejection, excessive responsibility and standards, and impaired limits schema domains were associated with IAT positivity. Finally, male gender and impaired autonomy and performance were associated with being positive to the SOGS.The results of the logistic regression models are shown in n = 1075) according to the new four schema domains model proposed by The study aimed to assess the possible association of some BAs  with EMS and at evaluating their self-perceived QoL. To the best of our knowledge, this is the first study regarding the investigation of EMSs on BA in a very large sample of young people (Thirty-two percent of participants had positive results to at least one BA. IA was the most frequent (17.1%), followed by FA (8.1%), and then GD (6.8%).Regarding gender distribution, in our study we found a different distribution between participants who scored positively to BAs. GD was more likely to occur among males, as previous reports have indicated . The preImpaired autonomy and performance and impaired limits were the schemas that had significantly higher scores among adolescents and young adults with gambling addictions.Participants who were screened positive to BAs expressed significantly higher values in their schema-domain scores. All four schema-domains results were more expressed in participants who were positive to FA and IA. Instead, a more specific pattern in maladaptive schemas emerged in people who were affected by GD. impaired limits domain were higher in the group of participants who were positive to all three of the investigated BAs. This is consistent with According to previous studies that have investigated the association between EMSs and eating psychopathology , our finRegarding QoL, we found that participants with IAs and FAs had low scores in physical and mental health, which was unlike those with high GD scores.Our data corroborate the results of previous research about impaired QoL among IA subjects . IA impaLiterature on QoL reports poorer values in all dimensions both among normal-weight and obese adolescents with FA . There iQuality of life was not found to be impaired among pathological gamblers. On the contrary, other studies found a stronger association with poorer mental health among gamblers than among non-gamblers . Our expInterestingly, QoL resulted is affected by the comorbidity between two or more BAs, especially the mental component. In other words, there is a summative effect of behavioral additions on the mental and physical health of young people.Logistic regression was performed to ascertain if demographic variables or schema domains were candidates for predicting the occurrence of BAs.impaired autonomy and performance). Many studies have demonstrated its increasingly young age of onset , and in the experience of pleasure , repeatedly reported in the literature among patients with BAs , 2018, mAlthough this study has many strengths , and GD with impaired autonomy and performance schema domain. For this reason, EMSs should be systematically assessed within psychotherapy of patients with BAs.Our findings partially confirmed our hypotheses. In fact, mental and physical health perceptions were impaired in IAs and FAs, but not in GDs. Nevertheless, the most striking result is that FA appears to be associated with the A priori, in line with the concept of personalized and precision medicine, ST could provide a real tailor-made therapy addressing the EMSs that seem to underpin the addictive behavior.The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by the Ethical Committee of Azienda Ospedaliera Universitaria Mater Domini. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.CS-G and PD contributed to the conception and design of the study. MA, MR, and RS organized the database. MA and CS-G performed the statistical analysis. MA wrote the first draft of the manuscript. MR and VV wrote sections of the manuscript. CS-G, PD, SJ-M, and FF-A critically revised the manuscript. All authors contributed to manuscript revision, and read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.