The perspectives of the Compounded Drug Preparation Information Exchange Expert Panel of the United States Pharmacopeia (CDPIE-EP) on the urgent need to create and maintain data standards to support the electronic transmission of an interoperable dataset for compounded nonsterile preparations (CNSPs) for children and the elderly is presented. The CDPIE-EP encourages all stakeholders associated with the generation, transmission, and preparation of CNSPs, including standards-setting and informatics organizations, to discern the critical importance of accurate transmission of prescription to dispensing the final product and an urgent need to create and adopt a seamless, transparent, interoperable, digitally integrated prescribing and dispensing system benefiting of all patients that need CNSPs, especially for children with special healthcare needs and medical complexity (CSHCN-CMC) and for adults with swallowing difficulties. Lay summary: Current electronic prescription processing standards do not permit the complete transmission of compounded nonsterile preparations (CNSPs) from a prescriber to dispenser. This lack creates multiple opportunities for medication errors, especially at transitions of care for children with medical complexity and adults that cannot swallow tablets and capsules. The United States Pharmacopeia Expert Panel on Compounded Drug Preparation Information Exchange aims to reduce this source of error by creating ways and means for CNSPs to be transmitted within computer systems across the continuum of care. Twitter: Digitizing compounded preparation monographs and NDC-like formulation identifiers in computerized prescription systems will minimize error. Some estimates place medical error as one of the leading causes of death in the United States , and one“any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer. Such events may be related to professional practice, health care products, procedures, and systems, including prescribing, order communication, product labeling, packaging, and nomenclature, compounding, dispensing, distribution, administration, education, monitoring, and use” .Incorporating standards that foster e-prescribing (eRx) is a key tenet in the US federal government’s plan to reduce medication errors, increase implementation of electronic health records (EHR), and develop a nationwide EHR infrastructure for the United States. Many states and Medicare part D now require electronic transmission of controlled substances . Soon, tNo data standards currently exist for the electronic transmission of pCNSP finished dose forms that include the liquid concentration or formulation ingredients. Manufactured products approved by the United States Food and Drug Administration (USFDA) as well as those found on the British National Formulary for Children  are listErrors related to a variety of medications for children have been reported in the literature. Studies conducted at the University of Michigan indicated that the number of pCNSP concentrations ranged from 1 to 9. The majority of pharmacies compounded more than three concentrations per pCNSP . To mitiIndeed, variability in pCNSP orders presents an urgent need to codify uniform vocabulary standards at the systems level to mitigate dispensing errors. Even for existing digitized drug products, a cursory review of recent eRx evidence from across the world illustrates that (1) RxNorm contains variability in ingredient, strength, and dose form terminology , (2) dosUnited States Pharmacopeia’s (USP) standards-setting role in the medication-use process is paramount to enhanced compatibility by creating digitized compendial monograph standards to aid in the management of medications of vulnerable populations, such as CSHCN-CMC and the elderly. USP’s Expert Panel (EP), Compounded Drug Preparation Information Exchange, is developing a set of encoding rules that would govern how pCNSPs are digitized and exchanged to improve medication management, especially at transitions of care. In this manner, transparency, interoperability, quality/safety, and reimbursement for pCNSPs would be optimized and systematic errors would be minimized. The primary outcome for encoding pCNSPs is to ensure CNSP formulation ingredients and compounding instructions are communicated to pharmacies, thereby decreasing the potential for medication errors caused by incomplete transmission of eRx information from authorized prescribers’ eRx platforms .In summary, with the future mandate for electronic transmission of all prescriptions, the need for data standards to ensure safety and quality through semantic interoperability and transparency for pCNSPs is even more pressing. A significant unmet need exists to improve the standardization and transferability of pCNSP prescription data and information between healthcare settings, especially at transitions of care. Current EHR systems are highly variable in configuration and often not able to accommodate additional data elements that prescribers and pharmacists need to transmit. Interoperability between care settings is not optimal. Many pCNSP claims are rejected for payment. Significant challenges must be overcome to achieve standardization and transferability of CNSP data, including the wide variety of roles played by potential users, and varying perceived needs regarding data elements to be transmitted. Beginning the digitization process with pCNSPs, we believe that the creation of CF-IDs in an NDC-like format for all scientifically-validated sterile and nonsterile compounded preparations that both codifies a compounding monograph and allows bi-directional standardized concentration nomenclature transmission seamlessly across computer platforms, will address four salient objectives: (1) minimize prescription and formulation errors; (2) optimize patient safety; (3) expand pragmatic pediatric pharmacotherapy research opportunities related to pCNSP use; and (4) improve reimbursement for services rendered.


Some evidence suggests that disruption of integrity in the superior longitudinal fascicle (SLF) may influence cognitive functions in chronic schizophrenia (CS) but the results are inconclusive.Using diffusion tensor imaging tractography, we investigated the differences in fiber integrity between patients with CS and healthy controls (HC) together with the relationship between fiber integrity and cognitive functions.Forty-two patients with CS and 32 HC took part in the study. Assessment of cognitive functions was performed using Measurement and Treatment Research to Improve Cognition in Schizophrenia.showed group differences, left and right in fractional anisotropy (FA) and mean diffusivity (MD) of the SLF, where patients showed less integrity than controls. Patients performed worse attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition tasks than HC. However, when premorbid IQ and level of education were controlled for, the differences were no longer statistically significant in verbal learning and social cognition. In patients with CS, a positive correlation was found between FA of the left SLF and attention/vigilance and working memory. Moreover, in this group there was a negative correlation between MD of the left and right SLF and working memory and social cognition.These findings provide evidence that SLF disruption appears in patients with CS and might account for impairment of cognitive functioning. This research was funded by the Polish Minister of Science and Higher Education’s program named “Regional Initiative of Excellence” number 002/RID/2018/2019 to the amount of 12 million PLN.No significant relationships.


Cognitive-linguistic assessments are often time-consuming, based on batteries initially developed for non-neurodegenerative causes such as stroke-induced aphasia, or consist of in-house protocols.2 In addition, standardized cognitive assessments commonly used in amnestic forms of dementia are not adequate for patients with PPA due to the predominant language symptoms that are characteristic of this syndrome. Thus, there is a clinical need for brief instruments designed to evaluate patients with PPA. These instruments should be constructed such that clinicians and researchers are able to utilize efficient means to determine a diagnosis of PPA and its variants. Additionally, such measures should show adequate psychometric and diagnostic properties and should also serve to monitor progression of symptoms.Primary progressive aphasia (PPA) is a clinical syndrome characterized by a progressive and predominant impairment of language function due to an underlying neurodegenerative process. Over the last few decades, knowledge surrounding the nature and treatment of this syndrome has notably expanded. Accurate diagnosis by variant is important in both research and clinical settings because classification into the three main clinical variants of PPA  has improved knowledge regarding clinicopathological associations. Current diagnostic consensus criteria suggest the use of several tasks to assess patients with PPA in order to achieve a correct classification by variant.Brain Communications. First, Patel et al.3 describe the Mini Linguistic State Examination (MLSE) and present the first validation study of the MLSE in a cohort of 54 patients with PPA. The MLSE is a brief test that consists of 11 subtests focused on speech and language. Five error types are registered, which are used to generate a profile of impairment according to the following domains: motor speech, semantic knowledge, phonology, syntax and verbal working memory. The authors obtained high levels of internal consistency and good areas under the curve. In addition, a random forest algorithm was trained and validated, obtaining diagnostic accuracies of 92–98%. A Spanish version has already been developed and validated in PPA,4 and many other language and cultural adaptations are currently underway.In this area of investigation, two major advances have been recently published in et al.5 recently investigated the utility of the third version of Addenbrooke’s Cognitive Examination (ACE-III) to differentiate the PPA variants. The authors created an automatic calculator based on individual item analysis. The development of the interactive calculator was initially based on an analysis of 90 patients with PPA and 104 healthy controls. The initial results were further validated in an independent sample of 49 patients with PPA, which also demonstrated high sensitivity. The ACE-III is a brief test, initially developed for the assessment of frontotemporal dementia and related disorders, that examines five main cognitive domains: attention and orientation, memory, verbal fluency, language and visuospatial abilities. The test has now been adapted and validated in >30 languages.In addition, Foxe 6 a tool specifically designed for PPA, and the Dépistage Cognitif de Québec,7 which is a more general cognitive test for assessment of atypical dementia. Additionally, measures for capturing the presence/severity of language symptoms in neurodegenerative disease have also been recently developed including the Progressive Aphasia Language Scale (PALS), Progressive Aphasia Screening Scale (PASS) and the Screening for Aphasia in NeuroDegeneration Battery (SAND).In addition to the two aforementioned instruments, other interesting tools for the rapid screening of PPA have emerged in recent years. These screening tools include the Progressive Aphasia RatIng Scale (PARIS)8 Conversely, the MLSE is focused on language, which could provide a more detailed assessment of language characteristics, but gathers no information about other cognitive functions, which are often involved in PPA, especially with disease progression. Furthermore, the ACE-III is scored using the accuracy of the responses, while the MLSE focuses on error types. Thus, each brief test provides unique information when assessing PPA patients and may guide clinical decision-making regarding treatment planning.Taken together, there have been recent efforts to develop clinically useful screening and assessment tools in the realm of PPA. Future studies should compare the diagnostic capacity between instruments to evaluate the optimal assessment tool for each clinical purpose or setting . However, it is worth mentioning that these tools could be combined in order to provide complementary information regarding a given patient’s profile. The ACE-III includes several language and non-language items, which is useful for establishing a cognitive profile.9 For example, Foxe et al.5 provided an automated calculator, and Patel et al.3 trained machine learning algorithms and proposed a decision tree for guiding PPA diagnosis. Machine learning techniques may be a promising method in the identification of subgroups, by predicting diagnoses using test scores and selecting the most sensitive test items, thereby reducing the length of evaluations and ultimately moving towards computer-aided diagnosis.10 In addition, new technologies could extract qualitative features or provide a more in-depth analysis of spontaneous speech, which could also be useful in improving the diagnosis of language disorders.Another interesting aspect of these studies is that the field is moving towards the development and application of automatic tools for PPA diagnosis.The studies mentioned above report novel tools for the assessment of patients with PPA. Importantly, these tools were developed specifically for the assessment of patients with PPA and/or neurodegenerative disorders. These novel tools provide the foundation for future adaptations of these tests to other languages and sociocultural contexts which may serve to promote multicentre studies enrolling larger and more culturally and linguistically diverse samples. The development and broader inclusion of common instruments specifically designed for PPA represents a crucial first step towards improving diagnosis and disease monitoring for patients with PPA. Lastly, such measures may be used in future clinical trials to capture the potential improvement of PPA-specific symptoms following targeted interventions.


