Natural History Data Research Articles

A 5-year natural history study in LAMA2-related muscular dystrophy and SELENON-related myopathy: the Extended LAST STRONG study

BackgroundSELENON-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive axial muscle weakness, rigidity of the spine, scoliosis, and respiratory insufficiency. Laminin-a2-related muscular dystrophy (LAMA2-MD) has a similar clinical phenotype, which ranges from severe, early-onset congenital muscular dystrophy type 1A (MDC1A) to milder forms presenting as childhood- or adult-onset limb-girdle type muscular dystrophy. The first 1.5-year natural history follow-up showed that 90% of the patients had low bone quality, respiratory impairments were found in all SELENON-RM and most of the LAMA2-MD patients, and many had cardiac risk factors. However, further extensive knowledge on long-term natural history data, and clinical and functional outcome measures is needed to reach trial readiness. Therefore, we extended the natural history study with 3- and 5-year follow-up visits (Extended LAST STRONG).MethodsThe Extended LAST STRONG is a long-term natural history study in Dutch-speaking patients of all ages diagnosed with genetically confirmed SELENON-RM or LAMA2-MD, starting in September 2023. Patients visit our hospital twice over a period of 2 years to complete a 5-year follow up from the initial LAST-STRONG study. At both visits, they undergo standardized neurological examination, hand-held dynamometry (age ≥ 5 years), functional measurements, muscle ultrasound, respiratory assessments (spirometry, maximal inspiratory and expiratory pressure, sniff nasal inspiratory pressure; age ≥ 5 years), Dual-energy X-ray absorptiometry (DEXA-)scan (age ≥ 2 years), X-ray of the left hand (age ≤ 17 years), lower extremity MRI (age ≥ 10 years), accelerometry for 8 days (age ≥ 2 years), and questionnaires (patient report and/or parent proxy; age ≥ 2 years). All examinations are adapted to the patient’s age and functional abilities. Disease progression between all subsequent visits and relationships between outcome measures will be assessed.DiscussionThis study will provide valuable insights into the 5-year natural history of patients with SELENON-RM and LAMA2-MD and contribute to further selecting relevant and sensitive to change clinical and functional outcome measures. Furthermore, this data will help optimize natural history data collection in clinical care and help develop clinical care guidelines.Trial registrationThis study protocol including the patient information and consent forms has been approved by medical ethical reviewing committee (‘METC Oost-Nederland’; https://www.ccmo.nl/metcs/erkende-metcs/metc-oost-nederland, file number: 2023–16401). It is registered at ClinicalTrials.gov (NCT06132750; study registration date: 2023-10-05; study first passed date: 2023-11-15).

Longitudinal Analysis of Natural History Progression of Rare and Ultra-Rare Cerebellar Ataxias Using Item Response Theory.

Degenerative cerebellar ataxias comprise a heterogeneous group of rare and ultra-rare genetic diseases. While disease-modifying treatments are now on the horizon for many ataxias, robust trial designs and analysis methods are lacking. To better inform trial designs, we applied item response theory (IRT) modeling to evaluate the natural history progression of several ataxias, assessed with the widely used scale for assessment and rating of ataxia (SARA). A longitudinal IRT model was built utilizing real-world data from the large autosomal recessive cerebellar ataxia (ARCA) registry. Disease progression was evaluated for the overall cohort as well as for the 10 most common ARCA genotypes. Sample sizes were calculated for simulated trials with autosomal recessive spastic ataxia Charlevoix-Saguenay (ARSACS) and polymerase gamma (POLG) ataxia, as showcased, across multiple design and analysis scenarios. Longitudinal IRT models were able to describe the changes in the latent variable underlying SARA as a function of time since ataxia onset for both the overall ARCA cohort and the common genotypes. The typical progression rates varied across genotypes between relatively high in POLG (~ 0.98 SARA points/year at SARA = 20) and very low in COQ8A ataxia (~ 0.003 SARA points/year at SARA = 20). Smaller trial sizes were required in case of faster progression, longer trials (~ 75-90% less with 5 years vs. 2 years), and larger drug effects (~ 70-80% less with 100% vs. 50% inhibition). Simulating under the developed IRT model, the longitudinal IRT model had the highest power, with a well-controlled type I error, compared to total score models or end-of-treatment analyses. The established longitudinal IRT framework allows efficient utilization of natural history data and ultimately facilitates the design and analysis of treatment trials in rare and ultra-rare genetic ataxias.

