Tuberous sclerosis complex (TSC) is associated with a wide range of physical manifestations for which international clinical recommendations for diagnosis and management have been established. TSC is, however, also associated with a wide range of TSC-Associated Neuropsychiatric Disorders (TAND) that are typically under-identified and under-treated yet associated with a profound burden of disease. The contemporary evidence base for the identification and treatment of TAND is much more limited and, to date, consensus recommendations for the diagnosis and management of TAND have also been limited and non-specific.The TANDem project was launched with an international, interdisciplinary, and participatory consortium of 24 individuals, including TSC family representatives, from all World Health Organization (WHO) regions but one. One of the aims of the TANDem project was to generate consensus recommendations for the identification and treatment of TAND. At the time of this project, no internationally adopted standard methodology and methodological checklists existed for the generation of clinical practice recommendations. We therefore developed our own systematic procedure for evidence review and consensus-building to generate evidence-informed consensus recommendations of relevance to the global TSC community.At the heart of the consensus recommendations are ten core principles surrounded by cluster-specific recommendations for each of the seven natural TAND clusters identified in the literature  and a set of wraparound psychosocial cluster recommendations. The overarching recommendation is to “screen” for TAND at least annually, to “act” using appropriate next steps for evaluation and treatment, and to “repeat” the process to ensure early identification and early intervention with the most appropriate biological, psychological, and social evidence-informed approaches to support individuals with TSC and their families.The consensus recommendations should provide a systematic framework to approach the identification and treatment of TAND for health, educational, social care teams and families who live with TSC. To ensure global dissemination and implementation of these recommendations, partnerships with the international TSC community will be important. One of these steps will include the generation of a “TAND toolkit” of “what to seek” and “what to do” when difficulties are identified in TAND clusters. TSC1 or TSC2 genes, a wide range of physical manifestations, and a highly heterogeneous clinical presentation [Tuberous sclerosis complex (TSC) is a rare genetic disorder associated with mutations in the entation –5. Untilentation  and was entation . The 199entation .all individuals with TSC and not only those with apparent concerns. The panel provided detailed guidelines for developmentally based, comprehensive assessment [To provide a more systematic and proactive set of recommendations for the assessment of “cognitive and behavioral problems” in TSC, a meeting was convened in Cambridge, UK, in 2003. The consensus panel, consisting of 20 clinicians, researchers, and family representatives from the USA, UK, and the Netherlands, made two main recommendations . First, sessment . The secsessment , 9–11. Tannual screening of all people with TSC. Some guidance for the intervention of TAND was provided in the consensus guidelines, but in a non-specific manner . The 2012 recommendations were updated in 2021, mainly to include consensus recommendations for the use of mTOR inhibitors for physical manifestations of TSC [In 2012, an International Consensus Conference was convened which included 79 experts from 14 countries. Expert panels, including a neuropsychiatry panel, made recommendations for diagnosis, monitoring, and treatment of the range of organ systems involved in TSC , 12. In Since the 2012 consensus conference and coining of the term “TAND,” a number of new research developments have emerged. These included development and pilot validation of the TAND Checklist  , 13, natwww.tandconsortium.org). The first aim was to develop and validate a self-report and quantified version of the TAND Checklist (referred to as the TAND-SQ Checklist) and to build it into a mobile application (“app”). The second aim of the project was to generate consensus clinical recommendations for the identification and treatment of TAND as the foundation for a “TAND toolkit” of evidence-informed consensus information and self-help tips to be built into the app. The third aim was to establish a global TAND network through research capacity-building and a range of impact activities [In 2019, the TANDem project was launched as an international, interdisciplinary, and participatory project with three main aims [all existing evidence from the TSC literature to ensure an unbiased evidence-informed approach to our consensus-building, thus balancing “evidence” and “expert consensus.” We also recognized that access to identification and treatment of TAND and resources to support these actions may be highly variable across the globe. This led us to prioritize higher-level conceptual rather than very detailed recommendations in our consensus-building process.There is an ongoing discourse in the literature about the need to balance “evidence” and “expert consensus” in the generation of clinical practice recommendations . HistoriHere we describe the process of evidence-informed consensus generation and present a set of core principles and cluster-based recommendations for the identification and treatment of TSC-associated neuropsychiatric disorders (TAND).There are at present no formal guidelines for the reporting of consensus-based methods in biomedical research or clinical practice, but encouragingly, a team of researchers has initiated a process to generate what will be known as the ACCORD guidelines . In the www.tandconsortium.org). The consortium also included “family representatives” of individuals with TSC or family members of people with TSC. Many of the family representatives had “lived expertise” as well as other professional expertise, such as in education or health services. All consortium members participated in the process. Here, we will refer to this group as the “consensus panel.”The TAND consortium included a group of 24 individuals from all World Health Organization (WHO) regions but one (Eastern Mediterranean), across multiple professional groups including psychiatry, psychology, pediatric neurology, nephrology, speech and language therapy, education, special education, intellectual disability medicine, engineering, and neuroscience   were presented, and items where consensus could not be reached even after modification and discussion were excluded.It became clear during the evidence review and consensus-building process that a number of core principles were emerging across all clusters. The consortium conference therefore also included the generation of potential core principles from all cluster-specific recommendations.All potential core principles were collated and consortium members were asked to vote in an online survey whether they “strongly agree,” “agree,” “disagree,” or “strongly disagree” with the proposed principles. From 18 potential principles, a final list of ten core principles was generated with 100% consensus.The process outlined above led to a final set of recommendations including 10 core principles and eight sets of cluster-specific recommendations. The psychosocial cluster was conceptualized as a “wraparound” cluster . All consensus panel members reviewed and approved all recommendations.Figure TSC1 or TSC2), or TAND profile. It recognizes that everyone with TSC is at risk of TAND manifestations (#1) and that it is therefore important to perform lifelong monitoring for the emergence of TAND difficulties (#2) with a minimum of annual screening (#3). The core principles recommend early identification and early intervention (#4) rather than to use a “watch-and-wait” strategy. The consensus panel proposes a cluster-based profiling and identification of needs, but acknowledges that clusters cluster together and that identification of needs in one cluster should also alert caregivers and clinical teams to explore other clusters (#5). In the context of a multi-system condition, core principle #6 points to the importance of the relationship between physical health manifestations and TAND manifestations. Core principle #7 underlines the importance of working with caregivers as lived experts in TSC. Recognizing the very limited traditional “evidence base” in TAND, caregivers, and family communities have valuable contributions to make both in identification and in intervention for TAND. Principle #8 serves as a reminder that TAND difficulties require a “whole-system” understanding to guide an intervention plan. This means that biological, psychological, and social  aspects should be considered to understand the needs and to provide interventions and support. By implication, this process requires contributions from many professional groups and disciplines and is not just about finding a “medication” to solve a problem. In spite of the limited evidence base from the scientific literature specifically on TAND, principle #9 recommends the need to be informed by whatever relevant evidence may exist and to guard against approaches known to have evidence of harm. The final principle (#10) is a reminder that the goal of “intervention” and support to individuals with TSC and their caregivers is not merely to reduce symptoms or difficulties, but to help everyone living with TSC achieve an optimal quality of life as individuals and as families and to facilitate their active participation in all aspects of society throughout their journey with TSC and TAND.The ten core principles for identification and treatment of TAND are shown in Table Consensus recommendations for the seven natural TAND clusters and the wraparound psychososocial cluster are presented in the text below and in Tables The autism-like cluster recommendations are shown in Table For these reasons, the consensus panel recommended lifelong monitoring of all individuals for manifestations in the autism-like cluster (AU1), from early in infancy and throughout adulthood (AU2). All individuals who show difficulties with autism-like cluster manifestations should be referred for a formal clinical evaluation for communication disorders and autism/autism spectrum disorder (AU3). In the absence of TSC-specific evidence, the consensus panel recommended that the autism literature on children and adults in