[Marketing authorisation for rare diseases: The European regulatory perspective using the example of gene and cell therapies]. / Arzneimittelzulassung im Bereich seltener Erkrankungen: die europäische regulatorische Perspektive am Beispiel der Gen- und Zelltherapeutika.

Technological and scientific innovations in the area of gene and cell therapies, so-called advanced therapy medicinal products (ATMPs), have contributed to the steep increase in treatment options for patients with rare diseases. They offer opportunities to address the underlying genetic defect by gene addition, i.e., the delivery of the gene of interest to the target cells, or by genome editing approaches through direct repair of disease-causing mutations. This paper outlines clinical evidence requirements in the context of marketing authorisations for rare diseases. Two out of fifteen gene therapies that have been approved in the European Union since 2018 are used as case studies: Libmeldy (atidarsagen autotemcel) for the treatment of patients with metachromatic leukodystrophy, and Roctavian (valoctocogen roxaparvovec) for the treatment of patients with haemophilia A. Special aspects of the evaluation of single-arm trials with small sample size and requirements with regard to the isolation and causal attribution of the treatment effect are discussed. The role of clinical data obtained under everyday conditions (real world data) to support the generation of evidence in the pre- and post authorisation phase is critically examined. Furthermore, the paper outlines aspects related to conditional versus standard marketing authorisations as well as aspects related to registry-based non-interventional studies in the context of market and patient access to urgently needed drugs.

Orphan and paediatric medical devices in Europe: recommendations to support their availability for on-label and off-label clinical indications.

INTRODUCTION: The Medical Device Regulation (EU)745/2017, increased the regulatory requirements and thus the time and the cost associated with marketing medical devices. For a majority of medical device manufacturers, this has lead to reconsiderations of their product portfolio. The risk of important or essential devices being withdrawn is particularly relevant for pediatric patients and other rare disease patients where limited numbers of devices can be sold and hence the investment needed may not be recovered. This generates critical challenges and opportunities from a regulatory and public health perspective. AREAS COVERED: This paper is based upon the experience of the authors who contributed to working groups, guidance development and research related to orphan and pediatric devices. We examine the use of medical devices in orphan and pediatric conditions, the relevant aspects of regulations and associated guidance, and we suggest possible policy and practice interventions to ensure the continued availability of essential devices for children and people with rare diseases. EXPERT OPINION: We recommend a more proactive approach to identifying devices at risk and essential devices, increasing the use of exceptional market approvals, expanding the role of expert panels, engaging with the rare disease communities and supporting registries and standards.

Pareto-principle in rare disease education: assessing the representation of common rare diseases in medical education and coding systems.

BACKGROUND: The Pareto Principle asserts that a large portion of results can be achieved with a small amount of effort. Wakap et al. found that around 80% of individuals with rare diseases (RD) suffer from one of 149 specific rare diseases. A significant challenge in the RD domain is the lack of information, compounded by the fact that most RD are not specifically codifiable in the ICD-10, leading to a deficit in reliable epidemiological data. Additionally, time constraints in medical education hinder the comprehensive teaching of all RD, contributing to the diagnostic odyssey problem through failure of recognizing diseases. We identified the most and second most prevalent RD (prevalences of 1-5/10,000 and 1-9/100,000, respectively) from the Orphanet Epidemiology File, totaling 454 diseases. We investigated the feasibility of specific coding using ICD-10-GM and whether these diseases were explicitly listed in the subject catalog (GK) of the second state examination in human medicine in Germany. A two-sided chi-square test was employed to identify statistically significant differences between prevalence groups. RESULTS: Out of 454 diseases, a total of 34% could be specifically coded in ICD-10-GM, with 49% of diseases in the 1-5/10,000 prevalence range (153 RD) and 26% in the 1-9/100,000 range (301 RD) having specific codes. Approximately 15% of all investigated diseases were part of the GK, with 25% of the most prevalent and 10% of the second most prevalent RD group, respectively. Statistically significant differences were observed between prevalence groups concerning the presence of a specific ICD-10-GM code and inclusion in the GK. CONCLUSION: Only 49% of the most prevalent RD can be specifically coded, highlighting the challenge of limited epidemiological data on RD. In Germany, the Alpha-ID was introduced in addition to ICD-10 in the inpatient setting to obtain more valid epidemiological data on RD. Recognizing the Pareto Principle's applicability, the study emphasizes the importance of including the most common rare diseases in medical education. While recognizing the limitations, especially in covering ultra-rare diseases, the study underscores the potential benefits of enhancing medical curricula to improve rare disease awareness and diagnostic accuracy.