Citizen Science for Invertebrate Biodiversity: Mobilizing Spider Occurrence Data through Facebook in India

India accommodates a huge diversity of plant and animal life across a variety of biomes. However, the degree of research, funding, and attention is asymmetric, largely focused on its charismatic vertebrates. Invertebrates, despite their megadiversity, are generally overlooked with some exceptions (for example, lepidoterans). One species-rich group, spiders, exemplifies this knowledge gap. More than 1,800 species from 63 families have been reported in the country (Mondal et al. 2020), even though the true number may be much higher, in part, owing to the need for taxonomic revisions. Several spider systematics and biogeographic studies have pointed out that spatial distribution, seasonality, and natural history data are lacking from India. The lack of foundational biodiversity information has led to poor opportunities to share knowledge between researchers and community scientists. Mining occurrences through scientific publications or databases (in some cases behind paywalls) may require specialized training. This restricted access inhibits more people from using the abundance of information. The prevalence of social media posts showcasing photographs of species in biodiversity contexts has experienced a significant increase, with a multitude of users sharing wildlife photographs on social media sites such as Instagram®, Facebook®, and Flickr®. These observations on social media are a potential source of primary biodiversity data when curated and validated (Barman and Barve 2022, Barman et al. 2022a). Such data can enhance biodiversity monitoring by expanding spatial and temporal coverage and involving a global network of citizen scientists in conservation research (Barve et al. 2023, Roy 2022, Kulkarni 2023). The India Biodiversity Portal (IBP, Vattakaven et al. 2016) has been cataloguing species diversity and spider data through citizen science. Meanwhile, major social media sites report many more species sightings than citizen science platforms. SpiderIndia, a popular Facebook group, has collected over 20,000 observations from 8,500 spider enthusiasts. However, these data remain unorganised and inaccessible to academic researchers and the public. In order to tackle these problems, we implemented a methodical process to enhance the occurrence data on spiders from well-known social media platforms, such as the SpiderIndia project. The procedure involved retrieving the relevant data, and ingesting it through a custom pipeline to parse and extract, scientific names, spatial and temporal data to generate occurrence records on the IBP. The data was then presented on a curation interface, enabling taxonomic experts to verify the records, and finally publishing the verified records on the Global Biodiversity Information Facility (GBIF) (Global Biodiversity Information Facility 2022, Barman et al. 2022b) to improve the records of spider species occurrence in India. This project showcases the capacity of citizen science via social media to involve citizen scientists in generating extensive datasets that make a significant contribution to scientific knowledge and improve our comprehension of invertebrate biodiversity. The final dataset encompasses over 15,000 observations, providing valuable insights into spider diversity and distribution across India (Fig. 1). This data is publicly available on GBIF, facilitating further research on Indian spider populations.

Long-term natural history in type II and III spinal muscular atrophy: a 4-year international study on the Hammersmith Functional Motor Scale Expanded.

Spinal muscular atrophy (SMA) is a genetic disorder caused by SMN1 gene mutations. Although studies on available disease-modifying treatments have reported their efficacy and safety, long-term natural history data are lacking for comparison. The aim of this prospective study was to report 4-year changes on the Hammersmith Functional Motor Scale Expanded (HFMSE) in type II and III SMA in relation to several variables such as age, functional status and SMN2 copy number. The study involves retrospective analysis of prospectively collected data from international datasets (Belgium, Italy, Spain, USA, UK). HFMSE longitudinal changes were analyzed using linear mixed effect models, examining annualized HFMSE change and its association with variables such as age at baseline, sex, motor function, SMN2 copy number. In SMA type II (n = 226), the 4-year mean change was -2.20 points. The largest mean changes were observed in sitters aged 5-14 years and the lowest in those who lost the ability to sit unsupported. In SMA type III (n = 162), the 4-year mean change was -2.75 points. The largest mean changes were in those aged 7-15 years, whilst the lowest were in those below 7 and in the SMA type IIIa subgroup over 15. Age and score at baseline were predictive of 4-year changes. Our findings provide natural history reference data for comparison with long-term follow-up of clinical trials or real-world data, highlighting the need to define patterns of changes in smaller SMA subgroups instead of reporting mean changes across an entire SMA cohort.

Endpoints and Design for Clinical Trials in USH2A-Related Retinal Degeneration: Results and Recommendations From the RUSH2A Natural History Study.