the general population  may be relevant to the TSC community (AU4). For this reason, young children with autism and TSC may benefit from naturalistic developmental behavioral interventions (NDBI) , 33, theThe dysregulated behavior cluster recommendations are shown in Table For these reasons, the consensus panel stated that dysregulated behaviors are common, have a major impact on families, and should be investigated in a systematic way (DB1). Given the many possible underlying meanings or functions of behaviors, a careful and systematic functional analysis of behavior should be conducted to generate an understanding of the problem behavior (DB2) . AnotherThe eat/sleep cluster recommendations are shown in Table Sleep difficulties are very common across all ages in TSC , 41, butFor these reasons, the consensus panel emphasized that sleep difficulties should be monitored regularly regardless of the age, sex, and genotype (ES4) of individuals and that sleep difficulties may be a “cause” and/or a “consequence” of TAND or other neurological manifestations (ES5). Clinicians and caregivers should therefore perform careful examinations to first identify and treat biological contributors to sleep, such as underlying health conditions and behavioral markers of pain (ES6). Next, psychiatric contributors to sleep should be examined and treated . Only once these have been identified and treated (or excluded), should other sleep management strategies be explored. Non-pharmacological strategies should always be used first  before pharmacological strategies  are considered (ES7). Given the very limited evidence base in this cluster, the consensus panel recommended targeted research on eating and sleeping difficulties in TSC (ES8).The mood/anxiety cluster consensus recommendations are shown in Table For these reasons, the consensus panel recommended that all children and adults should be monitored for the emergence of mood and anxiety symptoms to ensure early detection and treatment (MA1). Particular efforts should be made to look for mood and anxiety symptoms in those with intellectual and other neurodevelopmental disabilities where manifestations of depressed mood or anxiety may be different  (MA2). Mood and anxiety symptoms may be the consequence of underlying physical health problems or their treatments , and these may require specific management (MA3). Where mood and anxiety symptoms are identified, an appropriate diagnostic evaluation should be performed, and evidence-based non-pharmacological and pharmacological interventions as recommended in the general population should be used to treat mood and anxiety disorders (MA4). Given the heterogeneity in the individual physical health and TAND profiles of individuals with TSC, a personalized approach to management is recommended (MA5). In spite of the high rates of mood and anxiety disorders in TSC, the research evidence base is very limited, and further research, particularly interventional research, was recommended (MA6).The neuropsychological cluster consensus clinical recommendations are shown in Table For these reasons, the consensus panel recommended that all individuals with TSC should have a comprehensive assessment of their intellectual abilities (NP1) and should be monitored with annual screening for the emergence of neuropsychological deficits (NP2). The recommendations highlighted the fact that specific neuropsychological deficits may have an impact in many ways, including mood and anxiety difficulties , having dysregulated behaviors when task demands become too much , or on their scholastic skills  (NP3). Individuals with known neurodevelopmental disorders should receive a detailed evaluation of their profile of neuropsychological strengths and weaknesses and not only be screened for such deficits (NP4). Importantly, the consensus panel recommended that non-pharmacological coaching and training strategies should be used to strengthen areas of neuropsychological deficits (NP5) and that evidence of neuropsychological deficits is likely to require accommodations and specific support in educational or occupational settings (NP6).The overactive/impulsive cluster recommendations are shown in Table For these reasons, the consensus panel recommended ongoing screening for difficulties in this cluster and to proceed to appropriate next-step evaluations when difficulties are identified (OI1). All individuals who have difficulties in this cluster should be considered for a diagnostic assessment for ADHD (OI2) and, if diagnosed, be treated using the evidence-based approaches as recommended in the general population (OI3). When ADHD manifestations are moderate-to-severe, treatment with methylphenidate or other stimulant medications should be considered alongside non-pharmacological strategies to support the individual (OI4). Even when ADHD is accompanied by epilepsy, intellectual disability, autism, or other physical or TAND manifestations, the ADHD symptoms may respond appropriately to pharmacological treatments (OI5). The consensus panel also recommended further research to understanding pathways to overactive and impulsive behaviors and to generate an evidence base for intervention strategies  for these manifestations in TSC (OI6).The scholastic cluster recommendations are shown in Table For these reasons, the consensus panel recommended early and ongoing screening for scholastic cluster difficulties followed by appropriate action when concerns are identified (S1). The panel highlighted that delays in early developmental milestones may be markers of future scholastic difficulties (S2). All children with TSC should be considered for an individual educational plan (IEP/IEDP) to support their individual profile of learning needs (S3). There is no “one-size-fits-all” in education provision for children with TSC, and the goal should therefore be to match the comprehensive needs of each child with the most appropriate educational environment (S4). Acknowledging that educational environments and supports may vary significantly across the globe, the panel recommended that in all educational settings, high-quality teaching strategies, response-to-intervention (RTI) approaches, and appropriate accommodations  should be provided , 53 (S5)The wraparound psychosocial cluster recommendations are shown in Table For this reason, the consensus panel recommended monitoring of the psychosocial health and wellbeing of all individuals with TSC (PS1) and of all their family members (PS2), using screening , observation, family reports, or other standardized instruments. Based on their psychosocial needs, families should be provided with integrated and well-coordinated care (PS3). This should include practical support as well as psychosocial interventions  as required (PS4). The overall focus should be on “family quality of life” by helping individuals and families identify their goals towards, for example, social activities and active participation (PS5). TSC often has a major impact on the employment and professional lives of individuals with TSC and their families. This should therefore also be a specific focus of psychosocial support provided (PS6). The consensus panel recognized that families and caregivers are paramount to the wellbeing of individuals with TSC and of the whole family. It is therefore of fundamental importance to “care for caregivers” by monitoring caregiver wellbeing, dedicating time in consultations to family and caregiver wellbeing, and generating evidence of interventional approaches that could strengthen caregiver wellbeing (PS7).In this study, we set out to generate evidence-informed consensus recommendations for the identification and treatment of TSC-Associated Neuropsychiatric Disorders (TAND). We used a highly systematic process for evidence evaluation and consensus building. The process led to a set of ten core principles, seven sets of cluster-based clinical recommendations, and recommendations for a “wraparound” psychosocial cluster. Recognizing that individuals and families with TSC live in highly diverse global contexts and health, educational, and social care systems, we prioritized conceptual (“big picture”) recommendations over highly detailed ones.As outlined in the introduction, clinical practice recommendations for TAND over the years have moved from assessment and treatment when clinical concern was observed 1999), to comprehensive assessment at key developmental timepoints (2005), to annual screening (2013), and to early identification and treatment and psychosocial support for families 2021). The novel contribution of the consensus recommendations presented here was the focus on TAND clusters with the cluster-based evidence review and consensus-building. The search for natural TAND clusters started in response to the “overwhelming uniqueness” of the TAND profiles of individuals described by families and TSC clinicians which made them experience a “treatment paralysis” . Data-dr99, to co. The novThese consensus clinical recommendations represent the first systematic approach to the identification and treatment of TAND. Taking together all the recommendations presented, the overarching recommendation is shown in Fig. Where screening identifies any concerns, this should be followed by action , as well as professional partners in health, social care, and educational settings. One of the next step strategies identified as a specific objective in the TANDem project is to use the consensus recommendations as the foundation for the creation of a ‘TAND toolkit’ of information and tips on “what to seek”  and “what to do”  to be built into a “TAND toolkit app” . The next steps should include participation with the broader TSC community to ensure targeted dissemination and implementation of these recommendations. We acknowledge that services and access to interventions are highly variable across the globe and that many families may not immediately be able to access some of the evidence-informed recommendations made here. However, these consensus recommendations are, in part, also presented as an aspirational set of next steps. Families and their clinical teams should therefore use these recommendations to think about what is available in their local communities and collaboratively consider how to get access to support in line with the recommendations made here. We hope that these international consensus recommendations will empower families and professionals who support them with a systematic framework that will reduce the “assessment and treatment gap” in TAND across the globe.


