bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-stakeholder sessions on major innovation topics in rare disease clinical trials
Authors: Bodden Daniel , Schoenen Stefanie , Wied Stephanie , Verbeeck Johan , Dirani Maya , Abou Daya Hiba , Heussen Nicole , Molenberghs Geert , Hilgers Ralf-Dieter , Nabbout Rima 
Published: December 2024

Abstract
Background
The European Joint Programme on Rare Diseases aims to enhance the rare diseases research ecosystem by bringing together stakeholders such as research funders, institutions and patient organizations. Work Package 20 focuses on the validation, use and development of innovative methodologies for rare disease clinical trials. This paper reports on the outcomes of a retreat held in April 2023, where areas for innovation and educational needs in rare disease clinical trials were discussed in multi-stakeholder sessions.

Methods
Multi-stakeholder sessions covered the topics: Future Educational System, Randomization in Rare Disease Clinical Trials, Endpoints in Rare Disease Clinical Trials and Using History Course Data. The sessions began with expert presentations to set the scene, followed by guided discussions facilitated by questions on a collaborative digital whiteboard. Participants wrote responses, which were then discussed live with the experts.

Results
Training is needed for diverse stakeholders in rare disease clinical trials to enhance understanding and drive innovation. Challenges include a lack of standardized terminology for multiple endpoints, inadequate understanding of randomization in small sample studies and various obstacles in effectively using natural history data.

Conclusion
Creating a comprehensive and sustainable educational program for rare diseases clinical trial methodology requires strategic collaboration and adherence to FAIR principles. The workshop highlighted the need for innovations for topics in areas such as handling missing data, optimizing the extraction of information from small samples, remote endpoint measurement and new randomized inference techniques. Additionally, integrating innovations into tailored training programs is crucial for advancing the field.
Diagnosis of Diamond-Blackfan anemia in adulthood: case series and review of the literature
Authors: Versino Francesco , Bianchi Paola , Fermo Elisa , Barcellini Wilma , Fattizzo Bruno 
Published: December 2024

AbstractDiamond–Blackfan anemia (DBA) is a rare constitutional inherited bone marrow failure syndrome (iBMF) characterized by progressive severe non-regenerative anemia and congenital abnormalities. Diagnosis is made by identification of a DBA-causing variant, typically in a ribosomal protein gene. More than 99% of patients are diagnosed in the pediatric age, but clinical manifestation may be mild and severe anemia can occur later in the patient’s life. Moreover, the expanding availability of molecular testing is increasing the ability to identify DBA variants also in adults with a non-canonical DBA phenotype. Therefore, adult hematologists must maintain a high clinical suspicion and awareness towards possible DBA diagnosis in adulthood. In this context, the most common differential diagnoses are acquired BMFs such as pure red cell aplasia (PRCA) or hypoplastic myelodysplastic syndrome (MDS). Here, we present three adult patients diagnosed with DBA, where the identification of the causative mutation occurred several years from PRCA misdiagnosis or was made after screening for an affected relative. We also provide a review of 16 cases available in the literature and give hints on possible treatment strategies.
Dementia with lewy bodies patients with high tau levels display unique proteome profiles
Authors: Greally Sinead , Kumar Mukesh , Schlaffner Christoph , van der Heijden Hanne , Lawton Elisabeth S. , Biswas Deeptarup , Berretta Sabina , Steen Hanno , Steen Judith A. 
Published: December 2024

Abstract
Background
Clinical studies have long observed that neurodegenerative disorders display a range of symptoms and pathological features and, in some cases, overlap, suggesting that these diseases exist on a spectrum. Dementia with Lewy Bodies (DLB), a synucleinopathy, is a prominent example, where symptomatic similarities with tauopathy, Alzheimer’s disease, are observed. Although tau pathology has been observed in DLB, the interplay between tau and α-synuclein is poorly understood at a molecular level.

Methods
Quantitative mass spectrometry analysis was used to measure protein abundance in the insoluble fraction from cortical brain tissue from pathologically diagnosed DLB subjects (n = 30) and age-matched controls (n = 29). Using tau abundance, we stratified the DLB subjects into two subgroups termed DLBTau+ (higher abundance) and DLBTau− (lower abundance). We conducted proteomic analysis to characterize and compare the cortical proteome of DLB subjects exhibiting elevated tau, as well as the molecular modifications of tau and α-synuclein to explore the dynamic between tau and α-synuclein pathology in these patients.