Advanced Regenerative Medicines for Rare Diseases: A Review of Industry Sponsors Investment Motivations.

Despite regulatory changes designed to stimulate investment in therapies for rare diseases, many of these conditions lack government-approved treatments. Advanced regenerative medicines, which are therapies and clinical interventions aimed at healing or replacing damaged or defective human cells, tissues, and organs, offer great promise for addressing many rare diseases. A major challenge facing advanced regenerative medicines for rare diseases is securing financial support to assist in bringing a therapy to market. This paper describes the factors cited by pharmaceutical industry players globally for sponsoring the development of advanced regenerative medicines for rare diseases. The paper examines the motivations of 53 sponsors that meet the latter criteria. The motivations behind investments were broadly similar amongst sponsors and map closely onto regulatory requirements for clinical development and marketing authorization of advanced therapeutic products, including the presence of accelerated or attenuated pathways for regulatory approval, use for indications with high unmet medical needs, and/or that have advantages over existing therapies, and robust preclinical data. Other factors include availability of investment incentives and opportunities for off-label use in the post-approval stages.

Reporter Mice for Gene Editing: A Key Tool for Advancing Gene Therapy of Rare Diseases.

Most rare diseases are caused by mutations and can have devastating consequences. Precise gene editing by CRISPR/Cas is an exciting possibility for helping these patients, if no irreversible developmental defects have occurred. To optimize gene editing therapy, reporter mice for gene editing have been generated which, by expression of reporter genes, indicate the efficiency of precise and imprecise gene editing. These mice are important tools for testing and comparing novel gene editing methodologies. This review provides a comprehensive overview of reporter mice for gene editing which all have been used for monitoring CRISPR/Cas-mediated gene editing involving DNA double-strand breaks (DSBs). Furthermore, we discuss how reporter mice can be used for quickly checking genetic alterations by base editing (BE) or prime editing (PE).

A systematic review of studies that estimated the burden of chronic non-communicable rare diseases using disability-adjusted life years.

BACKGROUND: Initiatives aiming to assess the impact of rare diseases on population health might be hampered due to the complexity of disability-adjusted life years (DALYs) estimation. This study aimed to give insight into the epidemiological data sources and methodological approaches used in studies that estimated DALYs for chronic non-communicable rare diseases (CNCRD), and compare its results. METHODS: A literature strategy was developed for peer-review search in Embase and Medline, and also performed on grey literature databases and population health and/or rare disease-focused websites. We included studies that determined the burden of CNCRD listed on the Orphanet's and/or the Genetic and Rare Diseases information center (GARD) websites. We excluded communicable and occupational diseases, rare cancers, and cost-effectiveness/benefit studies. Two researchers independently screened the identified records and extracted data from the final included studies. We used the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER) statement to assess the quality of reporting of the included studies. The data synthesis depicted the studies' characteristics, their distribution by geographic coverage and the group of disease(s) they focused on, the methods and data input sources used and estimated DALY per case. RESULTS: In total, 533 titles were screened, and 18 studies were included. These studies covered 19 different CNCRDs, of which most fell in the disease category "Diseases of the nervous system". Diverse methodological approaches and data input sources were observed among burden of CNCRD studies. A wide range of DALY per case was observed across the different studies and diseases included. CONCLUSIONS: A low number of burden of CNCRD studies was observed and most estimates resulted from multi-country studies, underlining the importance of international cooperation to further CNCRD research. This study revealed a lack of epidemiological data and harmonization of methods which hampers comparisons across burden of CNCRD studies.

Preferences for coordinated care for rare diseases: discrete choice experiment.