Although digital health technologies (DHTs) help many people maintain a healthy life, including those of advanced age, these technologies are of little use to older adult populations if they are not being adopted in daily life. Thus, it is critical to identify ways to help older adults recognize and try new technologies and maintain their use of them to maximize the benefits of these technologies in a digital-based society.Our study aimed (1) to assess the current usage of DHT among older adults in Hong Kong and (2) to examine how high and low levels of eHealth literacy in this group affects the relationship between the Technology Readiness and Acceptance Model (TRAM) and attitudes and intention toward DHT.A total of 306 adults over 60 years of age in Hong Kong participated in this study. After conducting confirmatory factor analysis to validate the measurement model, the hypothesized model was tested using structural equation modeling.Optimism was significantly related to perceived usefulness, while optimism, innovativeness, and discomfort were significantly associated with perceived ease of use. Both perceived usefulness and perceived ease of use were significantly linked to attitude toward the use of DHTs. Meanwhile, attitude significantly predicted usage intention. Additionally, the results revealed the differences in the relationships of the TRAM between participants with high and low levels of eHealth literacy. The influence of optimism and innovativeness on perceived ease of use was stronger for the higher-level group than for the lower-level group, and the influence of discomfort for the higher-level group was much weaker.The findings provided partial support for the impact of eHealth literacy on encouraging older adults to use DHT and obtain health benefits from it. This study also suggests providing assistance and guidelines for older adults to narrow the aging-related technology gap and to further explore the associations of eHealth literacy, the TRAM, and actual behaviors. Rapid advances in medical science and technology have made it possible to detect diseases much earlier and provide appropriate treatment for those that were previously considered incurable. These advances have also enabled a variety of advanced health-related services and treatment techniques to be received more comfortably and effectively, which may lead to increased life expectancy . AccordiAmong various technologies to help people maintain a healthy life, digital health technology (DHT), which applies digital transformation technology to the health care field and includes mobile health  apps, wearable devices, electronic health records, and electronic medical records, is an innovative and efficient means to offer people a healthier life, particularly for older populations . For insAlthough DHT is presented as an important way to achieve a healthy life and new technologies have been designed and developed to provide a better quality of life for older individuals, these technologies are purposeless unless older adults use them. Therefore, identifying ways to help older people recognize and try new technologies and maintain their use of these technologies is critical to enable them to benefit from these technologies in a digital-based society. In the last 3 decades, many studies based on various theoretical models and theories have been conducted to understand older adults' intention to use these technologies and to identify relevant precedents . These mAmong the technology adoption models, the TAM has been the most frequently used to understand people’s information technology adoption behaviors in the health care context as well as in other fields. The TAM, developed by  based onAs mentioned, the TAM has been empirically replicated to explain people’s behaviors with regard to adopting technologies in various fields, such as marketing, education, banking, social media, and health care ,13, and As shown in As one of the extended models of the TAM, the TRAM incorporates TR and people’s propensity to accept and use new technologies to achieve their goals at home and work . TR is aPrevious literature on technology acceptance in health care and services has studied various individual characteristics and external variables that could affect the relationships proposed by the TAM, but no research has incorporated TR along with PU and PEU on attitudes and intentions. The conceptual model  and hypoHypothesis 1: TR  influences PU.Hypothesis 2: TR  influences PEU.Hypothesis 3: PEU influences PU.Hypothesis 4: PU influences attitudes toward the use of DHT.Hypothesis 5: PEU influences attitudes toward the use of DHT.Hypothesis 6: Attitudes toward the use of DHT influence continued usage intention.Hypothesis 7: The level of eHealth literacy will influence the relationships between TR and the variables.χ23=10.180; P=.006) and perceived socioeconomic status . The proportion of unmarried people included in the low eHealth literacy group (group A) tended to be high. Additionally, it was found that the higher people’s perceived socioeconomic status was, the more likely they were to be included in the high eHealth literacy group (group B).The population of this study comprised adults over 60 years of age in Hong Kong. A web-based survey method was used to collect data in this study via a convenience sampling method. A total of 357 participants completed the survey, of whom 306 provided usable responses. The demographic characteristics are shown in To measure eHealth literacy, an eHealth literacy scale  with 8 iFor TR , 16 itemPU, PEU, and attitude toward using digital health technology (ATDHT) are basic variables of the TAM. These variables were assessed by items developed by ,17. FinaAll responses were recorded on a 7-point Likert scale ranging from “strongly disagree” to “strongly agree.” First, the survey questionnaires were created in English because the original scales from the previous research were developed in English. The English version of the survey was then translated into Cantonese, which was the native language of the participants in this research, by an individual with a doctoral degree in sports management who also possessed a comprehensive understanding of public health literature and fluency in Cantonese and English. The Cantonese version was then back-translated into English by a different individual who possessed credentials similar to those of the individual who produced the Cantonese version. Finally, 10 potential participants who were above 60 years of age were recruited to check the questionnaire’s ease of use and clarity. As a result, the completed questionnaire was properly verified.First, confirmatory factor analysis (CFA) was conducted to validate the posited relations between the observed variables and the underlying constructs in the measurement model. Various indexes, such as chi-square, the Steiger-Lind root mean square error of approximation (RMSEA), the Tucker–Lewis index (TLI), and the comparative fit index (CFI), were used to assess the absolute and comparative fit of the model. Second, composite reliability (CR), average variance extracted (AVE), and Cronbach α coefficients were calculated for the components of each measurement scale to check convergent validity, discriminant validity, and reliability. Finally, structural equation modeling (SEM) was applied to test the proposed hypotheses. The proposed model was also assessed by the same indexes used for the CFA.The Research Ethics Committee of Hong Kong Baptist University in Hong Kong, China, approved the study (REC/20-21/0378).χ2532=915.575; P<.001; TLI=0.935; CFI=.942; RMSEA=0.049). Regarding internal consistency, the range of CR and Cronbach α were from .806 to .937 and from .759 to .936, respectively. That is, the CRs and Cronbach α coefficients of all latent variables were higher than the criteria value of .7. This means that all latent variables had appropriate internal inconsistency.To assess the validity and reliability of the measurement model, we applied a 2-step structural equation modeling approach . First, r=0.640), discriminant validity was also achieved. Convergent validity is achieved by 2 criteria recommended by . The CRsχ2542=994.158; P<.001; TLI=0.924; CFI=931; RMSEA=0.052).Based on an appropriate measurement model, SEM was conducted to test the hypothetical causal relationships among the 8 latent variables. The results showed that our structural model had fairly acceptable fit indexes (P=.002) and PEU . Additionally, innovativeness had a positive effect on PEU . However, discomfort about DHT had a negative influence on PEU .The hypothetical paths between TR and PU were not significant, except for the path from optimism to PU (H1-a). In the case of H2 regarding the effect of TR on PEU, all paths were significant except for the path from insecurity to PEU (H2-d). This means that H1 and H2 were partially supported. In other words, for adults over 60 years of age, optimism about DHT had a positive effect on PU . Additionally, 2 paths from PEU  and PU  to ATDHT were positively significant. Finally, ATDHT had a significant effect on older adults’ continued usage intention . This means that H3 to H6 were supported. Next, regarding hypothesis 7, our hypothesized model was independently analyzed for each group classified by the level of eHealth literacy. Four paths associated with the TAM were statistically significant in both groups. However, there was a difference in the paths in which TR affected PU and PEU. In the low eHealth literacy group, the negative influence of discomfort on PEU was found to be very powerful . In the rest of the paths, the high eHealth literacy group (group B) tended to have a stronger influence on PU and PEU than the low literacy group (group A). The results of the hypothesis testing are shown in The results of testing hypotheses H3 to H6 associated with the TAM were as follows. The path from PEU to PU was statistically significant  examined the factors affecting older adults’ intention to use DHT, (2) investigated their eHealth literacy level, and (3) explored the differences between participants with high and low levels of eHealth literacy regarding their DHT usage intentions. The findings are discussed below.This study validated the TRAM in older adults in Hong Kong in terms of its construct validity, convergent validity, discriminant validity, and internal consistency. The results demonstrated that the TRAM is an appropriate and meaningful framework to predict older adults’ intentions to use DHT. Previous TRAM- or TAM-based studies mostly focused on health professionals’ acceptance of information and communication technology  and paidThe participants in the current research expressed a considerable extent of optimism and low discomfort toward DHT usage. Meanwhile, limited innovativeness and a degree of insecurity were demonstrated among this group of people as well. In terms of the relationships between TR variables and PU/PEU, for optimism, the study results indicated that optimistic participants were more likely to perceive DHT as useful and easy to use. This finding was consistent with previous research ,21,27,28For the relationships among the TAM variables, the results were as expected and aligned with previous studies ,21,27,28This research investigated eHealth literacy among older adults in Hong Kong and found that marital status and perceived socioeconomic status can influence their eHealth literacy status. Married older adults were more likely to receive social support for the use of DHT devices, which could result in high eHealth literacy. Older adults with higher income could have more experience with DHT devices, which may also help develop high eHealth literacy. The correlation analysis also showed that eHealth literacy was significantly connected with all the variables except discomfort and insecurity. This might be because the current measurement for eHealth literacy is developed on the basis of Web 1.0 technology, which is a web-based environment, while new technologies  have been applied in current DHT . In thatOur findings are meaningful for older adults because older individuals with eHealth literacy can increase their interest in health and knowledge of health care, which leads to confidence in DHT and a positive attitude toward DHT . eHealthSeveral limitations are recognized in this study. First, the participants of this study were recruited via a web-based survey, which means that the current study excluded older adults with less willingness to interact with IT. The generalizability of the research findings might be hindered by this sampling method. Related studies targeting people who are less willing to use IT are required because their health demands might be more pressing and they may receive less support than those who use IT. Second, the respondents of this study were older adults from Hong Kong. Considering the cultural specificity, the application of the study findings in other groups or areas should be further examined. Third, factors beyond the TRAM may also predict users’ intention of DHT usage, but they have not been considered in the current research. More in-depth studies that consider other potential influencers of DHT usage are desirable. Finally, the outcome variable of this study was DHT usage intention. Since a gap naturally exists between behavioral intentions and actual behavior and it is actual behavior that can influence individuals’ health status, studies that integrate behavior and identify more components in this relationship are warranted.This study tested the TRAM in older Hong Kong adults and explored the difference in the relationships of the TRAM between participants with high and low levels of eHealth literacy. The findings provided partial support for the hypotheses, emphasizing the impact of eHealth literacy on encouraging older adults to use DHT and obtain health benefits from it. This study also suggests providing assistance and guidelines for this population to narrow the aging-related technology gap and to further explore the associations of eHealth literacy, the TRAM, and actual behavior.