Results
Proteomic analyses revealed distinct global protein dysregulations in DLBTau+ and DLBTau− subjects when compared to controls. Notably, DLBTau+ patients exhibited increased levels of tau, along with ubiquitin, and APOE, indicative of cortical proteome alterations associated with elevated tau. Comparing DLBTau+ and DLBTau− groups, we observed significant upregulation of cytokine signaling and metabolic pathways in DLBTau− patients, while DLBTau+ subjects showed increases in protein ubiquitination processes and regulation of vesicle-mediated transport. Additionally, we examined the post-translational modification patterns of tau and α-synuclein. Our analysis revealed distinct phosphorylation and ubiquitination sites on α-synuclein between groups. Moreover, we observed increased modifications on tau specifically within the DLBTau+ subgroup.

Conclusion
This molecular-level data supports the idea of neurodegenerative disease as a continuum of diseases with distinct PTM profiles DLBTau+ and DLBTau− patients in comparison to AD. These findings further emphasize the importance of identifying specific and tailored therapeutic approaches targeting the involved proteopathies in the neurodegenerative disease spectrum.
BRCA2 germline mutation carrier with five malignancies: a case report
Authors: Su Elena , Christinat Yann , McKee Thomas , Azzarello-Burri Silvia , Jochum Wolfram , Fischer Stefanie , Rothermundt Christian 
Published: December 2024

Abstract
Background
BRCA2 germline mutations are known to predispose carriers to various cancer types, including breast, ovarian, pancreatic and prostate cancer. An association with melanoma has also been reported. However, the full tumour spectrum associated with BRCA2 mutations, particularly in patients with other concurrent pathogenetic mutations, is unexplored.

Case presentation
We present a 70-year-old female patient with a pathogenic BRCA2 c.5946del variant. Over a period of 15 years, she has developed two independent breast cancers, well-differentiated liposarcoma, clear cell renal cell carcinoma and myeloproliferative neoplasia. This unusual tumour spectrum and the staggered occurrence of these tumours required multiple rounds of genetic testing and led to a delayed diagnosis of the BRCA2-associated tumour predisposition. In addition to the BRCA2 mutation, extended germline testing revealed an APC c.3920T > A variant and variants of unknown significance in the BRIP1 and ATR genes. The molecular analysis of the tumours revealed distinct profiles with differences in HRD status and in copy number variations, indicating no common origin.

Conclusions
Our case study revealed that the pathogenic BRCA2 c.5946del germline variant can be associated with an unusual tumour spectrum, which may lead to a delayed diagnosis of a hereditary tumour predisposition. Thus, upfront genetic testing using large multigene panels or whole-genome sequencing in encouraged, especially in cases with a prominent family history.
SARS-CoV-2 introductions to the island of Ireland: a phylogenetic and geospatiotemporal study of infection dynamics
Authors: Rice Alan M. , Troendle Evan P. , Bridgett Stephen J. , Firoozi Nejad Behnam , McKinley Jennifer M. ,   The COVID-19 Genomics UK consortium,   National SARS-CoV-2 Surveillance & Whole Genome Sequencing (WGS) Programme, Bradley Declan T. , Fairley Derek J. , Bamford Connor G. G. , Skvortsov Timofey , Simpson David A. 
Published: December 2024

Abstract
Background
Ireland’s COVID-19 response combined extensive SARS-CoV-2 testing to estimate incidence, with whole genome sequencing (WGS) for genome surveillance. As an island with two political jurisdictions―Northern Ireland (NI) and Republic of Ireland (RoI)―and access to detailed passenger travel data, Ireland provides a unique setting to study virus introductions and evaluate public health measures. Using a substantial Irish genomic dataset alongside global data from GISAID, this study aimed to trace the introduction and spread of SARS-CoV-2 across the island.