To evaluate functional and structural assessments as endpoints for clinical trials for USH2A-related retinal degeneration. People with biallelic disease-causing variants in USH2A, visual acuity ≥ 20/80, and visual field ≥ 10° diameter were enrolled in a 4-year, natural history study. Participants underwent static perimetry, microperimetry, visual acuity, fullfield stimulus testing (FST), and optical coherence tomography annually. Rates of change estimated from mixed-effects linear models and percentages of eyes with changes exceeding the coefficient of repeatability (CoR) or thresholds conforming with U.S. Food and Drug Administration (FDA) guidelines were evaluated. Rates of change were generally more sensitive to change than proportions of eyes exceeding a threshold such as the CoR. Baseline ellipsoid zone area ≥ 3mm2 was necessary to detect change. Mean sensitivity and volumetric hill of vision measures on static perimetry had similar properties and were the most sensitive to changes of the continuous measures. The highest 4-year proportions of eyes exceeding the CoR were from FST testing (47%) and microperimetry (32%). Specification of loci as functional transition points (FTPs) resulted in 45% (static perimetry) and 46% (microperimetry) at 4years, meeting FDA guidelines for progression. Rate of change of mean sensitivity on static perimetry was a sensitive perimetric continuous measure. Percentages of within-eye change were largest with FST testing and microperimetry. FTPs appear to be particularly sensitive to change. These results affect clinical trial design for USH2A-related retinal degeneration. Analyses of natural history data from the Rate of Progression in USH2A-Related Retinal Degeneration (RUSH2A) study can inform eligibility criteria and endpoints for clinical trials.

Using mangrove and field observation data to identify fine-scale species distributions: a case study in bockadams (Serpentes: Homalopsidae: Cerberus).

Characterization of species distributions is a fundamental challenge in biodiversity science, with particular significance for downstream evolutionary studies, conservation efforts, field-based faunal studies and estimates of species diversity. Checklists and phylogenetic studies often focus on poorly known, rare taxa with limited ranges. However, studies of widely distributed, ecologically important species that are abundant in their preferred microhabitats are also important for systematics and local conservation efforts, but less often studied. We collected novel natural history data during fieldwork (2019-2023) for Philippine populations of bockadams (Homalopsidae: Cerberus), one of the most abundant vertebrates in Southeast Asian aquatic systems. Considered a coastal snake, many studies report Cerberus inland. We report the frequency of encounters of Cerberus schneiderii, and the IUCN data-deficient, Philippine-endemic Cerberus microlepis during six expeditions (62 days; 1041 person-hours). We report new occurrence data for 69 C. schneiderii and 6 C. microlepis for coastal and inland populations, water measurements and dietary observations. Regression analyses and ecological niche models show the importance of coastal and mangrove habitats for Cerberus. Our study is the most comprehensive assessment of Philippine Cerberus populations to date and provides critical baseline natural history data for downstream research on widespread and range-restricted species of Southeast Asian snakes.

314P Protein biomarkers predicting clinical milestones in Duchenne muscular dystrophy combining natural history and real-world data

314P Protein biomarkers predicting clinical milestones in Duchenne muscular dystrophy combining natural history and real-world data

Development of a General Composite Scale (GENCOMS) for Progressive Neurodegenerative Diseases and Implications for the Assessment of Disease-Modifying Therapies.

The reliable assessment of treatment outcomes for disease-modifying therapies (DMT) in neurodegenerative disease is challenging. The objective of this paper is to describe a generalized framework for developing composite scales that can be applied in diverse, degenerative conditions, termed "GENCOMS." Composite scales optimize the sensitivity for detecting clinically meaningful effects that slow disease progression. The GENCOMS method relies on robust natural history data and/or placebo arm data from DMT trials. Validated scales that are core to the disease process have been identified, and item level data obtained to standardize the response outcomes from 0 (best possible score) to 1 (worst possible score). A partial least squares regression analysis was conducted with temporal change as the dependent variable and change scores in standardized items as the explanatory variables. The derived model coefficients constitute a weighted sum of items that most effectively measure disease progression. The resultant composite scale was optimized to detect disease progression and can be examined in a range of slow or fast progressing populations. The scale can be used in studies with comparable patient populations as an endpoint optimized to measure disease progression and therefore ideally suited to assess treatment effects in DMTs. The methodology presented here provides a generalizable framework for developing composite scales in the assessment of neurodegenerative disease progression and evaluation of DMT effects. By objectively selecting and weighting items from previously validated measures based solely on their sensitivity to disease progression, this methodology allows for the creation of a more responsive measurement of clinical decline. This heightened sensitivity to clinical decline can be utilized to detect modest yet meaningful treatment effects in the early stages of neurogenerative diseases, when it is optimal to begin a DMT.