BackgroundCoronavirus (COVID-19) was officially declared a pandemic in March 2020 and has had a major impact on global healthcare services, including radiology. However, little is known about the full impact of COVID-19 on the utilization of diagnostic imaging in Africa’s public healthcare sector.ObjectivesThe objective of this study was to compare public sector diagnostic imaging utilization by modality for the whole Western Cape Province (WCP) of South Africa (SA), as well as its metropolitan and rural areas, in 2019 and 2020 in terms of the absolute number of investigations and investigations per 1000 people.Method people. We calculated mammography utilization for women aged 40-70 years and compared data for 2019 and 2020.We performed a retrospective analysis of Western Cape Government Department of Health and Wellness and Stats SA District Council 2021 Mid-Year Population Estimates data. All diagnostic imaging investigations performed in 2019 and 2020 were collated and stratified by imaging modality, geographic region , and calendar year. Data are presented as the total number of investigations and investigations per 1000Resultsvs. 1,123,508, −261,433) and 20% (262/103vs. 208/103), respectively. Total numerical decline was highest in plain radiographs , accounting for more than three-quarters (78%) of the total reduction.Between 2019 and 2020, the provincial population increased by 1.9%, while total imaging investigations and investigations per 1000 people decreased by 19% , whereas computed tomography was the least impacted  with the remaining modalities decreasing between approximately one-quarter and one-fifth . Proportional metropolitan (−18.7%) and rural decreases (−19.3%) were similar.Percentage decline was most pronounced for mammography, as utilization was almost halved (15.7/10ConclusionCOVID-19 had a substantial impact on WCP imaging services, decreasing overall radiological investigations by almost one-fifth. The greatest impact was on elective investigations, particularly mammography. Although the proportional impact was similar for the metropolitan and rural areas, COVID-19 nonetheless exacerbated existing discrepancies in imaging utilization between the geographical regions. The medium- and long-term clinical impacts of decreased imaging are still to be defined. Severe acute respiratory syndrome coronavirus 2 was first reported in Wuhan, China, on December 31, 2019, and officially declared a pandemic on March 11, 2020. The first case in South Africa (SA) was documented on March 5, 2020, heralding the country’s first coronavirus disease 2019 (COVID-19) “wave,” which extended from March 2020 to November 2020 and peaked during the week of July 5-11 with 13,000 new cases daily. To curtail the spread of infection, a state of national disaster was declared on March 15 . During The pandemic had a major impact on global healthcare, as national authorities, including SA, scaled down routine services and prioritized emergency responses. Outpatient attendance was curtailed, elective surgery was postponed, and staff redeployed from routine services to COVID wards and intensive care units -8. BasicThe pandemic also influenced the nature of emergency care. Individuals showed diminished health-seeking behavior, particularly for less severe illnesses, while trauma admissions declined. In New Zealand, the United Kingdom, France, and Spain, the overall trauma workload decreased by 37%-75% during hard lockdown -13. SA rGiven radiology’s integral role in healthcare  and its Hard lockdown data for April 2020 from Ohio, USA, documented a 55% overall reduction in imaging utilization compared to the previous year. Outpatient, emergency, and inpatient studies decreased by 68%, 48%, and 31%, respectively, while mammography, ultrasound (US), magnetic resonance imaging (MRI), plain radiography, and computed tomography (CT) decreased by 93%, 58%, 56%, 53%, and 47%, respectively. Central and peripheral hospital utilization declined by 42% and 54%-64%, respectively . SimilarStudies of the impact of COVID-19 on imaging utilization have been limited to North America, Europe, and Asia ,17,19. TThis retrospective audit was conducted in the WCP, the southernmost of SA’s nine provinces, with approximately 12% of the national population . The WCPWCP health services are based on mirrored, tiered referral pathways for rural and metropolitan areas . InitialA digital imaging platform is used across the WCP, which has an amalgamated picture-archiving and communication system across various levels of care. Most facilities can view imaging studies performed across the platform, eliminating unnecessary service duplication. The Medical Imaging Services Sub-Directorate (MISSD) within the Directorate of Health Technology (DOHT) in the Western Cape Government Department of Health and Wellness is tasked with the collation of all data pertaining to the utilization of provincial diagnostic imaging services. These data include the utilization of services at each facility and form the basis of this study.We extracted imaging utilization data for 2019 and 2020 from the MISSD database and stratified them by imaging modality  and geographical location . Population statistics for 2019 and 2020 were based on Stats SA District Council 2021 Mid-Year Population Estimates, acquired using a cohort component methodology, and released at mid-year based on the latest available information  by modalWe stratified plain radiographs as either chest X-rays (CXR) or general X-rays. The workload was analyzed by the absolute number of investigations and investigations per 1000 people for each modality, for the whole province, as well as the metropolitan and rural areas. We used breast imaging analyses per 1000 women aged 40-70 years in keeping with a previous WCP analysis of radiological utilization .The study was approved by the Health Research Ethics Committee (HREC) of the Faculty of Medicine and Health Sciences at Stellenbosch University and by the Health Research Committee of the WCP under the auspices of the National Health Research Database .Provincial analysisPopulationIn the review period, the WCP population grew by 1.86% , as seen in Table Overall Imaging UtilizationOverall provincial imaging workload decreased by 19%, or more than a quarter of a million studies . In absolute numbers, the decline was most striking for plain radiographs, which decreased by more than 200,000 investigations  and accounted for more than three-quarters (78%) of the total reduction. The most striking percentage decrease was in mammography, where utilization was almost halved , representing a total decline of 5221 studies. CT was proportionally the least impacted modality, reduced by only 10%, which nonetheless equated to almost 10,000 fewer studies . Other modalities decreased between approximately one-fifth and one-quarter . The proportion of basic radiological investigations (plain radiographs and ultrasound combined) remained relatively constant, being 88.4% and 88.0% in 2019 and 2020, respectively.Imaging Utilization Per 1000 PeopleOverall investigations per 1000 people decreased by one-fifth, or 54 studies (265 vs. 211). Proportional decreases by modality were broadly aligned with those for absolute numbers, as seen in Table Analysis comparing metropolitan and rural areasPopulationAlthough there was an expansion of both the metropolitan  and rural  populations, proportional metropolitan growth exceeded rural growth by 24% (1.99% vs. 1.60%). Overall Imaging UtilizationCombined utilization of plain radiography, US, fluoroscopy, CT, and mammography decreased by 18.7%  and 19.3%  in the metropolitan and rural areas, respectively, with similar proportional reductions in the rural and metropolitan areas . Imaging Utilization Per 1000 People3 people) exceeded rural utilization (228 studies/103 people) by approximately 46 studies/103 people (20%). The most striking discrepancies by modality were for mammography , CT , fluoroscopy , and CXR . General radiography (102.4 vs. 101.9) and US (43.0 vs. 39.5) utilization were similar in the two areas. In 2019, combined metropolitan utilization of plain radiography, US, fluoroscopy, mammography, and CT . However, the patterns of impact were different across the modalities for the two regions. The proportional reduction in metropolitan mammography utilization  exceeded that of rural areas , whereas the proportional rural reduction in fluoroscopy utilization  was higher than that of metropolitan areas .In 2020, both metropolitan and rural regions recorded decreased combined utilization of the above-mentioned modalities  per 1000 people. However, the proportional rural decrease  was slightly greater than the metropolitan decrease , with the resultant increased discrepancy between metropolitan and rural utilization , being approximately four times that of CT (10%) and almost double that of the remaining modalities. The third was the relatively small difference in proportional impact, with the exception of mammography, between the metropolitan and rural areas. This, nonetheless, exacerbated existing discrepancies in imaging utilization between metropolitan and rural areas. The fourth was the broad alignment of findings from this study with those of similar assessments in other healthcare settings.The WCP data show close congruence with those of NHS England , which rThe extent of the impact of COVID-19 on elective WCP investigations is exemplified by the 42% decrease in mammography studies for 2020. The clinical impact of such a contracted mammography service is reflected in the 44% reduction (247 vs. 139) in new breast cancers diagnosed at a large WCP anatomical pathology laboratory in the first three months of lockdown (1 April to 30 June 2020), compared to the corresponding period in 2019 . Substan3 eligible women) compared to the metropolitan baseline (20.5 studies/103 eligible women). It is widely acknowledged that the full clinical significance of curtailed COVID-19 mammographic services is yet to be revealed globally . In the One strength of this study is its foundation on accurate data from all WCP public sector diagnostic imaging facilities, correlated with provincial population data over a two-year period. As such, it provides a robust overview of the impact of the pandemic on a provincial imaging system. The reported data are unique in the SA context and, to our knowledge, across low- and middle-income countries. The work allows appreciation of the elective imaging backlog in certain modalities in the metropolitan and rural areas of the WCP and can assist in future resource allocation, including potential redeployment of staff and resources in the post-COVID era, to address backlogs, particularly in mammography.The study is limited by its retrospective design and the absence of comprehensive demographic data for the imaged population. Additionally, the clinical indications for and acuity of investigations are not provided, while ultrasound, CT, and MRI studies were not stratified by body part. These shortcomings preclude detailed analyses of the clinical impact of decreased imaging during the pandemic. These limitations are common to other published work on the impact of COVID on radiological services and underscore the need for ongoing analyses of the medium- and long-term clinical impacts of the pandemic.COVID-19 had a substantial impact on WCP imaging services, decreasing overall radiological investigations by almost one-fifth. The greatest impact was on elective investigations, particularly mammography. Although the proportional impact was similar for the metropolitan and rural areas, COVID-19 nonetheless exacerbated existing discrepancies in imaging utilization between the geographical regions. The medium- and long-term clinical impacts of decreased imaging are still to be defined.