Methods
We recursively searched for 29,518 SARS-CoV-2 genome sequences collected in Ireland from March 2020 to June 2022 within the global SARS-CoV-2 phylogenetic tree and identified clusters based on shared last common non-Irish ancestors. A maximum parsimony approach was used to assign a likely country of origin to each cluster. The geographic locations and collection dates of the samples in each introduction cluster were used to map the spread of the virus across Ireland. Downsampling was used to model the impact of varying levels of sequencing and normalisation for population permitted comparison between jurisdictions.

Results
Six periods spanning the early introductions and the emergence of Alpha, Delta, and Omicron variants were studied in detail. Among 4439 SARS-CoV-2 introductions to Ireland, 2535 originated in England, with additional cases largely from the rest of Great Britain, United States of America, and Northwestern Europe. Introduction clusters ranged in size from a single to thousands of cases. Introductions were concentrated in the densely populated Dublin and Belfast areas, with many clusters spreading islandwide. Genetic phylogeny was able to effectively trace localised transmission patterns. Introduction rates were similar in NI and RoI for most variants, except for Delta, which was more frequently introduced to NI.

Conclusions
Tracking individual introduction events enables detailed modelling of virus spread patterns and clearer assessment of the effectiveness of control measures. Stricter travel restrictions in RoI likely reduced Delta introductions but not infection rates, which were similar across jurisdictions. Local and global sequencing levels influence the information available from phylogenomic analyses and we describe an approach to assess the ability of a chosen WGS level to detect virus introductions.
Neutrophil extracellular traps and oxidative stress in systemic lupus erythematosus patients with and without renal involvement
Authors: Liu Lu , de Leeuw Karina , van Goor Harry , Doornbos-van der Meer Berber , Arends Suzanne , Westra Johanna 
Published: December 2024

Abstract
Objectives
To investigate the levels of plasma neutrophil extracellular traps (NETs) and free thiols, the latter reflecting systemic oxidative stress (OS), and to explore the relationship between NETs and OS in quiescent systemic lupus erythematosus (SLE) patients with and without renal involvement.

Methods
Plasma levels of NETs and free thiols were measured cross-sectionally in 100 SLE patients with low disease activity (SLEDAI < 5), of whom 73 patients had no renal involvement (non-LN) and 27 patients had lupus nephritis (LN). Additionally, 22 healthy controls (HCs) were included. NETs were measured using a myeloperoxidase-DNA complex ELISA and free thiols were measured using a thiol assay kit.

Results
NETs levels were significantly higher in both non-LN and LN patients compared to HCs (p < 0.001, p = 0.013), with no difference between the two patient groups (p = 0.799). Free thiol levels were not significantly different between groups. Interestingly, NETs were negatively correlated with free thiols in all 100 SLE patients (rho = -0.32) and non-LN patients (rho = -0.38), but not in LN patients. Levels of free thiols were significantly lower in subgroups of patients with estimated glomerular filtration rate (eGFR) < 60, serum creatinine (sCr) ≥ 90, C reactive protein (CRP) levels ≥ 5 and body mass index (BMI) ≥ 30. In multivariable regression, disease duration, NETs levels, and eGFR were independently associated with free thiol levels.

Conclusions
Levels of NETs were increased in quiescent SLE patients. Although free thiol levels did not differ among the groups. The levels of NETs and free thiols were independently associated in SLE patients, suggesting a potential role of OS in NETs formation. Therefore, reducing OS might be an additional therapeutic target for SLE treatment.
Structural validity of the Brazilian version of the quality care questionnaire-palliative care for use in individuals with diabetes mellitus eligible for palliative care
Authors: Mendes-Júnior Abraão Albino , Santos-de-Araújo Aldair Darlan , de Oliveira Silva Santos Leonel Richard , Ladeira Lorena Lúcia Costa , Ferreira Meire Coelho , Godim Louise Aline Romão , Maia Mariana Campos , de Farias Diniz Marinete Rodrigues , Dibai-Filho Almir Vieira , Bassi-Dibai Daniela 
Published: December 2024

Abstract
Background
The Brazilian version of the Quality Care Questionnaire-Palliative Care (QCQ-PC) is an instrument designed to assess the quality of care provided in palliative care from the user’s perspective, featuring easy comprehension and applicability. It has demonstrated validity for use in individuals with cancer, but there is a need for validation in other populations due to the scarcity of instruments with this purpose.