This commentary features a review of two recently reformulated models of the development of child and adolescent: (1) social withdrawal by Rubin and Chronis-Tuscano 2021, and (2) social anxiety by Spence and Rapee 2016. The articles that present these reformulated models now cover advances made during the prior 12 to 18 years of research, including increased knowledge of genetic vulnerability to anxiety and longitudinal patterns of development, and acknowledgement of multiple pathways towards and away from the development of social withdrawal or social anxiety . However, these reformulated models also contain several blind spots. The model of social withdrawal development would be improved by explicitly referring to peer treatment , especially peer exclusion; and incorporating the potential development of clinically significant anxiety in childhood (not only adolescence) and delays in developmental milestones in adulthood. The model of social anxiety development would be improved by featuring social withdrawal as a proximal affective-behavioral profile (rather than a temperament) and drawing upon the literature on social withdrawal and its links to peer relations. Overall, there is a continuing lack of integration between developmental and clinical research and models of the development of social withdrawal and social anxiety. Conceptual models of the development of social withdrawal  and etioIntegrating developmental and clinical models and research on social withdrawal and social anxiety is important because it would foster a greater understanding of the developmental processes  that lead to divergent psychosocial adjustment among vulnerable children and youth over time. Vulnerable children and youth can move toward  or away from  the devSocial withdrawal is an umbrella term which identifies children and youths who remain alone at high rates relative to their age mates in social contexts  in which peers are available as interaction partners [partners . Social partners ,10,11. Apartners . Social partners . Rubin apartners  model posocial anxiety disorder  requires that an individual experiences fear or anxiety in social situations, avoids or endures social situations with anxiety, experiences these symptoms for at least six months, and that these symptoms are accompanied by distress or life impairment  [The diagnosis of or work) ,13,14. IA strength of Rubin and Chronis-Tuscano’s  model ofunfamiliar peers to social withdrawal among familiar peers, (2) sub-cultural differences in the prevalence and outcomes of social withdrawal, and (3) the development and consequences of social withdrawal in late adolescence and young adulthood. Additionally, they note that although the study of social motivations associated with social withdrawal has become popular [Rubin and Chronis-Tuscano  deliver  popular , there i popular .attitudinal variable that indicates that a child or youth is disliked by many of his or her peers [Although the description of the role of peer difficulties in maintaining and exacerbating anxious withdrawal in childhood and adolescence is a strength of Rubin and Chronis-Tuscano’s  model, ier peers . Althouger peers , but alser peers . Ironicaer peers , but it er peers . Nonetheer peers ,17,18,19Rubin and Chronis-Tuscano’s model  is ultimTo address another blind spot, in addition to internalizing problems, the equally important potential adult outcomes of childhood social withdrawal—delays in achieving adult developmental milestones   that are most often detrimental to healthy development in withdrawn children could be targeted for prevention and intervention . Third, Spence and Rapee’s model  posits tnon-shared environment  have a strong impact on anxiety. Major sources of non-shared environmental influences are children’s and youths’ peer relations and other experiences at school [The literature review, which provides the basis for this updated model, has multiple strengths. For example, it covers research on genetic vulnerability to anxiety. This literature indicates that both genes  and t school . Also, St school  review rt school , conveyst school  review rnot have a history of behaviorally inhibited temperament nonetheless develop SAD . Although they do not elaborate on this important observation, it may be that non-shared environmental influences that take on the form of negative interpersonal learning processes, such as peer adversity and other experiences at school, also contribute to the development of social anxiety in children and youths who do not have early histories of behavioral inhibition or withdrawal. In support of this contention, the literature on social withdrawal provides evidence that peer exclusion predicts increasing anxious solitude in early adolescence, even among youths without a prior history of social withdrawal in childhood [In their analysis of the extant literature, Spence and Rapee  also comhildhood .However, a major blind spot of Spence and Rapee’s model  is its tConsiderations of these recommendations in clinical prevention and early treatment for SAD in children and adolescents could yield many improvements in selection for intervention as well as intervention efficacy. First, at-risk children and adolescents could be targeted for intervention based on social withdrawal or the combination of social withdrawal and peer difficulties, not only behavioral inhibition. This may address the psychosocial needs and mental health of at-risk children and adolescents that are currently overlooked. Second, these children and adolescents’ peer relations  could become a target of intervention , alongsiRubin and Chronis-Tuscano and Spence and Rapee’s updated models ,4 reflec


The expansive field of aging science comprises diverse disciplines, perspectives, and approaches to address questions that extend from strengthening our understanding of biological aging to promoting wellbeing among diverse aging populations. Engaged research practices represent a cross-cutting series of diverse epistemological beliefs and pragmatic practices in the conduct of research with broad relevance to areas of inquiry across the translational aging research continuum. This presentation will describe experiences with the establishment, maintenance, and continual evolution of engaged research practices in an interdisciplinary program of health services research focused on Alzheimer’s disease and related dementias (AD/ADRD). Specifically, this presentation will discuss: a) conceptualizations of engagement and its relationship to equitable research, b) engagement as praxis for the conduct of equitable research, c) personal reflections on experiences with and the practice of humility, listening, and valuing stakeholders’ distinctive expertise, and d) practical recommendations for early career scholars approaching engaged research.