Evidence-informed decision-making is increasingly recognized as a standard for policymaking in many fields, including public health. However, many challenges exist in identifying the appropriate evidence, disseminating it to different stakeholders, and implementing it in various settings. The Israel Implementation Science and Policy Engagement Centre (IS-PEC) was established at Ben-Gurion University of the Negev to “bridge the gap” between scientific research and policy. As an illustrative case study, IS-PEC is conducting a scoping review on strategies to engage senior citizens in Israel when developing health policy. In May 2022, IS-PEC brought together international experts and Israeli stakeholders to increase knowledge in the field of evidence-informed policy, develop a research agenda, strengthen international collaborations, and create a community for sharing experience, research, and best practices. Panelists presented the importance of communicating clear, accurate bottom-line messages with the media. Also, they highlighted the once-in-a-generation opportunity to promote the uptake of evidence in public health due to the increased public interest in evidence-informed policymaking post-COVID-19 pandemic and the need to build systems and centers to support the systematic use of evidence. Group discussions focused on various aspects of communication, including challenges and strategies when communicating to policymakers, understanding the nuances of communication between scientists, journalists, and the public, and some ethical issues surrounding data visualization and infographics. Panelists participated in a passionate debate regarding whether and how values play a role when conducting, analyzing, and communicating evidence. Takeaway lessons from the workshop included that going forward, Israel must create lasting systems and a sustainable environment for evidence-informed policy. Novel and interdisciplinary academic programs must be developed to train future policymakers in various fields, including public health, public policy, ethics, communication, social marketing, and infographics. Sustainable professional relationships between journalists, scientists, and policymakers must be fostered and strengthened based on mutual respect and a shared commitment to creating, synthesizing, implementing, and communicating high-quality evidence to serve the public and individual wellbeing.The online version contains supplementary material available at 10.1186/s13584-023-00559-8. Evidence-informed decision-making and policymaking are increasingly becoming recognized globally as a standard in developing programs and policy interventions. However, many challenges exist in identifying the appropriate evidence, disseminating it to different stakeholders, and implementing it in and collaborating across different settings , 9. The The Israel Implementation Science and Policy Engagement Centre (IS-PEC) was established at Ben-Gurion University of the Negev in the summer of 2021 to “bridge the gap” between science and policy. IS-PEC is the first of its kind in Israel and one of the few centres worldwide focusing on implementation science and policy engagement .This research centre was founded by Moriah Ellen, a professor of health systems and policy at Ben-Gurion University, and is led by an interdisciplinary steering committee and internationally renowned strategic advisors. By bringing together the fields of Implementation Science (IS) and Knowledge Transfer and Exchange (KTE), the centre seeks to prepare future leaders in the most advanced methods. The centre also collaboratively works to build a strong culture of evidence-based implementation and evidence-informed policy in Israel while contributing to global knowledge.IS-PEC conducts impactful national and international research and investigates stakeholder and citizen engagement in policymaking, monitoring and evaluating existing KTE practices, and evaluating healthcare professionals’ perceptions of issues on IS and KTE. As an illustrative case study, in Israel, IS-PEC is conducting a scoping review to identify what is known regarding strategies to engage senior citizens and informal caregivers when developing health policy. Through mapping available strategies, IS-PEC uses updated methodological guidance to provide an evidence-based foundation to guide senior citizens’ engagement in health policy development . InternaTo Increase knowledge and skills in evidence-informed policy among the workshop's participants, including policymakers, researchers, and journalists;To develop a research agenda and strengthen collaboration between experts internationally; andTo create a community for sharing experience, research, and best practices in Evidence-Informed Policymaking.In May 2022, IS-PEC held a two-day workshop funded by the Bat-Sheva de Rothschild Foundation titled “Rethinking the Path from Evidence to Decision-Making.” The workshop included presentations, discussions, and expert panels led by world-renowned international experts in the field of evidence-informed policymaking . Balicer discussed that scientists are accustomed to taking particular care in their statements and are hesitant to make sweeping, strong statements. He emphasized that this approach is perceived as a “grey” message when communicating to the public and decision-makers and that it is necessary to communicate a clear, accurate bottom line during these communications.John Lavis iterated that we currently have a once-in-a-generation opportunity to work with political leaders to build on the “right” lessons learned from our own and other jurisdictions. Lavis emphasized the need for context-specific rapid jurisdictional assessments to identify what works well and what gaps exist in domestic evidence-support systems. Lavis encourages using a “rapid learning and improvement” approach in the remainder of 2022 to systematize  what is working well and fill the gaps in these systems.Tanja Kuchenmüller presented WHO’s evidence-to-policy work, in particular the Evidence-informed Policy Network (EVIPNet) , a globaThese opening lectures set the tone for the next day and a half in which researchers, policymakers, students, journalists, and leaders across various disciplines met to explore and consider how evidence-informed policymaking can be improved in Israel on the macro, meso, and micro levels.A major goal of the workshop was understanding the issues involved with communication between policymakers and researchers. Workshop participants broke into group discussions to explore some of the nuances and challenges of this communication. The first group discussion was led by Tanja Kuchenmüller and Jorge Barreto, a public health researcher and EVIPNet Global (WHO) steering group member, and addressed communicating research to policymakers, based on the findings from a recent rapid scoping review regarding research communication guidance, tools, and frameworks . The groThe second group session, led by Bruce Lewenstein, a professor of science communication at Cornell University, and Julia Belluz, an expert in science communication in journalism, discussed the nuances of communication between scientists, journalists, and different audiences. It was widely accepted that researchers and journalists must collaborate to effectively share scientific information with the public. However, each stakeholder has distinct roles and encounters challenges in science communication. From the researchers’ perspectives, challenges included thinking outside the disciplinary mindset, adjusting to short time frames (seizing the moment), and learning how to transform evidence into stories. For journalists, a lack of prior knowledge in the reported field, requirements to deliver sensational news, and converting messages from the scientific literature to social media platforms were major challenges. Tensions were discussed between science being developed by a professional elite and the idea that “science is too important to be left to the scientists” . Also, tScience infographics and data visualizations are powerful tools for shaping public opinion and policy. The third group discussion was led by Mushon Zer-Aviv, a designer, researcher, educator, and media activist, and Nadav Davidovitch, a professor of health policy and public health at Ben-Gurion University. During the session, participants discussed how to provide context when using infographics and ethical issues in data visualizations. For example, during the COVID pandemic, data infographics were frequently used to highlight trends in cases and mortality. However, other impacts of the pandemic on society and individuals, such as school closings and mental wellbeing, were seldom visualized. Excluding these aspects created an imbalance in the issues addressed by policymakers and sometimes did not allow for policies to be presented and understood in a broader contextualization. A responsible and ethical approach to data visualization needs to foresee the impact of “viral infographics” on human behavior and design infographics to have a positive influence. Acknowledging the complexity of this mission, the participants underscored the importance of roundtable discussions among designers, health professionals, social scientists, and public representatives when forming data visualizations. Also, designing data visualizations and science infographics were appreciated as specialties that need to be learned and taught through multi-disciplinary courses, including schools of public health and schools of art.The day continued with a panel discussion led by Moriah Ellen, including experts from the World Health Organization, the McMaster Health Forum, and Ben-Gurion University. During the panel discussion, a debate developed