Objective
To structurally validate the Brazilian version of the QCQ-PC for use in individuals with diabetes mellitus (DM) eligible for palliative care.

Methods
This is a structural validation study of a questionnaire according to the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN). The study was conducted with 100 individuals with DM. Data collection occurred in differents care services in São Luís (northeast Brazil) by means of the application of the QCQ-PC and a form with sociodemographic, clinical, and daily habit data. Descriptive data analysis was performed using absolute values, relative frequencies, and measures of central tendency and dispersion. Structural validity was assessed by means of exploratory factor analysis (EFA).

Results
Of the 100 participants included in the study, 66% were female, 54% were single, with a median age of 64 years, 44% were overweight (44%), 77% were on polypharmacy, and 70% were physically inactive. We found that one domain is the most appropriate for use of the QCQ-PC in individuals with DM eligible for palliative care, according to the parallel analysis implemented in the EFA. This domain was named “quality of care”. The fit indices for this one-dimensional internal structure were adequate: Kaiser–Meyer–Olkin test = 0.71, p value < 0.01 in Bartlett’s test, chi-square/degree of freedom = 1.07, comparative fit index = 0.993, Tucker-Lewis index. = 0.991, root mean square error of approximation = 0.028. The QCQ-PC presented factor loadings ranging from 0.480 to 0.883, maintaining a total of 12 items, which demonstrates the adequate relationship between the quality of care domain and its items.

Conclusion
Therefore, the internal structure with one domain (quality of care) is the most suitable for use in individuals with DM eligible for palliative care by means of the QCQ-PC.
SDG 18 for sustainable space exploration
Authors: Zimon Dominik , Lysenko-Ryba Kateryna , Szocik Konrad 
Published: December 2024

AbstractThe aim of this study is to fill out the gap that exists in the literature by discussing the main problems and barriers to sustainable development in space and the initial proposal to adopt SDG 18. Despite the fact that the subject of the sustainable development of space is little researched, it seems that in order to be able to properly prepare for it, a broader debate on this subject should now be undertaken. This is due to the fact that this issue is undoubtedly complex and multifaceted. The starting point for the development of SDG 18 seems to be the discussion of issues such as: sustainable financing of space exploration, laws and treaties. The considerations undertaken in the article may be helpful for government organizations in creating future sustainable development strategies. Business representatives will receive valuable information on the constraints associated with the implementation of space programs. On the other hand, scientists can treat the article as a starting point for deliberations on the 18 SDG and pose further questions to deepen the issues outlined in the article, and develop the 18 goal with further aspects omitted in this study.
3D analysis of soft tissue dimensional changes after dental implant placement with butt-joint vs. conical connection: a 12-month randomized control trial
Authors: Derakhshani André-Joubin , Beuer Florian , Wernfried Heinrich Böse Mats , Herklotz Insa , Unkovskiy Alexey 
Published: December 2024

Abstract
Purpose
to quantify the soft tissue dimensional changes after single-gap implant placement, during healing abutment and crown delivery phase for butt-joint and conical implant-abutment connection type.

Methods
forty patients were enrolled in the study and received randomly allocated implants with butt-joint and conical implant-abutment connection type. A standard healing abutment was placed after 6 months for two weeks. The definitive screw retained full-ceramic crowns were manufactured in a digital workflow. The soft tissue profile was digitized using IOS on following stages: pre-op, immediately, two, 7 and 14 days post-op, pre-exposure, immediately after exposure, two weeks after exposure (pre-delivery), immediately after crown delivery, 6 and 12 months after delivery. The intraoral scans were matched in the metrology software (Geomagic Control X). The mean maximum and mean average differences in mm were gathered to assess the soft tissues change. Various anamnesis parameters have been taken into account.

Results
the conical connection implant system exhibited more soft tissue gain and less recession, compared to the butt-joint connection type within the 12 months follow-up period. A higher loss of soft tissue was observed in the distal papilla than in the mesial one.

Conclusions
the implant-abutment connection type may influence the reaction of peri-implant soft tissue within the 12 months follow-up period.
A co-designed intervention to support people living with achalasia to eat in a social setting: a feasibility study
Authors: Kalantari Melika , Hollywood Amelia , Lim Rosemary , Hashemi Majid 
Published: December 2024

Abstract
Background
Achalasia is a rare oesophageal condition that can affect eating behaviours. This study aimed to evaluate the feasibility of recruitment and assess the acceptability of a co-designed, workbook-based intervention targeting one of the most challenging eating behaviours, which was eating in a social setting.