BACKGROUND: Evidence suggests that coordination of care for people affected by rare diseases is poor. In order to improve the way that care is coordinated it is necessary to understand the preferences of people affected by these conditions, and providers. The aim of this study was to examine patient, parent and carer, and health care professional preferences for different attributes of care coordination for people affected by rare diseases. We conducted a discrete choice experiment using online surveys. There were no restrictions on participants in terms of rare conditions, demographic factors other than age, or geographical location within the UK. Choice scenarios were based on the following attributes: annual cost of attending appointments; access to health records; access to clinical expertise; support of a care coordinator; access to a specialist centre; and, the existence of a documented plan for emergency care. Data were analysed using alternative-specific conditional logit regression models. RESULTS: Valid responses were obtained from 996 individuals (528 patients, 280 carers, 188 health care professionals) between August and December 2019. All attributes significantly influenced the type of service respondents preferred. Patients, carers and health professionals' preferences for care coordination were influenced by: the cost of attending appointments; access to health records; clinical expertise; role of care coordinators; access to specialist centres; and the existence of plan for emergency care. There were no statistically significant differences in the preferences between patients and carers. Preferences of health professionals differed to those of patients and carers. Both patients and carers selected responses which granted them a greater degree of autonomy in relation to the role of care coordinators, whereas health professionals preferred services where care coordinators had more autonomy. Health care professionals also expressed a stronger preference for a documented formal emergency plan to be in place. CONCLUSIONS: The findings highlight that people value better coordinated care, in line with policy documents emphasising commitments to coordinated care for people affected by rare diseases. This study highlights the factors that could be included in service provision as ways of improving the coordination of care for people affected by rare diseases.

Case report: Surgical treatment and literature review of a recurrent case of glucagonoma.

A 40-year-old male patient was admitted due to abdominal distension and discomfort in the upper abdomen persisting for three days. Enhanced CT of the upper abdomen revealed an irregularly dense soft tissue area in the body and tail of the pancreas, approximately 7.6 × 3.1 cm in size, with blurred boundaries, and indistinct separation from the splenic artery and vein. Multiple liver lesions of varying sizes and slightly lower densities were also observed. Liver tumor biopsy considering a neuroendocrine tumor G2, combined with the medical history, led to a diagnosis of pancreatic neuroendocrine tumor G2 with liver metastasis. Physical examination showed mild tenderness in the upper abdomen but no other significant positive signs. During treatment, the patient developed multiple red papular rashes around the mouth, on both lower limbs, and the perineum, accompanied by itching. The glucagon level was 1138.3 pg/L. The patient underwent resection of the pancreatic body and tail, splenectomy, partial liver tumor resection, and cholecystectomy. Within five days post-surgery, the skin lesions began to crust and flake off. On the 14th day post-surgery, the serum glucagon level was rechecked at 136.4 pg/L. As of April 2024, progression of liver lesions was noted, with no significant skin symptoms during the period.

PSAP-Genomic-Regions: A Method Leveraging Population Data to Prioritize Coding and Non-Coding Variants in Whole Genome Sequencing for Rare Disease Diagnosis.

The introduction of Next-Generation Sequencing technologies in the clinics has improved rare disease diagnosis. Nonetheless, for very heterogeneous or very rare diseases, more than half of cases still lack molecular diagnosis. Novel strategies are needed to prioritize variants within a single individual. The Population Sampling Probability (PSAP) method was developed to meet this aim but only for coding variants in exome data. Here, we propose an extension of the PSAP method to the non-coding genome called PSAP-genomic-regions. In this extension, instead of considering genes as testing units (PSAP-genes strategy), we use genomic regions defined over the whole genome that pinpoint potential functional constraints. We conceived an evaluation protocol for our method using artificially generated disease exomes and genomes, by inserting coding and non-coding pathogenic ClinVar variants in large data sets of exomes and genomes from the general population. PSAP-genomic-regions significantly improves the ranking of these variants compared to using a pathogenicity score alone. Using PSAP-genomic-regions, more than 50% of non-coding ClinVar variants were among the top 10 variants of the genome. On real sequencing data from six patients with Cerebral Small Vessel Disease and nine patients with male infertility, all causal variants were ranked in the top 100 variants with PSAP-genomic-regions. By revisiting the testing units used in the PSAP method to include non-coding variants, we have developed PSAP-genomic-regions, an efficient whole-genome prioritization tool which offers promising results for the diagnosis of unresolved rare diseases.