Advancing dual imperatives to conserve biodiversity and sustain ecosystem services requires reliable and resilient generalizations and predictions about ecosystem responses to environmental change and management3. Ecosystems vary in their biota4, service provision5 and relative exposure to risks6, yet there is no globally consistent classification of ecosystems that reflects functional responses to change and management. This hampers progress on developing conservation targets and sustainability goals. Here we present the International Union for Conservation of Nature (IUCN) Global Ecosystem Typology, a conceptually robust, scalable, spatially explicit approach for generalizations and predictions about functions, biota, risks and management remedies across the entire biosphere. The outcome of a major cross-disciplinary collaboration, this novel framework places all of Earth’s ecosystems into a unifying theoretical context to guide the transformation of ecosystem policy and management from global to local scales. This new information infrastructure will support knowledge transfer for ecosystem-specific management and restoration, globally standardized ecosystem risk assessments, natural capital accounting and progress on the post-2020 global biodiversity framework.As the United Nations develops a post-2020 global biodiversity framework for the Convention on Biological Diversity, attention is focusing on how new goals and targets for ecosystem conservation might serve its vision of ‘living in harmony with nature’ The International Union for Conservation of Nature’s Global Ecosystem Typology has been developed to provide a systematic framework for data on all of Earth’s ecosystems in a unified theoretical context to support biodiversity conservation and ecosystem services. Ecosystem functioning not only underpins biomass production, but also depends on and regulates the stocks and fluxes of resources, energy and biota7. These functions, together with ecological processes and species traits—collectively referred to as ‘ecosystem properties’ . Together with ecosystem function, the identity of constituent biota is central to biodiversity concepts, conservation goals and human values10. Although ecosystem functions and ecological processes support both the diversity of biota and human well-being, global assessments of ecosystems12 continue to rely heavily on species metrics or simplistic land-cover proxies that convey limited information about ecosystems themselves. This limits our ability to diagnose trends and to design and resource on-ground management and policy solutions for slowing and reversing current declines in biodiversity and ecosystem services.Sustaining ecosystem functions and services requires an understanding of ecological processes and mechanisms that drive ecosystem changeTo serve the dual needs of sustaining ecosystem services and conserving biodiversity, ecosystem assessments require a global typology to frame comparisons and standardize data aggregation for analysing ecosystem trends and diagnosing their causes. To support applications throughout Earth’s diverse ecosystems, users and scales of analysis, this typology should encapsulate: 1) ecosystem functions and ecological processes; (2) their characteristic biota; (3) conceptual consistency throughout the whole biosphere; (4) a scalable structure; (5) spatially explicit units; and (6) descriptive detail and minimal complexity , ecological processes , structural features  and species-level traits of characteristic organisms .We developed a conceptual model to inform the construction of the Global Ecosystem Typology, consistent with the six design principles, and to serve as a template for describing the units of classification. The model Fig.  frames w14). Evolutionary pressures are agents of selection that influence ecosystem function and constituent species traits, typically over longer time scales, through evolution and extinction within a dynamic species pool15.Our model postulates five groups of ecological drivers that may shape ecosystems by acting both as assembly filters and evolutionary pressures  may also produce functional convergences in independent lineages. These convergences are enablers of a functional classification framework represented in the upper three levels of our typology. Functional constraints may be imposed by the species pool, which is a dynamic outcome of vicariance, dispersal and evolution, depending on ecosystem location and biogeographic history21.Convergences in ecosystem properties are axiomatic to a functionally based ecosystem typology because they underpin robust generalizations and predictions about ecosystem responses to environmental change and management. Convergences in species traits may arise from common evolutionary origins and niche conservatism13, despite the vast array of potential drivers on Earth and the complex interactions among them. This principle was critical to design of assembly models of each ecosystem functional group and for developing a parsimonious global typology  biodiversity targets in the forthcoming post-2020 CBD global biodiversity framework and for reviewing progress towards them2. The United Nations Statistical Commission recently adopted the IUCN typology as a reference classification for extending the System of Environmental Economic Accounting (SEEA) framework to Ecosystem Accounts28, meeting a long-recognized need for a spatially explicit, functionally based ecosystem typology to underpin natural capital accounting29.The IUCN Global Ecosystem Typology facilitates integrated assessment of Earth’s ecosystems, enabling a more powerful and complete evaluation of progress towards biodiversity targets and sustainable development goals than previously possible. This fills a significant gap, exemplified by the limited range of ecosystems assessed in the Convention on Biological Diversity (CBD) Global Biodiversity Outlook 530 and Key Biodiversity Areas31, as well as broadly based nature education32.Integrating both functions and biota into the hierarchical structure of the typology confers versatility for diverse applications in ecosystem management and conservation Fig. . Our typ30, with improved ecosystem and threat distribution data, will strengthen capacity to forecast state changes that result in loss of ecosystem function, services and biota. Ecosystem groupings based on convergent drivers, properties and environmental relationships will reveal similarities in threats and mechanisms of degradation, and therefore inform the development of ecosystem-specific management strategies for recovery. Embracing the dynamic nature of ecosystems and its dependency on ecological processes is a key feature that differentiates the IUCN Global Ecosystem Typology from other ecological typologies , glacial lakes37 (F2.4) and tropical cloud forests38 (T1.3)  representation of ecological processes and ecosystem functions; (2) representation of biota; (3) conceptual consistency throughout the biosphere; (4) scalable structure; (5) spatially explicit units; and (6) parsimony and utility  than one representing composition at upper levels and functions at lower levels.We developed the structure of the Global Ecosystem Typology and the generic ecosystem assembly model at a workshop attended by 48 terrestrial, freshwater and marine ecosystem experts at Kings College London, UK, in May 2017. Participants agreed that a hierarchical structure would provide an effective framework for integrating ecological processes and functional properties  defining three groups of abiotic filters  and two groups of biotic filters (biotic interactions and human activity); (2) incorporating evolutionary processes that shape characteristic biotic properties of ecosystems over time; (3) defining the outcomes of filtering and evolution in terms of all ecosystem properties including both ecosystem-level functions and species-level traits, rather than only in terms of species traits and composition; and (4) incorporating interactions and feedbacks among filters and selection agents and ecosystem properties to elucidate hypotheses about processes that influence temporal and spatial variability in the properties of ecosystems and their component biota. In community assembly, only a small number of filters are likely to be important in any given habitat13. In keeping with this proposition, we used the generic model to identify biological and physical features that distinguish functionally different groups of ecosystems from one another by focusing on different ecological drivers that come to the fore in structuring their assembly and shaping their properties.To ensure conceptual consistency of the typology and its units throughout the biosphere (principle 3), we drew from community assembly theory to develop a generic model of ecosystem assembly. The traditional community assembly model incorporates three types of filters  that determine which biota from a larger pool of potential colonists can occupy and persist in an area25 highlight continuous variation in ecosystem properties, which is represented in the typology by transitional realms that mark the interfaces between the five core realms , estuaries (freshwater–marine), and so on). In Supplementary Information, Appendix 46.The top level of classification Fig. –4 define47, extended here to reflect dominant assembly filters and processes across all realms, rather than the more restricted basis of climate-vegetation relationships that traditionally underpin biome definition on land. Hence, the 25 functional biomes  include some ‘traditional’ terrestrial biomes47, as well as lentic and lotic freshwater systems, pelagic and benthic marine systems, and anthropogenic functional biomes assembled and usually maintained by human activity48.Functional biomes (level 2) are components of the biosphere united by one or more major assembly processes that shape key ecosystem functions and ecological processes, irrespective of taxonomic identity  that serve as simple and accessible proxies for biodiversity patterns51. Second, level 5 units  are also regional expressions of ecosystem functional groups, but unlike level 4 units they are explicitly linked to local information sources by bottom-up aggregation52 and rationalization of level 6 units from established subglobal ecological classifications. Subglobal classifications, such as those for different countries  to develop descriptions of the units within the upper levels of the hierarchy, subdividing realms into functional biomes, and biomes into ecosystem functional groups. We used definitions of the hierarchical levels . Indices such as human appropriation of net primary productivity55, combined with land-use maps56, offer useful insights into the distribution of some anthropogenic ecosystems, but further development of indices is needed to adequately represent others, particularly in marine, and freshwater environments. Beyond land-use classification and mapping approaches , we sought published global maps  .Extensive searches of published literature and data archives identified high-quality datasets for some ecosystem functional groups  and datasets that met some of these requirements for a number of other ecosystem functional groups  and recurrent disturbance regimes (fires). Despite the development of this critical knowledge base, savannas suffer from an awareness disparity that hinders effective conservation and management59. In other ecosystems, our assembly models rely more heavily on inferences and generalizations of experts drawn from related ecosystems, are more sensitive to interpretations of participating experts, and await empirical testing and adjustment as understanding improves. Empirical tests could examine hypothesized variation in ecosystem properties along gradients within and between ecosystem functional groups and should return incremental improvements on group delineation and description of assembly processes.Uneven knowledge of Earth’s biosphere has constrained the delimitation and description of units within the typology. There is a considerable research bias across the full range of Earth’s ecosystems, with few formal research studies evaluating the relative influence of different ecosystem drivers in many of the functional groups, and abiotic assembly filters generally receiving more attention than biotic and dispersal filters. This poses challenges for developing standardized models of assembly for each ecosystem functional group. The models therefore represent working hypotheses, for which available evidence varies from large bodies of published empirical evidence to informal knowledge of ecosystem experts and their extensive research networks. Large numbers of empirical studies exist for some forest functional groups, savannas, temperate heathlands in Mediterranean-type climates, coral reefs, rocky shores, kelp forests, trophic webs in pelagic waters, small permanent freshwater lakes, and others  or better), and time series of changes. Sixty of the maps currently in our archive27 aligned directly or mostly with the concept of their corresponding ecosystem functional group, while the remainder were based on indirect spatial proxies, and most were derived from polygon data or rasters of 30 arcsec or finer (Supplementary Table 2) spatial data.High-quality maps at suitable resolution are not yet available for the full set of ecosystem functional groups, which limits current readiness for global analysis. The maps most fit for global synthesis are based on remote sensing and environmental predictors that align closely to the concept of their ecosystem functional group, incorporate spatially explicit ground observations and have low rates of omission and commission errors, ‘high’ spatial resolution . We describe the roles of biotic and biotic drivers, dispersal processes and evolutionary legacies and their interactions in shaping ecosystem properties.Appendix S3Structure of the IUCN Global Ecosystem Typology. A description of the structure of the typology and its rationale. Three upper hierarchical levels distinguish functionally contrasting units and three lower levels distinguish compositionally different units with similar functional properties. We contrast postulated assembly filters and ecosystem properties from our assembly model (S2) across ecosystems within the five realms of the biosphere.Appendix S4The IUCN Global Ecosystem Typology v2.1: Descriptive profiles for functional biomes and ecosystem functional groups. Descriptions and explanatory notes for 25 functional biomes and 110 ecosystem functional groups in v2.1 of the typology. Descriptions include text, images, diagrammatic assembly models, indicative global maps and key references. Explanatory notes include keys to the diagrammatic models and map assembly methods and data sources.Appendix S5Development, review and revision process for the IUCN Global Ecosystem Typology. A full description of the review peer review processes undertaken during typology development. Tabulation of all reviewer comments and detailed responses of authors for all 110 ecosystem functional groups in level 3 of the typology.Appendix S6Applications of the IUCN Global Ecosystem Typology. A review of the role of the typology in applications including reporting on global conservation and sustainability goals and targets, natural capital accounting, ecosystem risk assessment, identification of key biodiversity areas, conservation planning ecosystem monitoring, comparative ecosystem research and environmental education.