Puberty changes the natural history of idiopathic scoliosis: three prediction models for future radiographic curve severity from 1563 consecutive patients.

Understanding idiopathic scoliosis (IS) natural history during growth is essential for shared decision-making between patients and physicians. We developed a retrospective model with the largest available sample in the literature and we aimed to investigate if using three peri-pubertal growth periods provides better prediction than a unique model. Secondary analysis of a previous study on IS natural history data from radiographs before and at the first consult. Three groups: BEFORE (age 6-10), AT (age 11-Risser 2) and AFTER (from Risser 3) the pubertal growth spurt. Available predictors: Cobb angle, curve type, sex, observation time, and Risser score. We used linear mixed-effects models to predict future Cobb angles in each group. We internally validated prediction accuracy with over 100 patients per group (3 to 5-fold cross-validation). We included 1563 participants (275 BEFORE, 316 AFTER, 782 females and 190 males AT). Curves increased over time mostly in AT, importantly in BEFORE, but also in AFTER. All models performed better than the general one. In BEFORE, 74.2% of the predictions were within ± 5o, 71.8% in AFTER, 68.2% in AT females, and 60.4% in males. The predictors (baseline curve, observation time also squared and cubic, and Risser score) were similar in all the models, with sex influencing only AFTER. IS curve severities increase differently during growth with puberty stages. Model accuracy increases when tailored by growth spurt periods. Our models may help patients and clinicians share decisions, identify the risk of progression and inform treatment planning.

SATURN: assessing the feasibility of utilising existing registries for real-world evidence data collection to meet patients, regulatory, health technology assessment and payer requirements

BackgroundSATURN (Systematic Accumulation of Treatment practices and Utilisation, Real world evidence, and Natural history data) for the rare condition osteogenesis imperfecta (OI) has the objective to create a common core dataset by utilising existing, well-established data sources to meet the needs of the various stakeholders (physicians, registry/dataset owners, patients and patient associations, OI community leaders, European [EU] policymakers, regulators, health technology assessments [HTA]s, and healthcare systems including payers). This paper describes the steps taken to assess the feasibility of one existing OI registry (i.e., the Registry of OI [ROI]) as a candidate for SATURN. The same methodology will be applied to other existing OI registries in the future and this same concept could be utilised for other rare disease registries.MethodsThe approach to assessing the feasibility of the ROI registry consisted of three steps: (1) an assessment of the registry characteristics using the Registry Evaluation and Quality Standards Tool (REQueST); (2) a gap analysis comparing SATURN required Core Variables to those being captured in the registry’s Case Report Form (CRF); and (3) a compliance check on the data exchange process following the Title 21 of Code of Federal Regulations (CFR) Part 11/EudraLex Annex 11 Compliance Checklist. The first registry that SATURN has assessed is the ROI database at the Istituto Ortopedico Rizzoli (IOR) in Italy.ResultsThe results from the ROI REQueST have demonstrated satisfactory complete responses in terms of methodology, essential standards, interpretability, and interoperability—readiness for data linkage, data sources, and ethics to meet the needs of data customers. However, the ROI data is from a tertiary referral centre which may limit the ability to understand the full patient journey. The gap analysis has revealed that an exact or logical match between SATURN requested variables and the ROI current variables exists for the following items: patient characteristics, treatment of OI (medical and surgical) and treatment of pain (with the exception of frequency of treatment and reasons for discontinuation), fracture history and bone density. However, data on safety was missing. The compliance check has implied that the ROI implemented appropriate controls for the web-based platform (i.e., Genotype–phenotype Data Integration Platform [GeDI]) that is involved in processing the electronic patient data, and GeDI is a validated/compliant application that follows relevant 21 CFR Part 11/EudraLex Annex 11 regulations.ConclusionsThis robust feasibility process highlights potential limitations and opportunities to develop and to refine the collaboration with the ROI as the SATURN programme moves forward. It also ensures that the existing datasets in the rare condition OI are being maximised to respond to the needs of patients, data customers and decision-makers. This feasibility process has allowed SATURN to build a compliant methodology that aligns with the requirements from the European Medicines Agency (EMA) and HTAs. More data variables will continue to be developed and refined along the way with more registries participating in SATURN. As a result, SATURN will become a meaningful and truly collaborative core dataset, which will also contribute to advancing understanding of OI diagnosis, treatment, and care.

Rett Syndrome: The Emerging Landscape of Treatment Strategies.