Methods
A mixed-method approach was employed, which involved pre- and post-intervention questionnaires and semi-structured interviews. The Achalasia Action group, a UK-based support group, facilitated participant recruitment. The intervention was a workbook designed collaboratively by the researchers and people living with achalasia, with strategies built on the COM-B model (Capability, Opportunity, Motivation-Behaviour). Outcome measures were based on recruitment and retention rates, the APEASE criteria for usability and acceptability, self-reported changes in eating behaviours, and qualitative feedback from participant interviews.

Results
The study aimed to recruit 20 participants, and this target was achieved, resulting in a 100% recruitment rate. However, the post-intervention questionnaires were completed by only 10 participants, indicating a 50% retention rate from baseline. No issues were raised with completing the pre- and post-questionnaires, from completers. The quantitative feedback from participants indicated that they found the workbook activities clear, easy to understand, and complete, with the majority reporting positive experiences. Qualitative feedback on the intervention described enhanced social support and improved symptom management of achalasia in a social setting. Furthermore, the intervention met the APEASE criteria, indicating its usability and acceptability.

Conclusions
This study explored the feasibility of recruiting and retaining people living with achalasia in intervention research, highlighting the acceptability of the co-designed intervention to improve social eating experiences. However, with a retention rate of only 50% at follow-up, it is evident that future studies should explore the reason behind this and also consider recruiting a larger baseline sample to ensure the target is achieved. The positive outcomes of the co-designed intervention underscore the importance of user involvement in developing interventions. The intervention demonstrated the potential to support people living with achalasia in eating in a social setting. The co-designed intervention has significant practical implications by providing healthcare professionals and support groups with a feasible, potentially effective method to enhance the social eating experience of people living with achalasia, potentially improving their overall quality of life.
Utility of platelet indices as a diagnostic indicator of hemodynamically significant PDA in preterm infants: a comparative cross-sectional study
Authors: Elbahy Samar Mahmoud , Ali Ola Galal , Ali Sara Soliman , Ali Ali Galal , Abdelrahman Eman Gamal 
Published: December 2024

Abstract

Background
Among preterm babies, patent ductus arteriosus (PDA) is a prevalent condition, and hemodynamically significant patent ductus arteriosus (hsPDA) constitutes an important problem that impacts their outcome. There has previously been a connection between platelet dysfunction and the hemodynamic significance of PDA. However, the results are conflicting, and more research is warranted. In this study, we investigated the relation of hsPDA with different platelet indices. In addition, we assessed the impact of hsPDA on patient outcomes, including hospital admission and survival rate.

Methods
This comparative cross-sectional study involved 150 preterm neonates (≤ 34 weeks gestational age) admitted to the neonatal intensive care unit. Following evaluation using the clinical Kindler score, echocardiography was used to confirm the diagnosis of hsPDA. A complete blood count comprising all platelet parameters and C-reactive protein was performed on the first day of life, and the association with the hsPDA was examined. Information was gathered about hospital stay duration, survival rates, and comorbidities.

Results
Platelet distribution width (PDW) was significantly higher in the hsPDA group than in the non-hsPDA group, p = 0.001. The receiver operating characteristic (ROC) curve analysis revealed a significant correlation of hsPDA with high PDW (p < 0.000) and clinical Kindler score (p < 0.001). High PDW and clinical Kindler score were found to be independent predictors of hsPDA by multivariate logistic regression analysis (odds ratio = 1.289, p = 0.004) for PDW, and (odds ratio = 3.452; p = 0.001) for clinical Kindler score. Regarding patient outcome, the hsPDA group demonstrated significantly longer hospitalization duration and higher respiratory complications and mortality rates.

Conclusions
PDW and clinical Kindler score were found to be significantly correlated with hsPDA, and both were independent predictors of hsPDA. The hsPDA has dramatically impacted patient outcomes, including higher incidence of respiratory complications, and subsequently longer hospitalization, and higher mortality.