We documented the contributions of Field Epidemiology Training Program (FETP) trainees and graduates to global COVID-19 preparedness and response efforts. During February–July 2021, we conducted surveys designed in accordance with the World Health Organization’s COVID-19 Strategic Preparedness and Response Plan. We quantified trainee and graduate engagement in responses and identified themes through qualitative analysis of activity descriptions. Thirty-two programs with 2,300 trainees and 7,372 graduates reported near-universal engagement across response activities, particularly those aligned with the FETP curriculum. Graduates were more frequently engaged than were trainees in pandemic response activities. Common themes in the activity descriptions were epidemiology and surveillance, leading risk communication, monitoring and assessment, managing logistics and operations, training and capacity building, and developing guidelines and protocols. We describe continued FETP contributions to the response. Findings indicate the wide-ranging utility of FETPs to strengthen countries’ emergency response capacity, furthering global health security. If a program director had responded to our first survey in 2020, they were asked to report on the activities conducted since that submission. If a program director had not responded to the first survey, we asked them to report on all the activities in which FETP trainees or graduates had engaged for COVID-19 preparedness or response. We followed up on incomplete or duplicate responses by email or telephone calls with respondents during April–July 2021 to complete or reconcile responses.We distributed invitations to respond to the online SurveyMonkey .We mapped the responding programs to describe the geographic distribution. We analyzed selected characteristics of responding programs: years between the establishment of the program and July 2021, and days between the report of the first case of COVID-19 in the country and the date of survey response. We calculated medians and reported minimum and maximum values aggregated by WHO region. We tabulated responses and calculated by WHO region and WHO pillar percentages of programs reporting FETP trainee or graduate engagement in COVID-19 preparedness or response activities by using Microsoft Excel . Each analyst reviewed the original codebook used for the qualitative analysis of the responses to our first survey (https://translate.google.com) for responses in Ukrainian and Chinese.Four team members conducted content analysis on qualitative responses using MaxQDA  responded, reporting on COVID-19 preparedness and response activities in 69 countries across all WHO regions , panel A>10 years old, and nearly all were in countries in which the earliest known COVID-19 case was >1 year prior  or target population-specific messaging . In Rwanda, “Advanced graduates provided radio and television interviews to disseminate public health messages.” In Egypt, trainees “[developed] timely and transparent communication messaging and materials for public regarding COVID-19 enquiries” and graduates “[developed] and updated the risk communication strategy, […detected] and quickly respond to misinformation and rumors.” Graduates were more commonly involved in the development of strategic planning or liaising with government officials—especially those who are employed at the ministry of health—whereas trainees were more frequently reported to be involved in direct interfacing with the public through public hotlines and social media. Graduates in Burkina Faso conducted “COVID media training [and] sensitization of leaders  on COVID.”FETPs supported infection prevention and control activities for public and private institutions such as schools and companies (in Tanzania and Rwanda), risk assessments for healthcare facilities and schools , and “monitoring and audit of infection prevention and control practices and feedback at hospital level” (in Egypt).Graduates in El Salvador worked on event-based monitoring. Both graduates and trainees in Turkey and Ukraine monitored case numbers, surveillance data, and laboratory testing data to evaluate surveillance methods. In India, the COVID-19 vaccine rollout also provided opportunities for graduates to conduct “[monitoring] and supervision [of] vaccine rollout in states” and do “field monitoring of surge staff.”FETP trainees and graduates managed logistics and operations at all levels, from testing and sampling to vaccine supply chain management, liaising between different institutions, and organizing staff deployments. In Zimbabwe, graduates worked on “adopting and disseminating SOPs [Standard Operating Procedures]… for specimen collection, management, and transportation for COVID-19 diagnostic testing.”FETP trainees and graduates were heavily involved in efforts to train and build COVID-19–related response capacity across sectors and levels of society. The data showed that from the community level  all the way to the national and state levels , their expertise was widely required. Programs reported their participation in training for the following response-related activities: point-of-entry screening, infection prevention and control at healthcare facilities and in the community, case management, specimen collection, and the incident management system.FETP trainees and graduates served as trainers for vaccine-related rollout activities. They contributed to training on cold-chain standards (Rwanda), training healthcare workers on how to administer the vaccine (Jordan); and “training on abnormal response monitoring,” also known as adverse events monitoring (China).FETP trainees and graduates were engaged in developing guidelines and protocols. They developed standard operating procedures and participated in national-level strategic planning, particularly for the preservation of essential health services and vaccine rollout. Their wide participation in vaccine-related planning was illustrative, as in this example from China: “FETP participants were integrated into the National Immunization Centre Vaccine Task Force to participate in the Vaccination Information Group.” Drafting case-management guidelines were also reported by many programs, such as in Jordan where both graduates and trainees “[established] guidelines to deal with suspected cases coming to Jordan and confirmed as well” and “were responsible for updating the management guidelines as soon as it needed and follow up [on] admitted cases.”We documented the diverse contributions of FETP trainees and graduates to COVID-19 preparedness and response activities 1 year into the pandemic, across all WHO regions and response pillars, including the new pillar 9: maintaining essential health services and systems, and pillar 10: vaccination. Programs more commonly reported graduate than trainee engagement. Through content analysis, common themes emerged describing active engagement and vital roles in all types of activities of COVID-19 preparedness and response. The more frequent reporting of trainees and graduates working in specific pillars and the emerging themes reflect the core competencies of the advanced and intermediate tiers of FETPs . The FETWe found differences between this survey and our March–April 2020 survey . Three  tool, developed to assess countries’ implementation of the IHR (2005), recognizes the importance of FETPs with a specific indicator (D.4.2 in JEE Tool version 1 and D.4.4 in version 2): FETP or other applied epidemiology training programs in place , highligWe identified 4 limitations in the contribution of FETPs to COVID-19 preparedness and responses worldwide. First, the response rate to the second survey was about half that of the first (35% vs. 74%); responses from programs >20 years old were absent in most regions . In the midst of the global pandemic, in the first quarters of 2021 when we conducted this follow-up survey, there were several factors that may account for the reduced response rate: program staff may have had limited time to respond to detailed surveys or to track graduates, and the expanded information requested made the second survey more time-intensive to complete. Second, FETP trainees and graduates bring diverse skillsets to the training, which limits our ability to attribute their contributions solely to their participation, particularly with regard to response pillar activities that do not align with FETP core competencies. Trainee and graduate engagement in pillars that did not require field epidemiologic competencies may be a function of either skills trainees had before enrolling in an FETP, skills they acquired elsewhere, seniority associated with career progression since FETP graduation, or a combination of those factors. Third, reporting bias is inherent to this documentation approach because of respondents’ motivation to inflate engagement of programs and their graduates. Quantifying the level of support needed by the trainees and graduates to participate effectively in response activities was beyond the scope of this effort. Finally, English was not the dominant language of some respondents. Misinterpretation of questions, inaccurate translations, and loss of nuance were possible. Nonetheless, the consistency of findings about engagement across the 2 surveys, in all WHO regions and response pillars, supports the importance of FETPs in countries preparing for and responding to public health threats.This second documentation of FETPs’ contributions to responses to the COVID-19 pandemic highlights 3 needs in field epidemiology training. Systematic chronicling of how trainees, graduates, and program staff work to detect, respond, and prevent public health threats would help to build the body of evidence that field epidemiology training is valuable, and merits continued investment. Periodic tier-by-tier assessments could ensure that the skills developed through this training are the skills required by most field epidemiologists. Finally, regular updating of each tier of the FETP curriculum would assure that new skills required for field epidemiologists can be developed through FETPs. Future assessments of FETPs could include eliciting feedback from public health institutions on the quality of the contributions to the COVID-19 response of trainees, graduates, and staff. FETP evaluators can also engage with human-resource offices to ensure alignment of competencies with job requirements, pay scale, and a career path for epidemiologists. In addition, assessments can elicit self-reported information from FETP graduates about progression in their career attributable to training in field epidemiology.