Rett syndrome (RTT) has enjoyed remarkable progress in achieving specific therapies. RTT, a unique neurodevelopmental disorder first described in 1966, progressed slowly until the landmark paper of Hagberg and colleagues in 1983. Thereafter, rapid advances were achieved including the development of specific diagnostic criteria and the active search for a genetic etiology, resulting 16 years later in identification of variants in the methyl-CpG-binding protein (MECP2) gene located at Xq28. Shortly thereafter, the NIH Office of Rare Diseases funded the RTT Natural History Study (NHS) in 2003, initiating the acquisition of natural history data on clinical features from a large population of individuals with RTT. This information was essential for advancement of clinical trials to provide specific therapies for this disorder. In the process, the International Rett Syndrome Association (IRSA) was formed (now the International Rett Syndrome Foundation-IRSF), which participated directly in encouraging and expanding enrollment in the NHS and, subsequently, in developing the SCOUT program to facilitate testing of potential therapeutic agents in a mouse model of RTT. The overall objective was to review clinical characteristics developed from the NHS and to discuss the status of specific therapies for this progressive neurodevelopmental disorder. The NHS study provided critical information on RTT: growth, anthropometrics, longevity, key comorbidities including epilepsy, breath abnormalities, gastroesophageal dysfunction, scoliosis and other orthopedic issues, puberty, behavior and anxiety, and progressive motor deterioration including the appearance of parkinsonian features. Phenotype-genotype correlations were noted including the role of X chromosome inactivation. Development of clinical severity and quality of life measures also proved critical for subsequent clinical trials. Further, development of biochemical and neurophysiologic biomarkers offered further endpoints for clinical trials. Initial clinical trials prior to the NHS were ineffective, but advances resulting from the NHS and other studies worldwide promoted significant interest from pharmaceutical firms resulting in several clinical trials. While some of these have been unrewarding such as sarizotan, others have been quite promising including the approval of trofinetide by the FDA in 2023 as the first agent available for specific treatment of RTT. Blarcamesine has been trialed in phase 3 trials, 14 agents have been studied in phase 2 trials, and 7 agents are being evaluated in preclinical/translational studies. A landmark study in 2007 by Guy et al. demonstrated that activation of a normal MECP2 gene in a null mouse model resulted in significant improvement. Gene replacement therapy has advanced through translational studies to two current phase 1/2 clinical trials (Taysha102 and Neurogene-401). Additional genetic therapies are also under study including gene editing, RNA editing, and X-chromosome reactivation. Taken together, progress in understanding and treating RTT over the past 40 years has been remarkable. This suggests that further advances can be expected.

A Systematic Literature Review of the Natural History of Respiratory, Swallowing, Feeding, and Speech Functions in Spinal Muscular Atrophy (SMA).

Respiratory and bulbar dysfunctions (including swallowing, feeding, and speech functions) are key symptoms of spinal muscular atrophy (SMA), especially in its most severe forms. Demonstrating the long-term efficacy of disease-modifying therapies (DMTs) necessitates an understanding of SMA natural history. This study summarizes published natural history data on respiratory, swallowing, feeding, and speech functions in patients with SMA not receiving DMTs. Electronic databases (Embase, MEDLINE, and Evidence-Based Medicine Reviews) were searched from database inception to June 27, 2022, for studies reporting data on respiratory and/or bulbar function outcomes in Types 1-3 SMA. Data were extracted into a predefined template and a descriptive summary of these data was provided. Ninety-one publications were included: 43 reported data on respiratory, swallowing, feeding, and/or speech function outcomes. Data highlighted early loss of respiratory function for patients with Type 1 SMA, with ventilatory support typically required by 12 months of age. Patients with Type 2 or 3 SMA were at risk of losing respiratory function over time, with ventilatory support initiated between the first and fifth decades of life. Swallowing and feeding difficulties, including choking, chewing problems, and aspiration, were reported in patients across the SMA spectrum. Swallowing and feeding difficulties, and a need for non-oral nutritional support, were reported before 1 year of age in Type 1 SMA, and before 10 years of age in Type 2 SMA. Limited data relating to other bulbar functions were collated. Natural history data demonstrate that untreated patients with SMA experience respiratory and bulbar function deterioration, with a more rapid decline associated with greater disease severity. This study provides a comprehensive repository of natural history data on bulbar function in SMA, and it highlights that consistent assessment of outcomes in this area is necessary to benefit understanding and approval of new treatments.