VUS next in rare diseases? Deciphering genetic determinants of biomolecular condensation.

The diagnostic odysseys for rare disease patients are getting shorter as next-generation sequencing becomes more widespread. However, the complex genetic diversity and factors influencing expressivity continue to challenge accurate diagnosis, leaving more than 50% of genetic variants categorized as variants of uncertain significance.Genomic expression intricately hinges on localized interactions among its products. Conventional variant prioritization, biased towards known disease genes and the structure-function paradigm, overlooks the potential impact of variants shaping the composition, location, size, and properties of biomolecular condensates, genuine membraneless organelles swiftly sensing and responding to environmental changes, and modulating expressivity.To address this complexity, we propose to focus on the nexus of genetic variants within biomolecular condensates determinants. Scrutinizing variant effects in these membraneless organelles could refine prioritization, enhance diagnostics, and unveil the molecular underpinnings of rare diseases. Integrating comprehensive genome sequencing, transcriptomics, and computational models can unravel variant pathogenicity and disease mechanisms, enabling precision medicine. This paper presents the rationale driving our proposal and describes a protocol to implement this approach. By fusing state-of-the-art knowledge and methodologies into the clinical practice, we aim to redefine rare diseases diagnosis, leveraging the power of scientific advancement for more informed medical decisions.

Machine-Learning Model Identifies Patients With Alpha-1 Antitrypsin Deficiency Using Claims Records.

Identifying patients with rare diseases like alpha-1 antitrypsin deficiency (AATD) is challenging. Machine-learning models may be trained to identify patients with rare diseases using large-scale, real-world databases, whereas electronic medical records have low numbers of confirmed cases and have limited use in training such models. We applied a machine-learning model to a large US claims database to identify undiagnosed symptomatic patients with AATD. Using deidentified data from the Komodo US claims database (April 26, 2016-January 31, 2023), a model was trained to identify symptomatic patients with high probability of AATD. Eighty claims records for high-probability candidates identified by the model were independently reviewed and validated by 2 clinical experts. The experts independently indicated that of the 80 high-probability candidate patients, 65 (81%) and 62 (78%) patients, respectively, should be tested for AATD. Feedback from this validation step informed model optimization. The optimized model was applied to claims data to identify symptomatic patients with probable AATD. Eleven and 14 "features" of the claims data were informative in distinguishing patients with AATD from patients with COPD without AATD and from unspecified chronic liver diseases. Moreover, patients with diagnosed AATD and COPD without AATD had unique cadences of similar medical events in their diagnostic journeys. Our work shows that a machine-learning model trained on a large US claims database can accurately identify symptomatic patients with AATD and provides useful insights into the diagnostic journey of patients with AATD.

Patient-Oriented Questionnaires and Machine Learning for Rare Disease Diagnosis: A Systematic Review.

Background: A major challenge faced by patients with rare diseases (RDs) often stems from delays in diagnosis, typically due to nonspecific clinical symptoms or doctors' limited experience in connecting symptoms to the underlying RD. Using patient-oriented questionnaires (POQs) as a data source for machine learning (ML) techniques can serve as a potential solution. These questionnaires enable patients to portray their day-to-day experiences living with their condition, irrespective of clinical symptoms. This systematic review-registered at PROSPERO with the Registration-ID: CRD42023490838-aims to present the current state of research in this domain by conducting a systematic literature search and identifying the potentials and limitations of this methodology. Methods: The review adheres to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was primarily funded by the German Federal Ministry of Education and Research under grant no. 16DHBKI056 (ki4all). The methodology involved a systematic search across the databases PubMed, Semantic Scholar and Google Scholar, covering articles published until June 2023. The inclusion criteria encompass examining the use of POQs in diagnosing rare and common diseases. Additionally, studies that focused on applying ML techniques to the resulting datasets were considered for inclusion. The primary objective was to include English as well as German research that involved the generation of predictions regarding the underlying disease based on the information gathered from POQs. Furthermore, studies exploring identifying predictive indicators associated with the underlying disease were also included in the literature review. The following data were extracted from the selected studies: year of publication, number of questions in the POQs, answer scale in the questionnaires, the ML algorithms used, the input data for the ML algorithms, the performance of these algorithms and how the performance was measured. In addition, information on the development of the questionnaires was recorded. Results: This search retrieved 421 results in total. After one superficial and two comprehensive screening runs performed by two authors independently, we ended up with 26 studies for further consideration. Sixteen of these studies deal with diseases and ML algorithms to analyse data; the other ten studies provide contributing research in this field. We discuss several potentials and limitations of the evaluated approach. Conclusions: Overall, the results show that the full potential has not yet been exploited and that further research in this direction is worthwhile, because the study results show that ML algorithms can achieve promising results on POQ data; however, their use in everyday medical practice has not yet been investigated.