Bipolar disorder (BD) is associated with premature death and ischemic heart disease is the main cause of excess mortality. The predictive power of heart rate variability (HRV) for mortality has been confirmed in patients with or without cardiovascular disease. While several studies have analyzed the association between HRV and BD, their results are incongruent; and none has analyzed the effect of the clinical factors characterizing illness burden on HRV.To assess the association between HRV and the following factors characterizing illness burden: illness duration, number and type of previous episode(s), duration of the most severe depressive or hypomanic/manic episode, severity of episodes, co-morbid psychiatric disorders, family history of BD or suicide, and duration and polarity of current episode in participants experiencing one.We used a wearable device in 53 BD participants to assess the association between HRV using 4 measures  and the abovementioned clinical factors characterizing illness burden. For each of the 4 HRV measures we ran 11 models, one for each burden of illness clinical factor as an independent variable.Longer illness duration, higher number of depressive episodes, and family history of suicide were negatively correlated with HRV; in the 14 participants experiencing a depressive episode, the MADRS score was negatively correlated with HRVOur study analyzed the association between burden of illness and HRV in BD, while controlling for functional cardiovascular status, age, sex, BMI, education, and treatment. Our results showed that high illness burden is associated with reduced HRV.No significant relationships.


Polypharmacy is an increasing health concern among older adults and results in many health risks. Nurses have an important role to play in supporting medication management and promoting medication safety across different settings. This study aims to provide a meta-synthesis of qualitative studies investigating the perceptions and experiences of nurses in caring for older adults with polypharmacy. Electronic databases including PsycArticles, CINAHL Complete, MEDLINE, and ERIC were searched between September 2001 and July 2022. Potential studies were checked against inclusion and exclusion criteria. We included peer-reviewed studies reporting data on the experiences of nursing staff across different settings. Studies unitizing any qualitative approach were included, and the included studies were reviewed and analyzed using a thematic synthesis approach. Study quality was examined using the Critical Appraisal Skills Programme checklist for qualitative research. A total of nine studies with 91 nurses were included. Four major themes emerged: older adults suffering from polypharmacy, the importance of multidisciplinary teams, nursing roles in caring for older adults, and the complexity and barriers of implementing polypharmacy management. Healthcare professionals should pay attention to the impacts of polypharmacy in older adults’ lives and should acknowledge the importance of team-based polypharmacy care in supporting older adults. Nurses play a key role in caring for older adults with polypharmacy, therefore, they should be empowered and be involved in medication management. Due to rising health issues in older adults, polypharmacy has become more common. The term polypharmacy can be defined either quantitatively (multiple medications) or qualitatively (unnecessary prescriptions) . The pheAlthough using multiple medicines or polypharmacy may be clinically appropriate in many cases, the negative clinical consequences of polypharmacy have been reported. Older people with polypharmacy may have a higher likelihood of drug–drug interactions  and adveNurses play an important role in helping to identify people with polypharmacy and facilitating risk reduction . An inteQualitative research is suggested as an appropriate research design to provide insights into particular phenomena. The output of qualitative research may help inform the effectiveness, feasibility, and acceptability of nursing practice . Given tThe report of this synthesis adhered to the enhancing transparency in reporting the synthesis of qualitative research (ENTREQ) statement .An electronic search of APA PsycArticles, CINAHL Complete, MEDLINE, and ERIC was conducted between September 2001 and July 2022 with keywords and index terms used to describe the studies. The search strategy was adapted for each data source, and an additional search was conducted before the submission of this review. The electronic search was complemented by tracking reference lists of the most relevant reviews and expert counselling in the region. We adapted the search strategy to meet the requirements of different databases. To ensure a comprehensive search, no search filters were used.A full search strategy was presented below as an example:DatabaseCINAHL Complete via EBSCO PlatformInitial date of search1 October 2021Additional date of search20 July 2022Search strategy:  or multiple medication* or many drug* or many medication*) AND (nurse or nurses or nursing or nursing staff or registered nurse) AND  AND (older adults or elderly or geriatric or geriatrics or aging or senior or seniors or older people or aged 65 or 65+).This review considered primary studies that (1) involved nursing staff across health care settings, (2) drew on experiences, perceptions, and attitudes regarding polypharmacy among older adults (people at least 65 years of age), (3) adopted qualitative designs including, but not limited to, grounded theory, phenomenology, and action research, (4) were reported in English or Chinese, and (5) were published in peer-reviewed journals.All the citations from the search were transferred into Endnote X9  and duplicates were removed. Two reviewers screened the titles and abstracts of those citations based on the inclusion criteria and retrieved the full text of potential studies. The reviewers then checked the full-text studies against the inclusion and exclusion criteria.Two reviewers critically appraised the data quality of the included studies using the Critical Appraisals Skills Programme (CASP) for qualitative research . Any disThe data extracted included the phenomena of interest, research settings, participants’ characteristics, study methods, key findings, and related illustrations.The extracted qualitative findings were inductively analyzed using the thematic synthesis method . This isTo ensure quality, memos were taken as part of the analysis process, and a matrix of synthesized findings regarding the interpretation was developed. Any disparities or discrepancies in coding were resolved through discussion or consultation with a third party, if necessary.The screening process adhered to the Preferred Reporting Items for Systematic Reviews (PRISMA) protocol . The floA primary search across five electronic databases yielded 275 records. After removing duplicates, 222 were screened for inclusion; 161 records were excluded based on their titles and abstracts. The remaining 61 records were retrieved and reviewed in full text for eligibility. After a full-text review, 8 records were eligible, and 53 were excluded according to the exclusion criteria. One record was identified through citation searching. All studies reported at least seven of the ten CASP checklist items. Most studies did not meet the criteria of adequately considering the relationship between researchers and participants. No study was excluded due to low quality. The quality assessment of the included studies is presented in n = 4), focus group interviews (n = 3), interviews combined with observations (n = 1), and combined means of interviews (n = 1). Data were analyzed using thematic analysis (n = 3), content analysis (n = 1), the critical incident technique (n = 1), framework approaches (n = 1), grounded theory (n = 1), and systematic condensation (n = 1). One study used qualitative methods. The key characteristics of the included studies are presented in The process of data analysis yielded four major descriptive themes: older adults suffering from polypharmacy, the importance of multidisciplinary teams, nursing roles in caring for older adults, and the complexity and barriers to implementing polypharmacy management. Each major theme was formed by several subthemes, which are supported by illustrative quotes. An overview of each major theme and subtheme is shown in This meta-analysis is the first work to examine existing findings regarding nurses’ experiences of polypharmacy in older adults. From nine included studies, we abstracted a plethora of nurses’ experiences and identified four interrelated syntheses related to: older adults’ daily interactions with polypharmacy, the significance of multidisciplinary teams, the role of nurses, and the complexity of and barriers to medication management. Based on these findings, several recommendations are proposed to improve care for older adults with polypharmacy. This study also suggests future research directions for understanding medication-related experiences and facilitating interventions within this population.The first theme we identified was that nurses recognize that polypharmacy is a common health concern among older adults which might impose burdens and challenges in their daily lives. This finding was consistent with the perceptions and beliefs of patients with multimorbidity ,32, as wIn line with prior research , we founMany health care professionals feel powerless to manage and advocate for improved outcomes in patients living with polypharmacy due to a lack of formal training regarding this subject . A plausThe past literature has outlined the irreplaceable role of nurses in medication management ,40,41. WWe adopted four central criteria for identifying the strengths and limitations of this meta-synthesis: credibility, transferability, dependability, and confirmability ,45.We maintained and enhanced the credibility of our findings by searching, extracting, and analyzing qualitative data from different studies using a comprehensive and systematic review method. We also used the ENTREQ checklist to improve transparency in reporting this review.The transferability of this review might be limited by several factors. First, the nurses in this review worked in various health care settings and had different academic and/or practical backgrounds. For example, half of the research settings were hospitals, and the rest were nursing homes where nursing staff might report distinct experiences concerning medication management. Next, the heterogeneity of the data describing nurses’ experiences and research settings may hinder an understanding of experiences across this geographical and ethnic region and within subgroups of the population. The countries in which studies were conducted tended to have higher incomes; therefore, data from middle- and low-income nations are lacking. Moreover, the subjective nature of our analysis might lead to a risk of bias. The varied definitions of polypharmacy used in each study might lead to increased heterogeneity of our findings. Readers should note that the findings of this review might provide in-depth perspectives of specific individuals and may not be representative of all nurses.To ensure dependability, we examined the credibility of each finding based on the included studies and ensured that all the findings emerged from the original text. We also used a logical, three-stage process of thematic analysis and documented the research process.A potential criticism impacting the confirmability of this synthesis is that the authors might influence the process of data extraction and synthesis. However, the authors of this study were experienced qualitative researchers. They participated in the analysis process and approved the presentation of major themes, subthemes, and illustrative quotes in this review. In addition, we have taken memos as part of the analysis process.A strength of this study was that we used the CASP checklist to critically appraise the included studies. However, more than half of the studies did not identify the relationship between researcher and participants; thus, potential bias may occur. This meta-synthesis might have publication bias, as we only included studies published in English or Chinese and excluded grey literature such as conference abstracts.Evidence relating to nurses’ prescribing practices may not have emerged in all the included studies. Although researchers have demonstrated that nurses play a vital role in maintaining medications, jurisdictional solutions between nurses and medical professionals regarding prescribing work vary between countries. In addition, the competency of nurses in prescribing medications needs to be further examined.There is a research gap in the engagement of key stakeholders in polypharmacy management for older adults. Nurses presented a variety of perspectives on the effectiveness of multidisciplinary teams in polypharmacy management. However, multiple layers of health care professionals  are involved in the long-term care of elderly individuals. There are challenges in ensuring the participation and collaboration of all three specialties in actual practice.The implementation of best practices regarding polypharmacy management across health care settings is important for promoting the health of older adults. Research should be undertaken to identify best practices and provide polypharmacy-related awareness and/or deprescription education to older adults and health care professionals. Additionally, the identification of barriers and enablers will help to develop and adopt best practices for older adults with polypharmacy.Based on the limited studies available and the diversity of nursing standards globally, this meta-synthesis has uncovered four major themes regarding: the burden of polypharmacy, multidisciplinary teams, the role of nurses, and the complexity of medication management. We recommend that health care professionals be aware of the challenges and consequences of polypharmacy in older adults’ everyday lives and work to promote collaboration between various professionals, such as GPs, nurses, and pharmacists, in polypharmacy care plans. Multidisciplinary collaboration and communication between different health care professionals are essential for effective polypharmacy management. Nurses should be considered an essential element in the health care team when evaluating polypharmacy and medication management.