between members of the panel discussion regarding whether and how values play a role when conveying evidence. It is well established that knowledge alone cannot influence policy change in complex political environments. Rather, the evidence must be accompanied by several elements, including but not limited to policymaker heuristics, successfully maintained networks, and persuasive narratives . HoweverJohn Lavis agrees that understanding the interplay between technical, social, and political values is critical for policy analysis and designing appropriate policies . HoweverConversely, while Nadav Davidovitch agrees that experts need to base their statements on the best available evidence, he maintains that “evidence and what kind of data you want to collect is already based on your values.” For example, the researcher’s answer to the question, “Is health a right or a commodity?” affects how he or she designs the study, collects the data, and interprets the information. Davidovitch encourages experts to be upfront and transparent about their values when presenting the data, as he sees the two as intrinsically connected.3 cups of evidence3 cups of well-chosen storiesOne tablespoon of political willA sprinkle of good timing and a dash of luck.Bake into the public conversation.Using compelling case studies on topics ranging from the global anti-vaccine movement to America's staggering maternal mortality problem, Julia Belluz went beyond the daily headlines to take a deeper look at science communication from the journalist's perspective. Corresponding to the group discussion held during the workshop, Julia proposed the following "Recipe for Impact":Her point was that evidence alone is insufficient to move people and change policy. It would be best if you also had illustrative stories and, for real impact, political will about the issue you are reporting on, along with some luck and good timing. While ingredients and ratios can be debated, Julia’s proposed recipe illustrates the need to combine facts with narratives and other elements when communicating scientific evidence to a wide audience. In her presentation, Julia also emphasized the need for collaboration among researchers—who produce the evidence—and journalists—who humanize the information with stories.Day two of the workshop continued with a roundtable exercise dedicated to exploring several domains and processes necessary for institutionalizing evidence-informed policymaking. Tanja Kuchenmüller, Marge Reinap, and Mark Leys led the group discussions. The session was founded in the WHO EIP institutionalization framework that comprises six domains: 1) governance; (2) standards and routinized processes; (3) leadership and commitment; (4) resources and capacity building/strengthening; (5) partnership, collective action and support; and (6) culture , 8. Tabl governanAs defined by the WHO EIP institutionalization framework, governance relates to the rule-making and steering-related functions that promote the institutionalization of evidence-informed policymaking, such as knowledge translation platforms that connect research and policy , 8. The This group discussion emphasized the importance of creating and improving multi-sectoral partnerships, such as engaging the Ministry of Finance in policy decisions beyond economics. Similarly, partnerships between the Ministry of Health and the HMOs are essential due to the HMOs’ data and policy influence.A suggestion was put forth to coordinate between the chief scientists of different sectors to create a joint evidence-informed policymaking system to showcase EIPM leadership and emphasize a commitment to promote the routine use of evidence at the national level. Group members suggested that policymakers take lessons from the multisectoral work utilized in the health sector and implement similar practices in policy areas beyond health.Group members also highlighted the need to create an interagency platform that can serve as a safe space for actors to convene and deliberate on policy issues. The EVIPNNet situation analysis was posited as a potentially helpful tool to identify relevant stakeholders for such a platform . The groThe group discussed several questions regarding capacity building in evidence-informed policy: (1) Building capacity of whom? (2) What capacities need to be built? (3) How to provide capacity building? And (4) how to ensure effectiveness, impact, and sustainability.Regarding the first question, key stakeholder groups include researchers, policymakers, and intermediary influencers. The latter group encompasses journalists, lobbyists, NGOs, and state auditors. Specific emphasis was placed on capacity building for young professionals, such as student researchers, internship participants, and middle managers.Capacities that need to be built include storytelling and sloganizing, knowledge translation, and stakeholder engagement. Specifically, how to engage with citizens and decision-makers using science infographics and data visualizations should be prioritized as part of capacity building. Also, the group discussed the importance of rethinking the roles of chief scientists and better equipping them with relevant tools, so they may effectively serve as intermediaries between scientists and decision-makers.Capacity building should encompass evidence-informed policy (EIP) training by dedicated centers, academic education , training of trainers programs, and peer-to-peer role modeling. Training of trainers programs was deemed especially relevant for middle managers in government offices. Also, e-training tools in EIP should be developed and incorporated into capacity-building initiatives. The group also discussed the need to tailor scaled capacity building according to individuals’ levels and needs, including those who develop their careers in the field of EIP.The lessons, insights, and conclusions from this two-day workshop were numerous and far-reaching. They can be summarized by how they pertain to the macro , meso (capacity), and micro  levels.macro or institutionalization level, the workshop identified the dire need to create stable systems and a sustainable environment for evidence-informed policy in Israel. The evidence systems created in Brazil serve as an excellent example of EIP institutionalization that remains in place, separate from changing political realities. The Brazilian evidence centres address varied health initiatives, from the COVID-19 rapid evidence summary series to health issues among indigenous communities [On the munities . A similmunities .In the Israeli context, the Israel Institute of Health Policy Research’s stable budget, which is required by the National Health Law (1995), is a positive example of the type of institutionalization necessary to sustain EIP best practices. The law (Section 52b) requires that the Health Council carry out research, surveys, and professional expert opinions on health policy research and promises sustained funding to ensure this occurs . This lameso or capacity level, participants identified the dire need for academic programs to train people proficient in multiple disciplines related to evidence-informed policy and science communication, such as public health, communication, social marketing, infographics, and arts. Some notable examples of this in Israel include Ayelet Baram Tazabari’s research group in the Technion and publications by the Davidson Institute at the Weizmann Institute of Science. However, despite these examples, a significant gap exists between the aforementioned fields, and the Israeli academic landscape would benefit by integrating novel programs and courses to combine these disciplines.On the micro level, the EIP workshop helped highlight the pressing need to foster professional relationships and training between scientists and journalists in Israel. Throughout the workshop, the sentiment arose that the current state of the relationships between Israeli scientists and journalists is sub-optimal, and efforts must be made to foster and strengthen these relationships. Going forward, policymakers, researchers, experts, journalists, and public members must work together to cultivate each others’ skills while creating an environment of collaboration and partnership in which each player’s expertise is respected. Only through shared goals of creating, synthesizing, implementing, and communicating the best possible evidence to the public can we hope to foster an environment that prioritizes decisions based on evidence and change Israeli society for the better.Lastly, on the Looking forward, IS-PEC plans to collaborate with government agencies and lead projects in the evidence-informed policy field, both in Israel and in collaboration with international partners. This includes the formation of a steering committee dedicated to improving evidence-support in government ministries, a rapid jurisdictional assessment of existing evidence-support systems throughout the Israeli government and with external partners, and conducting symposia on knowledge transfer and exchange for chief scientists and their staffs. IS-PEC benefits from the expertise of international scholars and practitioners of evidence-informed policy and the support of parallel centers worldwide. Due to its interdisciplinary expertise, the long and diverse experiences of its members, being trusted and well-situated within the Israeli context, and commitment to improving the uptake of evidence-informed policy-making, IS-PEC is uniquely positioned to advance the field in Israel and abroad with the international EIP community.Additional file 1. The workshop included presentations, discussions, and expert panels led by world-renowned international experts in the field of evidence-informed policymaking.