Voices of Parent-Carers Navigating the Care for Children With Osteogenesis Imperfecta.

Parent-carers of children with rare diseases, including osteogenesis imperfecta (OI), represent a vulnerable and largely invisible population. Despite existing research on familial OI caregiving, the unique experiences, perspectives, and feelings of parent-carers remain poorly understood, prompting this study to delve into these aspects through the subjective lens of voices. The aim of this study was to explore the voices of parent-carers in navigating the complexities of pediatric OI care. Employing a narrative design informed by social constructionism, 15 parent-carers of pediatric OI patients were purposively sampled from a tertiary hospital in Shandong Province, China, between May and August 2021. Individual face-to-face interviews were conducted, and data were analyzed using the voice-centered relational approach followed by thematic analysis. Parent-carers' narratives revealed two overarching themes. The first theme, "the all-encompassing caregiver role," highlighted the profound internal transformation parent-carers underwent, with three key aspects of experiences: "the centrality of care," "life on hold," and "guarded silence." The second theme, "navigating ambivalence," captured the complex psycho-emotional journey of parent-carers as they balanced denial and acceptance, experienced the burden and responsibility of caregiving, navigated uncertainty with hope, and sought to normalize the care recipients' experiences while acknowledging their unique needs. Our findings suggest the need for developing tailored support strategies that address not only practical challenges but also the psychosocial dimensions of caregiving, to effectively assist and empower this marginalized carer population.

Building a National Policy for Rare Disease in Brazil.

Rare diseases (RD) are individually rare, although encompass a significant proportion of the population, affecting not only the individuals but also their families. In Brazil RD is defined by the Ministry of Health as a disorder that affects up to 65 individuals in 100,000, or 1.3 individuals in every 2,000. In this review the environment that led to the publication of a National Policy for Comprehensive Care for People of Rare Disease in 2014, a national plan with the aim to decrease morbidity and mortality of RD, improving the care of people with RD in the public health system are described. The process that finally led to such policy took over a decade, moving forward not only due to technical needs, but having patient organizations as essential actors and advocates. Specialized centers in RD were licensed and, since its publication, 33 centers have been accredited; such process, however, has been slow and concentrated in specific regions and larger cities of the country. Despite the incorporation of genetic tests in 2014 and exome sequencing later in 2020, many genetic tests are not offered by specialized centers, with unequal availability across the country. Public health system in Brazil uses ICD-10 for disease coding, preventing appropriate epidemiologic knowledge of RD in Brazil. Incorporation of new technologies as orphan drugs has been in place and regulation for expedite licensing for new RD drugs were issued, although high cost and availability to RD population has been a challenge.

Operational description of rare diseases: a reference to improve the recognition and visibility of rare diseases.