The adoption of new and expensive technologies is one of the main causes of the growing expenditure on health. Regulators are concerned that health care providers purchase (and use) imaging technologies in quantities that exceed the need, increasing expenditure with little value. We review how countries regulate the purchase and use of imaging technologies.Qualitative. We collected data using a questionnaire completed by researchers from 17 high-income countries purposefully selected based on variation of policies. We built and compared case studies.Eleven of the 17 countries analyzed have clear criteria for planning and purchasing imaging technologies. Countries plan different areas, such as supply of specialist care, hospitals by level and type of services, quantity or type of equipment, as well as expenditure on health services and resource allocation. Most countries combine three mechanisms that manage the purchase or use of imaging technologies: (1) seven countries regulate by requiring certificates of need, licenses, or purchase approvals; others regulate by directly limiting the amounts, types and quality of technologies. (2) All countries use financial tools such as activity-based payment, limited and conditional budgets, and caps on income or volume of services. (3) Nine countries centralize purchase by a government agency. The literature provides inconclusive evidence regarding the impact of these mechanisms on expenditure on health and access to imaging services.Planning the imaging technologies market with clear criteria is essential to avoid abuse. Most countries combine the three mechanisms . Financial tools are more common and effective. Countries with single payers implement more regulation than countries with multiple, competing, payers. In the later, regulated competition seems to replace regulation. There is a trend of adopting centralized procurement.• Planning the imaging technology market is a precondition to avoid abuse.• Regulation, financial tools, and centralized purchase can be combined to manage the use of imaging technologies.


Improving care coordination is particularly important for individuals with rare conditions . To develop and evaluate strategies to potentially improve care coordination, it is necessary to develop a method for organising different ways of coordinating care for rare conditions. Developing a taxonomy would help to describe different ways of coordinating care and in turn facilitate development and evaluation of pre-existing and new models of care coordination for rare conditions. To the authors’ knowledge, no studies have previously developed taxonomies of care coordination for rare conditions. This research aimed to develop and refine a care coordination taxonomy for people with rare conditions.This study had a qualitative design and was conducted in the United Kingdom. To develop a taxonomy, six stages of taxonomy development were followed. We conducted interviews  and focus groups . Interviews and focus groups were audio-recorded with consent, and professionally transcribed. Findings were analysed using thematic analysis. Themes were used to develop a taxonomy, and to identify which types of coordination may work best in which situations. To refine the taxonomy, we conducted two workshops .Our taxonomy has six domains, each with different options. The six domains are: (1) Ways of organising care , (2) Ways of organising those involved in care , (3) Responsibility for coordination , (4) How often appointments and coordination take place , (5) Access to records (full or filtered access), and (6) Mode of care coordination .Findings indicate that there are different ways of coordinating care across the six domains outlined in our taxonomy. This may help to facilitate the development and evaluation of existing and new models of care coordination for people living with rare conditions.The online version contains supplementary material available at 10.1186/s13023-022-02321-w. The complexity of the organisation and delivery of health care has been further complicated in recent years, due to the need to manage a higher demand for health care and the introduction of new technologies, increased availability of treatments and provision of care across many settings . These cPrevious research has indicated that a lack of coordination has many negative impacts on patients and carers living with rare conditions, including on their physical health, finances, psychological wellbeing, and social aspects of their lives . A recenIn order to better understand and potentially improve care coordination, it is necessary to identify and describe the different ways in which care can be coordinated for rare conditions. One way to facilitate the organisation of care coordination is to develop a taxonomy of care coordination for rare conditions. Taxonomies are systems used to organise complex concepts into common conceptual domains and dimensions based on similarities , 15. DevTaxonomies aim to provide clear definitions , and havTo the authors’ knowledge, no previous studies have attempted to develop a taxonomy of coordination of care specifically for rare or chronic conditions. This study aimed to develop and refine a taxonomy of care coordination for people living with rare conditions, based on learning from the UK healthcare context and the National Health Service. Whilst there are many different rare conditions and the care needs for each of these may differ slightly, it is necessary to develop a taxonomy that can be used to outline the different options and then these options can be adapted and applied to suit different contexts and different rare, ultra-rare and undiagnosed conditions. We present our findings on what types of coordination may be appropriate in different situations and the development of hypothetical models of care coordination separately .This study is part of a larger mixed-methods research project which aims to explore coordination of care for people living with rare conditions . This stA summary of the methods used in this study are provided below . Participants took part in interviews , focus groups (four groups of 6–8 patients/carers)  and workStudy adverts included details of the researcher’s contact details and asked individuals to get in touch via email or telephone. Interested individuals contacted the researcher and were provided with an information sheet. Participants were asked to sign consent forms in advance of the interviews, focus groups and workshops. Participants were informed that their data would be kept confidential, fully anonymised and that they could withdraw without reason.To develop the taxonomy, one researcher (HW) conducted interviews with health care professionals, commissioners and charity representatives. Two researchers (HW/AS), with a third observer (EH) conducted four focus groups with patients and carers . Interviews and focus groups were recorded with consent, professionally transcribed, checked for accuracy and fully anonymised. To develop the taxonomy and identify different ways of coordinating care, we used an interview topic guide and a focus group topic guide  IdeTo refine the taxonomy, we coded workshop notes and grouped them into themes . Participants included patients, carers, health care professionals, commissioners and charity representatives. Overall, data from 52 participants  informed the development of the taxonomy. Data from 27 workshop participants informed the refinement of the taxonomy. Demographic characteristics are shown in Table Whilst it would not have been possible to represent all 6000–8000 conditions within our study, the patients, carers, healthcare professionals, charity representatives and commissioners that took part in our study were selected to represent a range of different rare conditions . Additionally, professionals, charity representatives and commissioners were able to draw upon experiences of working across different types of rare conditions. Examples of groups of rare conditions included in this study included rare skin conditions, rare chromosome conditions and rare autoinflammatory conditions. We sampled a range of different rare, ultra-rare and undiagnosed conditions to ensure that our sample was as representative of care coordination for rare conditions as possible. We included a range of different professionals with different job roles in our study, including health and social care professionals , charity representatives (with various roles) and national and local commissioners  ways of organising care; (2) ways of organising those involved in a patient’s care; (3) responsibility for coordination; 4) how often appointments and coordination take place; (5) access, and (6) mode  or a network of multiple services or centres.We also identified some ‘hybrid’ options, which combine both national or regional specialist and local care. Hybrid options include hub and spoke networks, and outreach. There are different types of hub and spoke models. For example, in one type of hub and spoke model of care, the national centre or centres (hub) coordinate care but the actual care delivery happens at a local hospital or GP (spokes). In other types of hub and spoke models, the national centre (hub) provides some care delivery, but other aspects of care are delivered at local hospitals or GPs (spokes). There are also different types of outreach models. Examples of outreach models include outreach clinics  and outreach relating to care coordination . Outreach models relating to education included specialist teams providing support for local teams .Findings highlighted the importance of specialists being involved in care for rare conditions. However, findings also indicated that routine care and non-standardised or tailored care should be delivered locally, and that regular contact with local professionals would be useful. On the other hand, some focus group participants reported wanting all of their care to be delivered locally, or regionally. For some, there was a lack of local care provided.Our findings highlighted different ways of organising those involved in a patient’s care . This includes two types of collaboration: collaborative working between professionals, and collaborative working between professionals, patients and carers. Options ranged from collaboration between many or all of the individuals involved in a patient’s care, to collaboration between some of the individuals involved in a patient’s care, to a lack of collaborative working  and multidisciplinary meetings held between all professionals (and the patient/carer where appropriate). Different types of condition-specific clinics exist, ranging from: multidisciplinary team appointments including all professionals (and the patient/carer where appropriate); one stop shops where patients receive all care in one place at the same time; multidisciplinary clinics that involve professionals seeing patients both together as a team but also separately; and carousel clinics whereby the health care professional moves around whilst the patient stays in the same room.One example of collaboration between some of the professionals involved in a patient’s care is joint clinics. Joint clinics consist of a couple of professionals working together to provide care. For example, joint clinics consisting of an adult and a child provider; joint clinics consisting of multiple consultants; and joint clinics consisting of specialist and local providers. Additionally, close working between different professionals may occur (e.g. paediatrician contacting adult provider when the patient is ready to transition to adult care).In some cases, examples demonstrating a lack of collaborative working between those involved in a patient’s care were identified, including a lack of multidisciplinary team clinic, lack of transition methods and lack of ownership.Our findings highlighted different types of responsibility and roles involved in coordinating care for rare conditions  across health care, social care and voluntary sectors. Figure Administrative