EHerbarium: A Global Platform for Exploring and Sharing Herbarium and Live Plant Images to Enhance Biodiversity Preservation

Historically, herbaria have been instrumental in preserving and studying plant biodiversity. The widespread use of smartphones has led to a surge in the digital documentation of plants. Over the last decade, herbarium digitizing projects are also underway. Many of the digitized herbarium images are available online through different portals. The examples of these portals include Kew Gardens and New York Botanic Garden Herbarium. Combining the latest mobile, cloud and AI technologies as well as plant taxonomy and herbarium artifacts, the mission of eHerbarium*1 is to provide an accessible digital platform for plant enthusiasts, including botanists, researchers, students, as well as the general public around the world, to collect, identify and share live plant and herbarium images. It promotes data collection and data sharing around the globe for biodiversity preservation. It further provides educational benefits about plants and the plant biodiversity around us and the world. eHerbarium offers access to an extensive collection of herbarium images from Kew’s Herbarium at the Royal Botanic Gardens, Kew. The platform is also extensible, allowing it to host images from other herbaria. In addition, this platform provides high-quality botanical visuals, enabling users to capture and share live plant photos or herbarium images, or upload from existing collections. Customizable licensing options facilitate community use and enhance collaborative botanical research. The platform’s AI-powered tools streamline plant identification, offering autocomplete suggestions for taxonomy details such as scientific name, family name or common names. Our proprietary technology ensures seamless and accurate botanical data entry by automatically retrieving corresponding scientific or common names. Additionally, eHerbarium enriches botanical records by automatically associating image locations with Biodiversity Information Standards (TDWG) Level 2 regions. TDWG Level 2 regions are specific geographical areas defined by TDWG to standardize the recording and reporting of biodiversity data. These regions, which typically correspond to large countries or significant subnational areas, help ensure consistent and accurate geographical referencing in botanical studies and herbarium records, while also respecting image owners' location privacy. eHerbarium has more than 40,000 worldwide downloads since its debut less than six months ago on March 18, 2024. We encourage further collaborations to expand our repositories for herbarium and live plant images. We also welcome partnerships to tailor the application to specific needs for natural history and biodiversity data collection.

Enhancing Study Power in Pediatric Research through Bayesian Extrapolation

Pediatric populations, comprising individuals aged 18 or younger, and rare disease populations pose significant challenges in clinical trial design due to limited participant numbers, patient sensitivity, and insufficient natural history data. Addressing these challenges often involves data extrapolation, leveraging existing data from adults to inform pediatric trials. Bayesian hierarchical modeling is increasingly recognized as a valuable tool for combining information across disparate sources, such as adult and pediatric datasets. This manuscript introduces an extension of an existing statistical model to enhance the efficiency of borrowing strength from multiple historical trials under consistent assumptions. A quantitative method is developed to improve the borrowing of historical information. The methods are illustrated with a simulation study motivated by real case study in pediatric clinical trial, and practical considerations are provided regarding the selection of prior distributions. This work aims to provide comprehensive insights and practical guidance for leveraging historical data effectively in clinical trial design.

DiSSCover the Potential of FAIR Digital Object Annotations and How You Can Use Them!