Improving health and social equity for persons living with a rare disease (PLWRD) is increasingly recognized as a global policy priority. However, there is currently no international alignment on how to define and describe rare diseases. A global reference is needed to establish a mutual understanding to inform a wide range of stakeholders for actions. A multi-stakeholder, global panel of rare disease experts, came together and developed an Operational Description of Rare Diseases. This reference describes which diseases are considered rare, how many persons are affected and why the rare disease population demands specific attention. The operational description of rare diseases is framed in two parts: a core definition of rare diseases, complemented by a descriptive framework of rare diseases. The core definition includes parameters that permit the identification of which diseases are considered rare, and how many persons are affected. The descriptive framework elaborates on the impact and burden of rare diseases on patients, their caregivers and families, healthcare systems, and society overall. The Operational Description of Rare Diseases establishes a common point of reference for decision-makers across the world who strive to understand and address the unmet needs of persons living with a rare disease. Adoption of this reference is essential to improving the visibility of rare conditions in health systems across the world. Greater recognition of the burden of rare diseases will motivate new actions and policies to address the unmet needs of the rare disease community.

Artificial intelligence empowering rare diseases: a bibliometric perspective over the last two decades.

OBJECTIVE: To conduct a comprehensive bibliometric analysis of the application of artificial intelligence (AI) in Rare diseases (RDs), with a focus on analyzing publication output, identifying leading contributors by country, assessing the extent of international collaboration, tracking the emergence of research hotspots, and detecting trends through keyword bursts. METHODS: In this bibliometric study, we identified and retrieved publications on AI applications in RDs spanning 2003 to 2023 from the Web of Science (WoS). We conducted a global research landscape analysis and utilized CiteSpace to perform keyword clustering and burst detection in this field. RESULTS: A total of 1501 publications were included in this study. The evolution of AI applications in RDs progressed through three stages: the start-up period (2003-2010), the steady development period (2011-2018), and the accelerated growth period (2019-2023), reflecting this field's increasing importance and impact at the time of the study. These studies originated from 85 countries, with the United States as the leading contributor. "Mutation", "Diagnosis", and "Management" were the top three keywords with high frequency. Keyword clustering analysis identified gene identification, effective management, and personalized treatment as three primary research areas of AI applications in RDs. Furthermore, the keyword burst detection indicated a growing interest in the areas of "biomarker", "predictive model", and "data mining", highlighting their potential to shape future research directions. CONCLUSIONS: Over two decades, research on the AI applications in RDs has made remarkable progress and shown promising results in the development. Advancing international transboundary cooperation is essential moving forward. Utilizing AI will play a more crucial role across the spectrum of RDs management, encompassing rapid diagnosis, personalized treatment, drug development, data integration and sharing, and continuous monitoring and care.

RNA exon editing: Splicing the way to treat human diseases.

RNA exon editing is a therapeutic strategy for correcting disease-causing mutations by inducing trans-splicing between a synthetic RNA molecule and an endogenous pre-mRNA target, resulting in functionally restored mRNA and protein. This approach enables the replacement of exons at the kilobase scale, addresses multiple mutations with a single therapy, and maintains native gene expression without changes to DNA. For genes larger than 5 kb, RNA exon editors can be delivered in a single vector despite AAV capacity limitations because only mutated exons need to be replaced. While correcting mutations by trans-splicing has been previously demonstrated, prior attempts were hampered by low efficiency or lack of translation in preclinical models. Advances in synthetic biology, next-generation sequencing, and bioinformatics, with a deeper understanding of mechanisms controlling RNA splicing, have triggered a re-emergence of trans-splicing and the development of new RNA exon editing molecules for treating human disease, including the first application in a clinical trial (this study was registered at ClinicalTrials.gov [NCT06467344]). Here, we provide an overview of RNA splicing, the history of trans-splicing, previously reported therapeutic applications, and how modern advances are enabling the discovery of RNA exon editing molecules for genetic targets unable to be addressed by conventional gene therapy and gene editing approaches.

Unlocking the Door for Precision Medicine in Rare Conditions: Structural and Functional Consequences of Missense ACVR1 Variants.