support for appointment organisation was highlighted as important. Additionally, having a point of contact for patients and having a point of contact for other professionals was felt to be important. Some patients and carers highlighted that they do not currently have a point of contact. Different options were highlighted in relation to who should provide administrative support  and who should be the point of contact for patients .Formal coordination responsibilities across three roles were identified: (1) those conducted by a coordinator, (2) those conducted by a clinical lead in secondary/tertiary care, and (3) those conducted by a GP in primary care.Our findings highlighted many roles of a care coordinator . Many different types of coordinators were identified: (1) administrative coordinators, (2) care coordinators and (3) clinical coordinators. Administrative coordinators are individuals who arrange MDTs and clinics . Care coordinators are individuals who have a formal/professional role for coordinating care in addition to system and condition knowledge . Clinical coordinators are individuals with sufficient clinical expertise to coordinate complex cases (e.g. doctors or GPs).Our findings highlighted many roles of a clinical lead, including overseeing or managing care in a service, clinical case management, supervision of professionals, decision-making about extent to which different levels of coordinator are needed, and delegating and ensuring accountability of responsibilities. Clinical leads were identified from a range of roles , the patient’s favourite doctor, a specialist nurse, or geneticists). Some patients and carers reported that they did not have a clinical lead responsible for their care.Findings highlighted that GPs may have the potential to be involved in coordination in numerous ways, including as a coordinator , clinical lead , and implementing care plans provided by specialists . However, findings indicate that many GPs do not take ownership and that some patients do not have a named GP. A lack of communication between GPs and specialists indicated a need for further collaboration between GPs and specialists .Supportive roles were also identified, including those conducted by charities/patient organisations and carers and those conducted by patients/carers  and professionals . Charities also have direct roles in coordination . Whilst charities provide funding currently there were views that charities should not be filling gaps for health care services and that charities may not have the capacity to be the main coordinator. Additionally, charities play a role in service quality and improvement .Findings indicated that patients and carers currently have lots of direct involvement in coordinating care. Patients and carers act as coordinators of care  or collaborate with health care professionals to coordinate care . Patients and carers also support transition to adult services, provide education to health care professionals, and monitor their own care.Our findings highlighted different time periods for care appointments and coordination activities. Options included regular appointments, on demand appointments and hybrid of regular and on demand appointments , frequency of regular care appointments (ranging from multiple appointments in one week to every 6 months), frequency of contact (ranging from monthly check-ins to yearly check ins), frequency of outreach visits , frequency of contact with coordinator  and frequency of MDT meetings between health care professionals (ranging from weekly to twice a year). Participants indicated that the regularity of appointments is and should be guided by condition-specific guidelines (where available).Findings from some focus group participants and some interviewees indicated that on demand contact or care appointments  may be better than regular contact for some patients. One caveat to on demand appointments was that there needs to be quick access to expertise and care in emergencies.Workshop findings highlighted the need for a hybrid category that combines both regular care (at a minimum) with on demand support.Our findings highlighted different types of access. Options ranged from full or restricted access to records for patients and providers and access to support for patients and health care professionals . Some patients highlighted that they would like to control who has access to this information. Workshop participants highlighted that full access to records with a summary may be helpful.Our findings highlighted different modes , portals , mobile applications for patients (e.g. Patient Knows Best app or apps for patients to hold and share information from their records), and patient information. Digital options for communication between professionals  and between professionals and patients  were identified.Many different written methods of information sharing were also identified: (1) written care documentation, (2) service planning, (3) guidelines and pathways. For written care documentation, this included: written records , letters, care plans  plans and transition plans) and reports. For service planning, written methods included plans to specify hospital and professional roles and responsibilities, and standard operating procedures to record MDT working. For guidelines and pathways, this included evidence-based service specifications outlining service standards, quality assurance standards, national guidelines (e.g. NICE or charity produced), international best practice and training policies and frameworks for care coordinators and supervisors.Telephone was also identified as a mode of communication between professionals  and between professionals and patients (e.g. emergency point of contact and telephone advice services).A lack of information sharing was also highlighted throughout the focus groups and interviews (including a lack of communication between team members and a lack of information sharing).In terms of care and coordination appointments and communication, our participants described many different modes, including face to face, digital, phone and a combination of methods.Face-to-face care delivery was identified for many aspects of care and coordination, including meetings , care appointments  and support .Digital options for care delivery and coordination appointments were identified. For coordinated care delivery, this included: video appointments with professionals , virtual centres and MDT clinics, digital monitoring , virtual tours of wards, diagnostic technology. For coordination this included: video appointments with coordinators , coordination in the cloud, and virtual review (as the lowest level of coordination).Options for telephone care delivery  and coordination  were also discussed. Workshop findings highlighted that COVID-19 has accelerated the shift to digital and telephone delivery of care for people living with rare conditions.We have developed a taxonomy of care coordination for rare conditions, based on learning from the UK health system and the National Health Service. We identified six domains of care coordination: (1) ways of organising care ; (2) ways of organising those involved in a patient’s care ; (3) responsibility for coordination ; (4) how often appointments and coordination take place ; (5) access (full or filtered access to records), and (6) mode of information sharing, care coordination/delivery and communication.These findings extend knowledge on care coordination. National policy documents and previous research have highlighted the importance of care coordination , 13, 32.Our findings highlighted three main options for organising care, including nationally centralised, hybrid and local care. This supports previous research which has highlighted the importance of specialist centres for people living with rare conditions  but exteOur findings on the organisation of professionals and the patient/carer for rare conditions supports previous research that indicates the importance of collaboration and MDTs for rare conditions , 39 and Our findings extend previous research by outlining different types of responsibilities and roles needed to coordinate care for rare conditions. Previous research indicates the importance of care coordinators , 41, 42.Our findings highlight the importance of following clinical guidelines and service specifications which outline how often appointments should take place. However, findings indicate that patient and provider factors need to also be taken into account when considering how often patients should be seen (see ).Findings highlighted the potential for remote methods of coordination, including digital information sharing , virtual clinics and care coordination appointments. This shift to digital methods has been accelerated during the COVID-19 pandemic. This supports previous research, which indicates that digital methods may show some potential for use in health care delivery , 44. OurOne strength of our study is that we used robust analysis procedures which strengthen the validity of this study. Twenty percent of data were coded by a second researcher. Additionally, the research team and members of the PPIAG were continually involved in discussions about analysis and findings. We also triangulated findings outputs from other parts of the CONCORD study , 21 to eWhilst we sampled from a variety of rare conditions, locations and sectors, we were unable to include every rare condition. Some groups, including individuals from minority ethnic groups and certain roles (e.g. GPs) were under-represented. Therefore, whilst we collected extensive data, and included as many different views as possible, we are unlikely to have captured every possible option of care coordination. It is therefore possible that our taxonomy may not be applicable to all rare conditions, and there may be other domains or subdomains that we have not captured. However, we did speak with a range of patients, carers, professionals, commissioners and charity representatives with experience of a wide range of rare conditions and groups of rare conditions. To account for this possibility, we designed the taxonomy so that it can be applied flexibly , and any application of this taxonomy should take into account a range of patient, professional, resource and societal factors that influence coordination, which will differ for all rare conditions . These These findings could be particularly helpful during the development of the rare disease action plan in response to the new Rare Disease Framework ; in whicGiven similarities between common and rare chronic conditions that were highlighted in previous research , researcFuture research is needed to explore where different ways of coordinating care have been implemented and to evaluate the implementation, effectiveness, and cost-effectiveness of different models of care coordination for rare conditions in practice. This is important given that it is not yet clear whether coordinated care leads to better outcomes for patients/carers, professionals and organisations. Further research is needed to operationalise care coordination models so that delivery of care coordination can be measured.Additionally, future research on care coordination and views on care coordination from professionals working in social care, mental health and other sectors such as education may be beneficial in determining whether the taxonomy can apply in these situations or whether amendments are needed.Findings from our qualitative study with key stakeholders  provide a thorough taxonomy of care coordination for rare conditions. Our taxonomy can facilitate the development and evaluation of existing and new models of care coordination for people living with rare conditions. The process outlined in this manuscript provides a template that could be adapted to develop taxonomies for other health care services.Additional file 1: Topic guides for interviews and focus groups.Additional file 2: Topic guide for workshops.Additional file 3: Visual representation of workshop findings.