The infrastructure for the Distributed System of Scientific Collections (DiSSCo) is in full development. Work within the DiSSCo Transition Project has been focused on building infrastructure, creating data models, and setting up Application Programming Interfaces (APIs) (Koureas et al. 2024). In the past years, DiSSCo has presented this work at different Biodiversity Information Standards (TDWG) conferences (Leeflang and Addink 2023, Leeflang et al. 2022, Addink et al. 2021). In this year’s session, we would like to focus on the human-facing application: DiSSCover. DiSSCover is the graphical user interface through which users can interact with Findable, Accessible, Interoperable and Reusable (FAIR) Digital Objects (FDOs), facilitating the curation and enhancement of specimen data (Islam 2024). Development started in 2022 and is ongoing. The interface acts as a gateway into the DiSSCo infrastructure, providing access to digital specimens and media. Extracted from the core DiSSCo API, the data is converted into an easily readable format and made discoverable through a diverse set of filters. DiSSCover’s main focus is to allow users to make annotations upon the data. Through the concept of annotations, we connect expert and machine-generated information, to create extended digital specimens (Hardisty et al. 2022), e.g, by creating linkages to other infrastructures, correcting or adding new information, or by triggering machine annotation services. Machine annotation services are automated scalable tools that run in the background and automatically curate and extend the specimen (Addink et al. 2023). Human users will remain important, as all annotations made by machine annotation services can be reviewed by a trusted person. Annotations are Fair Digital Objects and target a specific part of a specimen, be it a data fragment or an associated media file. At the heart of DiSSCover lies the Open Digital Specimen data specification (Leeflang and Addink 2023). It tries to harmonise multiple data standards into one generic specification based on the new Global Biodiversity Information Facility (GBIF) Unified Model (Robertson et al. 2022). The data is stored as JavaScript Object Notation (JSON) based on JSON Schemas (Anonymous 2024). Annotations are linked to specific data attributes using a JSON-path as the identifier. Data attributes can be individual terms, collections of terms called classes, or the whole object. This creates a flexible but complex data structure, the basis for which we used the World Wide Web Consortium (W3C) web annotation data model (Sanderson et al. 2017). The W3C Web annotation data model contains two main components: the target and body. The target specifies which data attribute the annotation is made on, for example, the term: ‘ods:specimenName’. This is a local term within the open Digital Specimen namespace (ods), which holds the accepted name of the digital specimen. The annotation body holds the value(s) that are appended to the digital specimen, and differ based upon the annotation motivation. DiSSCo recognises five different annotation motivations: addition, modification, comment, assessment and deletion, each of which has its own unique function. This creates a flexible structure that should be able to handle any information the user wants to add to the object. The challenge of DiSSCover is to preserve the complex structure of annotations, whilst making it convenient for users to work with. The session will provide a look at the different kinds of annotations and their use from a practical perspective. A demonstration of DiSSCover will show how users can create annotations, providing knowledge about the process that will give shape to DiSSCo’s main goal of enriching natural history data.

The first record of ants as potential pollinators of a Neotropical tree species (Lomatia hirsuta Diels ex J.F.Macbr., Proteaceae)

AbstractWe provide evidence that Camponotus chilensis (Spinola) visit flowers of the Radal tree (Lomatia hirsuta Diels ex J.F.Macbr.), possibly acting as pollinators of this important tree of the Proteaceae family in the Andean Patagonian forests of Argentina. We found several ant workers transporting pollen from different trees during the blooming season. Pollen transported by workers varied in amount, with some individuals observed fully coated with pollen grains. This note constitutes the first observation of ant activity on the flowers of this plant species and also the first potential example of a tree pollinated by ants in the Neotropics. This note highlights the importance of natural history data in the emergent study field of ant‐pollination.

Retinal Sensitivity in Macular Subfields and Their Association with Contrast Sensitivity in Early and Intermediate Age-Related Macular Degeneration.

The objective of this study was to evaluate retinal sensitivity in subfields and its association with the novel quantitative contrast sensitivity function (qCSF) in patients with early age-related macular degeneration (eAMD), in patients with intermediate AMD (iAMD), and in healthy controls. In this prospective longitudinal study, retinal sensitivity of a customized 24-point grid was assessed by microperimetry Macular Integrity Assessment (MAIA, CenterVue, Padova, Italy) and divided into different subfields. The Multiple Contrast Vision Meter (Adaptive Sensory Technology, San Diego, CA, USA) was used for qCSF testing. Linear models were used to test the association of functional metrics with variables of interest. 92 study eyes from 92 participants were analyzed (13 eAMD, 31 iAMD, and 48 controls). Microperimetry subfield comparison showed significant differences (p < 0.0001) in the control group between superior and inferior hemifield as well as between central and peripheral subfields. For eAMD, significant differences were found between central and peripheral subfields (p < 0.001) and specific subfields (p < 0.05) and finally for iAMD between specific quadrants (p < 0.05) and specific squares (p < 0.05). Significant associations of retinal sensitivity with qCSF metrics were found for the area underneath the logarithmic contrast sensitivity function, contrast acuity and for the contrast sensitivity at specific spatial frequencies. This study showed significant differences in the evaluated retinal sensitivity subfields, providing localized natural history data for retinal sensitivity in healthy controls and patients with eAMD and iAMD.