Introduction: Advanced Therapy Medicinal Products are a type of therapies that, in some cases, hold great potential for patients without an effective current therapeutic approach but they also present multiple challenges to payers. While there are many theoretical papers on pricing and reimbursement (P&R) options, original empirical research is very scarce. This paper aims to provide a comprehensive international review of regulatory and P&R decisions taken for all ATMPs with centralized European marketing authorization in March 2022.Methods: A survey was distributed in July 2022 to representatives of 46 countries.Results: Responses were received from 20 countries out of 46 (43.5%). 14 countries reimbursed at least one ATMP. Six countries in this survey reimbursed no ATMPs.Conclusion: Access to ATMPs is uneven across the countries included in this study. This arises from regulatory differences, commercial decisions by marketing authorization holders, and the divergent assessment processes and criteria applied by payers. Moving towards greater equality of access will require cooperation between countries and stakeholders, for example, through the WHO Regional Office for Europe’s Access to Novel Medicines Platform. Advanced Therapy Medicinal Products (ATMPs) are medicines for human use that are based on genes, tissues or cells . Some ofThe generation of evidence in therapeutic areas where there is an unmet medical need can be challenging . The PRIIn order to facilitate early access for patients, where a product addresses an unmet need, regulators can give a conditional MA on the basis of early data, providing certain conditions are met including the provision of further evidence . HoweverWhilst regulatory policies are being adopted in Europe to facilitate the accelerated approval of ATMPs , the comThe way ATMPs are administered has relevance for decision making both from clinical and reimbursement perspectives. Unlike most medicines, which can be withdrawn if no response is achieved, gene therapies are one-off treatments. Out of the 15 indications (13 ATMPs) in our sample, 14 are intended for single administration . Due to Payers handling the difficult task of managing financial risk and uncertain evidence, where it exists, need to embed risk management strategies into their pricing and reimbursement (P&R) decision making processes, and they often do so through special pricing mechanisms . While tA survey was distributed in July 2022 to 46 countries see  through By March 2022, 13 ATMP had received European central MA via the EMA. 2 of them have 2 licensed indications with European central MA , making Data collection sheets were pre-filled with information from the literature review or previous PPRI Network enquiries where available. Respondents were allowed approximately 3 weeks to respond, with one reminder, and were contacted again to clarify responses that were unclear. The survey included questions about the regulatory approval status in the country , reimbursement status, the reasons for not reimbursing in case the ATMP is not reimbursed, whether any special arrangements are in place to finance the therapy  . 6 of th14 countries reimbursed at least one ATMP . Austria4 of the ATMPs included in our study were chimeric antigen receptors (CAR) T-cells medicines (CAR-Ts) . Previous research in a smaller sample of countries  and ATMPs  found that the CAR-Ts they included in their study were being reimbursed in the countries they observed . Our resIn Australia, the purpose of all special arrangements used to finance ATMPs was to share risks. These agreements were always associated to the collection of further evidence. The Pharmaceutical Benefits Advisory Committee (PBAC) does provide advice on the nature of the patient registry that is most suitable in each case , as well as the minimum data to be collected. For instance, for both indications of ATMP11 and ATMP5, they recommend the Australian Bone Marrow Transplant Recipient Registry, for ATMP7 they recommended including data from Australian patients in the Novartis international registry, and for ATMP12 they noted that a disease-based registry would be suitable, instead of therapy-based registries. For all therapies the manufacturer would be responsible for providing any new data to the HTA committee, which would re-assess the new evidence. The periods for reassessment varied between 2 years from commencement of public financing for both indications of ATMP11 and ATMP5, 3 years for ATMP7 and 5 years for ATMP12.The special pricing and reimbursement arrangements used for ATMPs were confidential. However, the PBAC does publish its recommendation. For ATMP11, ATMP7 and ATMP12, the PBAC recommended a P4P risk sharing arrangement combined with a confidential discount. For ATMP5, they recommended a P4P.In Canada the regulatory authority  of Health Canada) can issue a Notice of Compliance (NOC), which corresponds to an MA, or a NOC with conditions, corresponding to a Conditional MA. Special agreements to finance medicines are confidential. They may involve simple discounts , incremental rebates in the event an annual threshold is exceeded, and other forms of risk-sharing arrangements. There are special arrangements in place for all 3 ATMPs being reimbursed . Whether the agreements are linked to the collection of further evidence is also confidential. For therapies that are indeed being subject to the collection of further evidence as part of managed access schemes, such evidence would be meant to inform the clinical and cost-effectiveness parameters of a reassessment (HTA). The institutions responsible for the collection and analysis of this further evidence are the pan-Canadian Pharmaceutical Alliance (pCPA) and/or provincial and territorial drug plans. In Canada, any drug that is reimbursed in the public healthcare system could be eligible for a proactive or reactive reassessment .Israel applies special pricing and reimbursement agreements for both indications of both ATMP11 and ATMP5, ATMP2, ATMP7, ATMP10 and ATMP12. However, information about the arrangements is either confidential, not publicly available or not known to the respondents of our survey. In all cases, the schemes are subjects of the collection of further evidence, which is to be collected and analyzed by the Ministry of Health of Israel, although no further information about this is publicly available.In the Czechia, the national HTA body only makes assessments of drugs for outpatient settings. ATMP2 and ATMP3 have been recommended in this context. ATMP2 is subject to a special confidential reimbursement arrangement to control expenditure. ATMP3 is reimbursed without any special arrangement. The HTA body does not assess therapies for in-hospital settings, and have no record of their use. Reimbursement in the hospital settings is theoretically possible for all products within the scope of our study and lies within the competency of health insurance companies and hospitals.Denmark reimburses 4 ATMPs: ATMP3, ATMP7, ATMP12 and ATMP5 (only its indication for B-cell acute lymphoblastic leukemia). ATMP7 is financed by a P4P model in yearly instalments conditioned on continuing clinical response, with data collected by the national procurement agency and healthcare providers . The maiFrance reimburses most ATMPs , with coAll ATMPs in this study were being reimbursed in Germany , except Greece applies confidential special arrangements to finance ATMP11 (indications 12 and 13) and ATMP5 (indications 5 and 6), ATMP12 and ATMP7. The main aim of the special arrangements is to control expenditure. For ATMP11 and ATMP5 there is a budget cap , with additional data collection over 2 years, followed by a planned reassessment and renegotiation.At the time of writing, Italy had decided to reimburse 8 of the ATMPs included in our study, for 10 different indications. To reimburse them, Italy uses a range of types of P&R arrangements see . Most ofAll ATMPs reimbursed in Italy are subject to the collection of further evidence collected by AIFA registries. The technological architecture of the registries is resourced by companies but governed by AIFA . This evThe special arrangements to finance ATMPs are confidential in nature, but in general terms, they were implemented to improve cost-effectiveness and to control expenditures. Only 2 of the special arrangements in place to finance ATMPs in the Netherlands (Kingdom of the) were organized centrally by the government (ATMP7 and ATMP12). The rest were arranged by insurance providers. ATMP11 was re-evaluated based on 3-year survival data and budget impact, which resulted in a confidential discount of the price of at least 5%. Netherlands (Kingdom of the) is also a member of the BENELUXA Initiative, which recently published an HTA jointly produced between the Netherlands (Kingdom of the), Ireland and Belgium for ATMP6 , resultiSlovenia applies special arrangements for the reimbursement of ATMP5 (indication 5 and 6), ATMP2 and ATMP12. The main purpose of these financing schemes is to control expenditures, and they achieved this through confidential discounts. None of these schemes are associated with the collection of further evidence.In Spain, the special arrangements to finance ATMPs aimed to share risk and to control expenditure. In most cases this comprised a P4P scheme, combined with restrictions in the eligible patient populations. ATMP7 and ATMP12 were financed with P4P schemes combined with expenditure cap and a price-volume agreement respectively. All of them involved the collection of further evidence, which was in all cases operationalized through a national registry operated by the health ministry  . VALTERMIn Sweden, the county councils are responsible for in-patient care, which includes ATMPs. A committee called the New Therapies Council supports county councils, enabling the equality of the system. Also, upon request of the regions, the national HTA agency can perform an assessment of the health economic evidence. This level of fragmentation makes it difficult to access information about what financing schemes are in place in Sweden for ATMPs and how they are operationalized. Nevertheless, county councils do publish information about which therapies have a managed entry agreement in place, and the dates associated with reassessment.Considering the above, although limited in scope, we do have some information about the reimbursement status of ATMPs in Sweden and how it has been operationalized. ATMP11 (indications 12 and 13), ATMP5 (indication 5 only) and ATMP12 are financed through special arrangements. For ATMP11 (indications 12 and 13), a rebate may be required conditional on further evidence collection through the European Society for Blood and Marrow Transplantation (EBMT) patient register and quality local registers. The same registry is used to collect further evidence for ATMP5, but there is no further detail available around the financing arrangement. For ATMP12, the agreement consists of a confidential discount, and the collection of further evidence, operationalized through the national quality register for neuromuscular diseases (NMiS). ATMP7 is the only ATMP reimbursed in Sweden for which there is no public report of a special financing arrangement being in place.Six countries in this survey reimbursed no ATMPs due to a variety of