Rare diseases and conditions have thus far received relatively less attention in the field of precision/personalized medicine than common chronic diseases. There is a dire need for orphan drug discovery and therapeutics in ways that are informed by the precision/personalized medicine scholarship. Moreover, people with rare conditions, when considered collectively across diseases worldwide, impact many communities. In this overarching context, Activin A Receptor Type 1 (ACVR1) is a transmembrane kinase from the transforming growth factor-ß superfamily and plays a critical role in modulating the bone morphogenetic protein signaling. Missense variants of the ACVR1 gene result in modifications in structure and function and, by extension, abnormalities and have been predominantly linked with two rare conditions: fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma. We report here an extensive bioinformatic analyses assessing the pool of 50,951 variants and forecast seven highly destabilizing mutations (R206H, G356D, R258S, G328W, G328E, R375P, and R202I) that can significantly alter the structure and function of the native protein. Protein-protein interaction and ConSurf analyses revealed the crucial interactions and localization of highly deleterious mutations in highly conserved domains that may impact the binding and functioning of the protein. cBioPortal, CanSAR Black, and existing literature affirmed the association of these destabilizing mutations with posterior fossa ependymoma, uterine corpus carcinoma, and pediatric brain cancer. The current findings suggest these deleterious nonsynonymous single nucleotide polymorphisms as potential candidates for future functional annotations and validations associated with rare conditions, further aiding the development of precision medicine in rare diseases.

Pamidronate for pain in adult chronic nonbacterial osteitis: protocol of a randomized, double-blind, placebo-controlled trial.

Chronic nonbacterial osteitis (CNO) is a rare auto-inflammatory bone disease affecting children and adults. Adult CNO is characterized by painful bone lesions, primarily of the anterior chest wall. There is no approved therapy for adult CNO. Current off-label treatments include intravenous bisphosphonates, which have been shown to alleviate pain through decreasing bone turnover. However, no adequately powered randomized controlled trials (RCTs) have been conducted. This double-blind, placebo-controlled RCT investigates the efficacy of intravenous pamidronate to decrease bone pain in adult CNO patients. Recruiting at the Dutch national referral center for CNO, adult patients with persistent bone pain despite non-steroidal anti-inflammatory drugs, or optionally other standard-of-care treatments are randomized to receive two courses of intravenous pamidronate (at 0 and 3 mo, 30 mg daily, on 3 consecutive d) or placebo. From 6 mo onwards, all patients receive open-label pamidronate for another two courses. The primary outcome is change in score for maximum pain from 0 to 6 mo. Secondary outcomes include change in quantitative intralesional bone turnover as measured on sodium-fluoride positron emission computed tomography ([18F]NaF-PET/CT), inflammation markers, shoulder function, general health, quality of life, fatigue, physical, and work activity. The pamidronate for pain in adult chronic nonbacterial osteitis trial addresses the need for evidence-based treatments in adult CNO. Results will directly impact daily clinical practice, either validating the use of intravenous pamidronate in CNO at the dose used in this trial or prompting the search for alternative regimens or agents. This trial was registered in EudraCT (reference 2020-001068-27) and the Dutch Trial Register (reference NL68020.058.20).

Exploring What Motivates Parents of Children Living With Medical Complexity to Participate in Research.

BACKGROUND: The study aimed to understand the experience of and identify the motivations for parents participating in health research for their children with medical complexity (CMC). Patient-oriented research strategies are increasingly important in health research to ensure that the voices of patients and parents help shape and direct research programmes. To bring a family-centred and patient-oriented focus to our research and objectives, we asked parents about their experiences when they participated in healthcare research related to their child with CMC. METHODS: A parent partner, who also has a CMC, interviewed 12 parents (11 mothers and 1 father) of children living with medical complexity to understand their motivations to participate in healthcare research for their child. The parent partner conducted and transcribed the interviews and led our data analysis. Interpretive phenomenological analysis (IPA) was used to inform our data coding and analytic process. RESULTS: Parents described numerous reasons for their participation in research about their children. These motivations landed within four main themes: feeling helpless and hopeful, child-centred motivation, being part of something good and forming a relationship with the research team. In addition to these themes, parents highlighted factors that influenced their ability or desire to participate, such as time, capacity and the level of invasiveness for their child. Ultimately, the reflections by parents emphasized their unique lives in caring for their CMC and the need to integrate their lived experiences with the research they engage in. CONCLUSION: This study offers important insights for healthcare teams who want to engage parents of CMC to participate in research. Understanding parents' motivation to participate in research can help researchers create richer engagement and more meaningful experiences for themselves and their participants, thereby bolstering research programmes.