Mapping the evidence about the natural history of acute infections commonly seen in primary care and managed with antibiotics: a scoping review

BackgroundKnowing the natural history of acute infections in primary care, defined as the course of a disease over time in the absence of specific therapy or treatment, can inform clinicians’ and patients’ expectations about illness recovery, but this evidence is fragmented across the literature. This scoping review aimed to map existing research and research gaps relevant to the natural history of acute infections.MethodsWe searched MEDLINE, Embase and CENTRAL using a 2-phase hierarchical search approach. In Phase A, we focused on identifying systematic reviews synthesising natural history data for eligible infections (acute respiratory, urinary, and skin and soft tissue) and systematic reviews of treatment effectiveness (of RCTs with placebo or no treatment arm, or cohort studies). For infections without existing reviews, in Phase B, we searched for primary studies (placebo-controlled RCTs or cohort studies). Two reviewers independently screened and extracted the data (study characteristics, outcome data - e.g., symptom duration, proportion with resolution at various time points).ResultsWe identified 40 systematic reviews, reporting on 45 infections, most commonly (90%) respiratory tract infections. Six (15%) of these aimed to synthesise natural history information. Most reviews reported the proportion of participants with symptom resolution at various time point/s, with 58% providing data on mean symptom duration. Recovery data show the spontaneous resolution of some infections in some people. We found no eligible studies for cellulitis, ecthyma, carbuncle, and erysipelas.ConclusionsOur review has shown that natural history evidence exists for many common acute infections. It can be utilised by clinicians in implementing patient-centred antibiotic stewardship strategies in primary care. Future research should focus on generating natural history evidence for skin and soft tissue infections and urinary tract infections.

Integrated Applied Clinical Pharmacology in the Advancement of Rare and Ultra-Rare Disease Therapeutics.

The introduction of safe and effective rare/ultra-rare disease treatments is a focus of many biotherapeutic enterprises. Despite this increased activity, a significant unmet need remains, and the responsibility to meet this need is augmented by enhanced genomic, biologic, medical, analytical, and informatic tools. It is recognized that the development of an effective and safe rare/ultra-rare disease therapeutic faces a number of challenges with an important role noted for clinical pharmacology. Clinical pharmacology is foundationally an integrative discipline which must be embedded in and is interdependent upon understanding the pathogenic biology, clinical presentation, disease progression, and end-point assessment of the disease under study. This manuscript presents an overview and two case examples of this integrative approach, the development of C5-targeted therapeutics for the treatment of generalized myasthenia gravis and asfotase alpha for the treatment of hypophosphatasia. The two presented case examples show the usefulness of understanding the biological drivers and clinical course of a rare disease, having relevant animal models, procuring informative natural history data, importing assessment tools from relevant alternative areas, and using integrated applied clinical pharmacology to inform target engagement, dose, and the cascade of pharmacodynamic and clinical effects that follow. Learnings from these programs include the importance of assuring cross-validation of assays throughout a development program and continued commitment to understanding the relationship among the array of Pd end points and clinical outcomes. Using an integrative approach, substantive work remains to be done to meet the unmet needs of patients with rare/ultra-rare disease.

Description of Babesiacoryicola sp. nov. from Florida pumas (Puma concolor coryi) from southern Florida, USA

Previously, a high prevalence of piroplasms has been reported from Florida pumas (Puma concolor coryi) from southern Florida. In the current study, we describe the biological characteristics of a novel Babesia species in Florida pumas. Ring-stage trophozoites were morphologically similar to trophozoites of numerous small babesids of felids including B. leo, B. felis, and Cytauxzoon felis. Parasitemias in Florida pumas were very low (<1%) and hematologic values of 25 Babesia-infected Florida pumas were within normal ranges for P. concolor. Phylogenetic analysis of near full-length 18S rRNA gene, β-tubulin, cytochrome c oxidase subunit I, cytochrome c oxidase subunit III, and cytochrome b gene sequences indicated that this Babesia species is a member of the Babesia sensu stricto clade and is related to groups of Babesia spp. from carnivores or ungulates, although the closest group varied by gene target. Internal transcribed spacer (ITS)-1 region sequences from this Babesia sp. from 19 Florida pumas were 85.7–99.5% similar to each other and ∼88% similar to B. odocoilei. Similarly, an ITS-2 sequence from one puma was 96% similar to B. bigemina and 92% similar to a Babesia sp. from a red panda (Ailurus fulgens). Infected pumas were positive for antibodies that reacted with B. odocoilei, B. canis, and B. bovis antigens with titers of 1:256, 1:128, and 1:128, respectively. No serologic reactivity was noted for Theileria equi. No molecular evidence of congenital infection was detected in 24 kittens born to 11 Babesia-infected female pumas. Pumas from other populations in the United States [Louisiana (n = 1), North Dakota (n = 5) and Texas (n = 28)], British Columbia, Canada (n = 9), and Costa Rica (n = 2) were negative for this Babesia sp. Collectively, these data provide morphologic, serologic, genetic, and natural history data for this novel Babesia sp. which we propose the name Babesia coryicola sp. nov. sp. This is the first description of a felid-associated Babesia species in North America.