reasons, including regulatory and reimbursement decisions made by the regulators, the payers or the companies themselves see ).There was considerable variation in the type of P4P schemes for ATMPs in our sample. We identified areas where examples of best practice can be helpful for schemes to achieve their objectives. These included the provision of clear objectives, sharing of information between different departments of the health system, availability of information about the parameters of the agreement (or even whether one exists), and clarity about when, how or by whom the data will be analyzed and re-assessed. Improvement in these areas is a prerequisite that enables the necessary alignment between key stakeholders, including industry and health system actors, for these kinds of schemes to successfully fulfil their purpose, but the necessary human resources and expertise needs to be invested by all involved parties into reaching excellence and productive cross-stakeholder collaboration .P4P databases in our sample were usually set up using either existing disease registries or purpose-build stand-alone platforms. None of the responses received indicated that routine healthcare administrative databases were used. This may be because, for example, such platforms do not collect the appropriate diagnosis, treatment or outcome variables. The new regulation on European cooperation on HTA does not have any provision for collaboration on post-launch evidence generation (PLEG) . This woAt a European level, data sharing across jurisdictions may be essential to leverage the benefits of further evidence generation, especially for ultra-rare diseases . The rolAt a country level, the United Kingdom (England) created the Innovative Medicines Fund to ensure fast, provisional access to promising but uncertain treatments, particularly ATMPs, while further evidence is generated  and contIn the sample of responses received, information about the price or the P&R arrangement used to fund a therapy tended to be confidential in nature. While a degree of confidentiality can facilitate negotiation , ethicalThere appears to be considerable variation across regulatory body outcomes. For example, Türkiye has not approved any ATMP and other regulatory bodies have yet to assess all the products. The individual companies choose whether to submit products for regulation and registration in particular countries. For example, whilst a product may have a central European authorization the companies can then decide when and where to launch or file for reimbursement. Our survey shows that the variability of access is in part due to choices made by regulatory and reimbursement authorities, and in part due to commercial decisions by companies about regulatory and reimbursement submissions.The new European regulation on HTA will help shape the a landscape for ATMPs in the EU, since it stipulates that from 2025 onwards, ATMPs will be required to undergo joint clinical assessments, with the potential of significantly mitigating current differences between national comparative effectiveness assessments . HoweverThe results of our study highlight considerable variation in the approaches used by individual countries to provide access to ATMPs and the scope for voluntary collaborations to overcome some of the existing barriers, particularly for smaller countries. For example, some of the options available to them include joint P&R negotiations for new medicines for demand pooling (to increase the volume), collaboration on the administration of ATMPs (through joint treatment centers), or cross-country collaboration on real-world-evidence generation . There aThe development of detailed treatment protocols , and clear communication of it to stakeholders, would facilitate cross-border collaboration enabling international multidisciplinary care teams to build on existing infrastructures such as the European Reference Networks (ERNs) to deliver care and to collect evidence, which would provide a European instrument to collaborate towards mitigating uncertainties . The vieAs the evidence we present in this paper shows, many products are not submitted for reimbursement in individual countries with priority being given to larger markets. Members of the European Federation of Pharmaceutical Industries and Associations (EFPIA) have committed to “file for pricing and reimbursement in all EU countries as soon as possible and no later than 2 years from the central EU market authorization, provided that local systems allow it” . The PhaOur survey has only included “commercial” ATMPs, developed by private MA holders. There are also now several so-called “academic” ATMPs , developThis paper has described the P&R landscape in 2022 for 15 ATMPs in 20 countries, a much larger sample of products and countries than other articles . There mIn this section, and in The work undertaken has demonstrated that there is wide variation in access to ATMPs between the countries surveyed. Furthermore, that this variation has a number of reasons including regulatory differences, commercial decisions by MA holders, and the divergent assessment processes and criteria applied by payers. Moving towards greater equality of access will require cooperation between countries and stakeholders, together with relevant international actors such as the WHO Regional Office for Europe’s Access to Novel Medicines Platform.There is also considerable cross-country variation in how P4P schemes are used for a particular ATMPs. This imposes transaction costs on healthcare systems and MA holders, and limits opportunity for data sharing. In line with WHA 72.8, greater transparency, particularly where public funding has been used, will enable dialogue about the schemes in use, and the development of common protocols, terminology and standards for data collection, will lower costs and generate better quality evidence, ultimately with benefits for patients.The inclusion of post-launch evidence generation in the new European regulation on cooperation in HTA could formalize arrangements. A specific proposal along these lines was made by EURORDIS, which suggested the co-creation, with multi-stakeholder input, of a data strategy for the European Reference Networks (ERNs) to progress towards the common implementation of a European data infrastructure, building on the existing infrastructure of the Networks .Demand pooling and pooled procurement of ATMPs has not yet been frequently used, should be considered more widely  and coulThere have been several examples of non-profit development of “academic” ATMPs. Careful evaluation of these initiatives should be undertaken, considering the legal and regulatory framework, accounting methods for estimating costs, incentives, P&R pathways for these kinds of products and the implications for competition with commercial medicines.In the mid-term, more investment in enhancing HTA and (other) infrastructures to support P&R processes , accompanied by coordinated efforts to further develop the necessary expertise, would highly benefit decision makers dealing with complex P&R decisions for ATMPs.


Miguel de Cervantes, the great Spanish writer, once wrote that those “who read much and walk much, go far and know much" . The samThe practice of critical thinking helps us understand the disease manifestations and the related processes and actions that might be relevant to prevent, diagnose and treat diseases. To critically appraise the way we perform evidence-based practice, we must combine best quality research with clinical expertise. This link between exploration and practice will allow radiologists and related disciplines to impact the way medicine is practiced.Insights into Imaging, and it is my privilege as editor-in-chief to describe in this editorial how the journal, and each author, can contribute quality through critical thinking, and hence improve the way we practice radiology by re-shaping our understandings.These concepts are the cornerstones of It is universally recognized that, in medical imaging, strong levels of evidence are needed to assess the results of the different possible actions and to guide decisions  toward the most effective or safe outcome considering the benefit of patients and value-based healthcare pathways. Consequently, solid levels of evidence are required to assess the results of different possible actions derived from imaging findings. And, in doing so, we continuously generate more data in our diagnostic and therapeutic activities, whether they are processes or outcomes. This new information will then be transformed into new evidence, real world evidence. In this way, the observed relationship between action and outcome generates causality course actions that will improve our understanding of the best clinical pathways, eliminating the many confounding thoughts that we unconsciously carry during the process of learning and implementing our clinical practice.Socratic inquiry and Skepticism as foundation. Critical thinking can be understood as the process of analyzing and questioning existing and established knowledge with the intention of improving it. Previous knowledge, either eminence- or evidence-based, should continuously be critically reconsidered and reevaluated for the benefit of the patients, as knowledge is always changing in Precision Medicine. In the real world of medical imaging, this critical thinking must be focused on the evaluation of the effectiveness and clinical impact of all those processes in which images are involved, from the acquisition with different modalities to the processing of the data, from the biological correlation of radiomics as an image biomarker to the therapeutic orientation, and finally in image-guided interventional treatments. Developing critical thinking helps to improve any medical discipline by asking ourselves how to establish better and more precise processes based on existing accumulated evidence, how to recognize and control the biases when approaching a clinical problem, and how to adapt the new clinical information in service of the best solutions. Socratic inquiry and a skeptic attitude can be used to consolidate the best knowledge and construct new associations to be more efficient and to approach excellence in our daily work. Critical thinking is therefore necessary to improve both clinical practice and research in radiology, avoiding disruptive uncertainties and wrong assumptions.These “questioning and solving” skills require learning, practice, and experience , but maiIn summary, critical thinking develops evidence-based knowledge, provides continuous improvements, and avoids spurious technical and clinical misconceptions. Insights into Imaging is dedicated to manuscripts with a clear critical approach, focusing on excellence in clinical practice, evidence-based knowledge and causal reasoning in radiology. Science is based on long-lived critiques and authors are encouraged to systematically identify, analyze, and solve problems by identifying inconsistencies and correcting errors.Insights into Imaging welcomes critical thinking papers and will incorporate a new “Critical Relevance Statement” in all their publications, where authors are asked to summarize in one sentence the question they are trying to answer and the improvement they are providing to the issue at hand.To foster this,