Although the trend of progressing morbidity is widely recognized, there are numerous challenges when studying multimorbidity and patient complexity. For multimorbid or complex patients, prone to fragmented care and high health care use, novel estimation approaches need to be developed.This study aims to investigate the patient multimorbidity and complexity of Swiss residents aged ≥50 years using clustering methodology in claims data.We adopted a clustering methodology based on random forests and used 34 pharmacy-based cost groups as the only input feature for the procedure. To detect clusters, we applied hierarchical density-based spatial clustering of applications with noise. The reasonable hyperparameters were chosen based on various metrics embedded in the algorithms  and the clinical relevance of the obtained clusters.Based on cluster analysis output for 18,732 individuals, we identified an outlier group and 7 clusters: individuals without diseases, patients with only hypertension-related diseases, patients with only mental diseases, complex high-cost high-need patients, slightly complex patients with inexpensive low-severity pharmacy-based cost groups, patients with 1 costly disease, and older high-risk patients.Our study demonstrated that cluster analysis based on pharmacy-based cost group information from claims-based data is feasible and highlights clinically relevant clusters. Such an approach allows expanding the understanding of multimorbidity beyond simple disease counts and can identify the population profiles with increased health care use and costs. This study may foster the development of integrated and coordinated care, which is high on the agenda in policy making, care planning, and delivery. Health care systems worldwide are facing considerable challenges from the increasing number of chronic and multimorbid patients, characterized by complex needs and frequent transitions between care settings . In SwitWe included data of 240,511 insured people aged ≥50 years continuously enrolled in one of the largest health insurance companies in Switzerland, Groupe Mutuel, for the 2015-2018 period. In addition to demographic information (age and gender), data contained PCGs for each individual, costs covered by the patient (cost sharing), type of health insurance model (with or without gatekeeping), and reimbursed health care services: number of visits to various physicians with associated costs and physicians’ specialization and hospitalizations. To identify insured persons with cost-intensive, chronic diseases and correspondingly high health care use based on their drug consumption, health insurance companies are translating the drug use data reflecting active ingredient and quantity, based on Anatomical Therapeutic Chemical and defined daily dose, into the PCGs. This procedure was developed and officially accepted by the Federal Office of Public Health in Switzerland . In our Data were deidentified by the insurance company to guarantee anonymization, and ethical approval for this study was waived by the Cantonal Commission for the Ethics of Research on Human Beings .We adopted a clustering methodology based on random forests (RFs) —a populaIn a preprocessing step, we extracted 34 PCGs as the only input feature for the clustering procedure. We grouped the 34 PCGs into 15 disease categories, which were valued meaningful from a clinical perspective . We thenproximity measure, an embedded RF metric of similarity between points. An RF aggregates the prediction of multiple decision trees (DTs) by considering the class they predict in majority. DTs are classification models that separate the data points into subspaces (leaves) by imposing thresholds on the input variables and predicting the class within each subspace as the majority class. The proximity between two points is then computed as the number of times they fall in the same leaf across the trees in the forest. To stabilize the random effects of RFs, we trained 10 RF models, computed the proximities for all pairs of points for each model, and averaged them to obtain a mean proximity matrix characterizing the data. We then used multidimensional scaling (MDS) [out-of-bag (OOB) misclassification error, which shows how well RF differentiates the original data from the synthetic one. The outcome reflects how much structure there is in the data [normalized stress, measuring whether the distances between points are reasonably preserved after projection [cluster persistence, HDBSCAN embedded metrics indicating how well the clusters are defined and separated from each other [To initiate the clustering procedure, we created a synthetic data set of the same size as the original data, by random sampling from the distributions of each input variable within the data. The idea is then to train an RF model to classify synthetic and original points, with the aim of taking advantage of the ng (MDS)  to projeng (MDS)  to detecthe data . Anotherojection , and thech other . In pracpoints). An initial examination of the data set exhibited three large “single” clusters that we extracted prior to the clustering procedure, showing no PCGs, only hypertension PCGs, and only mental disease PCGs, representing 67.9% , 9.7% (n=1813), and 4.1% (n=765) of the population, respectively. Clustering analyses, performed on the remaining 3434 patients not included in the latter “single” clusters, identified four distinct clusters: Cluster 0 to Cluster 3, numbered in the order in which they are detected while applying HDBSCAN (After discarding individuals with missing information, our data set comprised 18,732 individuals ( HDBSCAN . The clu HDBSCAN ; and a gThe 4 detected clusters encompass different mixes of PCGs : ClusterThe following description and interpretation of clusters is based on the descriptive statistics of health care use and costs data , which hOur study shows that performing cluster analysis to explore patient multimorbidity and complexity is feasible. We demonstrated that individuals with single PCGs of mental diseases or hypertension, individuals with multiple PCGs, or individuals with a single high-cost PCG have different health care use patterns and represent different complexity groups.Earlier studies focusing on chronic conditions identified from electronic health records evidenced the existence of systematic associations between chronic diseases, whereby chronic diseases, often from dissimilar disease categories, coappeared within a multimorbidity pattern or cluster -26. ImpoThe existing literature on the use of cluster analysis to identify homogenous segments based on health care use and expenditures is limited -37. SpecTo our knowledge, this is the first study using cluster analysis to explore patients’ multimorbidity and complexity, reflected by the mix of PCGs and health care use patterns. In addition, it benefits from the richness of health care use data, a large sample size, and advanced clustering methods. However, the study has certain limitations. The first limitation stems from the process of multiple parameters configuration, which increases complexity while not allowing results validation. Thus, the cluster interpretation has to rely on metrics from the algorithms, descriptive statistics, and clinical relevance. Second, as the data were lacking clinical information, we only relied on PCGs mapping, which may give an incomplete picture of drug data ,11,12.Our study shows that PCG-based cluster analysis of health care use claims data allows diverting from an approach of simple comorbidity counts and can identify the population profiles with increased health care use and costs. Such results may provide insightful information for policy making, care planning, and care delivery to facilitate the transformation from procedures and guidelines focusing on a single disease toward development of integrated and better coordinated care.


Childhood exposure to social risk has the potential to disrupt brain development and increase vulnerability to adverse mental health outcomes. Here, we examine the effect of adversity on brain structure and psychopathology in the Adolescent Brain and Cognitive Development (ABCD) study, a US population-based sample of 10 year-olds.Personal, caregiver, family and neighborhood characteristics were considered in 9299 unrelated children . Hidden Markov Models were used identify clusters of participants based on their psychosocial exposure. The identified clusters were compared in terms of current psychopathology, lifetime psychiatric diagnosis, intelligence and brain structure.ABCD participants clustered in to a “disadvantaged” group (N=4205) with multiple adverse exposures, and an “enriched” group (N= 5094) with limited exposure to adversity and multiple protective factors. Compared to the enriched group, the disadvantaged group had higher levels of all types of psychopathology and lifetime psychiatric diagnoses; lower scores on fluid and crystallized intelligence; smaller subcortical volumes; thinner sensorimotor cortices and thicker cortex in frontal regions; smaller surface area in temporal regions and larger surface area in the posterior cingulate cortices .Social adversity has significant and wide-ranging consequences for brain development and psychopathology, that shows little specificity for types of symptoms.No significant relationships.