bluuebunny/crossref_metadata_2025_split huggingface dataset:
Review article: Recommendations for detection, assessment and management of suspected drug‐induced liver injury during clinical trials in oncology patients
Authors: Fettiplace Anna , Marcinak John , Merz Michael , Zhang Hui‐Talia , Kikuchi Luciana , Regev Arie , Palmer Melissa , Rockey Don , Fontana Robert , Hayashi Paul H. , Tillmann Hans L. , Di Bisceglie Adrian M. , Lewis James H. 
Published: September 2024

SummaryBackgroundDrug‐induced liver injury (DILI) is a major concern for oncology drugs in clinical practice and under development. Monitoring cancer patients for hepatotoxicity is challenging as these patients may have abnormal liver tests pre‐treatment or on‐study for many reasons including liver injury due to past oncology treatments, hepatic metastases, medical co‐morbidities such as heart failure, and concomitant medications. At present, there are no regulatory guidelines or position papers that systematically address best practices pertaining to DILI detection, assessment and management in oncology patients.AimsThe goals of this review are (1) to examine and interpret the available evidence and (2) to make recommendations for detection, monitoring, adjudication, and management of suspected hepatocellular DILI during oncology clinical trials.MethodsThis manuscript was developed by the IQ Consortium (International Consortium for Innovation and Quality in pharmaceutical development) DILI Initiative that consists of members from 17 pharmaceutical companies, in collaboration with academic and regulatory DILI experts. The manuscript is based on extensive literature review, expert interpretation of the literature, and several rounds of consensus discussions.ResultsThis review highlights recommendations for patient eligibility for clinical trials with or without primary/metastatic liver involvement, as well as changes in liver tests that should trigger increased monitoring and/or discontinuation of study drug. Guidance regarding causality assessment for suspected DILI events, rechallenge and dose‐modification is provided.ConclusionsThis review brings together evidence‐based recommendations and expert opinion to provide the first dedicated consensus for best practices in detection, assessment, and management of DILI in oncology clinical trials.
“I Forgot My Numbers and the Machine Swallowed It Up”: Adults With Learning Disabilities Share Their Perspectives on the Shift to a Cashless Society
Authors: Watts Paul , Hoskin Janet , Upadhyay Radhika , Tapley Emma , Kwiatkowska Gosia 
Published: September 2024

ABSTRACTIntroductionThis paper examines the experiences of people with learning disabilities in the United Kingdom as society transitions towards cashless transactions and services. It is a significant study because it highlights the need to understand their digital financial experiences.MethodsThis study employed an inclusive, interpretivist approach, focusing on participatory methods. Reflexive thematic analysis was used to analyse data from focus groups including 40 people with learning disabilities across 3 day services. This original study included co‐researchers with lived experience of learning disabilities who assisted in data collection and analysis.ResultsFour key themes emerged: heterogeneity of preferences for cash versus digital payments; the urgent need for support and training in digital financial literacy; balancing safeguarding and fostering independence; and accessibility challenges in physical and online banking environments.ConclusionsThe shift to a cashless society poses significant challenges for people with learning disabilities, requiring tailored support and training in digital finance. Financial institutions should be cognisant of these needs, suggesting that systemic changes are required for improved financial inclusion. The study highlights the importance of including people with learning disabilities in the design of digital financial tools and policies, to support their financial autonomy and independence.
Selective modulation of epileptic tissue by an adenosine A3 receptor‐activating drug
Authors: Ghosh Anwesha , Ribeiro‐Rodrigues Leonor , Ruffolo Gabriele , Alfano Veronica , Domingos Cátia , Rei Nádia , Tosh Dilip K. , Rombo Diogo M. , Morais Tatiana P. , Valente Cláudia A. , Xapelli Sara , Bordadágua Beatriz , Rainha‐Campos Alexandre , Bentes Carla , Aronica Eleonora , Diógenes Maria José , Vaz Sandra H. , Ribeiro Joaquim A. , Palma Eleonora , Jacobson Kenneth A. , Sebastião Ana M. 
Published: September 2024

AbstractBackground and PurposeAdenosine, through the A1 receptor (A1R), is an endogenous anticonvulsant. The development of adenosine receptor agonists as antiseizure medications has been hampered by their cardiac side effects. A moderately A1R‐selective agonist, MRS5474, has been reported to suppress seizures without considerable cardiac action. Hypothesizing that this drug could act through other than A1R and/or through a disease‐specific mechanism, we assessed the effect of MRS5474 on the hippocampus.Experimental ApproachExcitatory synaptic currents, field potentials, spontaneous activity, [3H]GABA uptake and GABAergic currents were recorded from rodent or human hippocampal tissue. Alterations in adenosine A3 receptor (A3R) density in human tissue were assessed by Western blot.Key ResultsMRS5474 (50–500 nM) was devoid of effect upon rodent excitatory synaptic signals in hippocampal slices, except when hyperexcitability was previously induced in vivo or ex vivo. MRS5474 inhibited GABA transporter type 1 (GAT‐1)‐mediated γ‐aminobutyric acid (GABA) uptake, an action not blocked by an A1R antagonist but blocked by an A3R antagonist and mimicked by an A3R agonist. A3R was overexpressed in human hippocampal tissue samples from patients with epilepsy that had focal resection from surgery. MRS5474 induced a concentration‐dependent potentiation of GABA‐evoked currents in oocytes micro‐transplanted with human hippocampal membranes prepared from epileptic hippocampal tissue but not from non‐epileptic tissue, an action blocked by an A3R antagonist.Conclusion and ImplicationsWe identified a drug that activates A3R and has selective actions on epileptic hippocampal tissue. This underscores A3R as a promising target for the development of antiseizure medications.
Vortioxetine reduces the development of pain‐related behaviour in a knee osteoarthritis model in rats: Involvement of nerve growth factor (NGF) down‐regulation
Authors: Tomić Maja , Nastić Katarina , Dinić Miroslav , Brdarić Emilija , Kotur‐Stevuljević Jelena , Pecikoza Uroš , Pavićević David , Micov Ana , Milenković Danijela , Jovanović Aleksandar , Stepanović‐Petrović Radica 
Published: September 2024

AbstractBackground and PurposeVortioxetine, a multimodal‐acting antidepressant, has recently shown analgesic properties. We aimed to investigate its prophylactic effect in the osteoarthritis (OA) model and gain insights into the underlying molecular mechanisms. Duloxetine was studied as a reference.Experimental ApproachIn the monoiodoacetate (MIA)‐induced rat model of knee OA, pain‐related behaviour was assessed in weight‐bearing and Von Frey tests. Antidepressants were administered orally once daily for 28 days. Gene expression of pain‐related mediators (Ngf, Il‐1β, Tnf‐α, Bdnf, and Tac1 encoding substance P) and oxidative stress parameters were determined after completion of the treatment/behavioural testing protocol.Key ResultsVortioxetine and duloxetine dose dependently reduced weight‐bearing asymmetry and mechanical hyperalgesia of the paw ipsilateral to the MIA‐injected knee. Vortioxetine reduced the increased Ngf mRNA expression in the MIA‐injected knees to the level in sham‐injected counterparts. It reduced oxidative stress parameters in the affected knees, more effectively in females than males. Duloxetine showed no effect on Ngf mRNA expression and oxidative stress. Both antidepressants decreased mRNA expression of pain‐related mediators in the lumbar L3–L5 ipsilateral DRGs and spinal cords, which were up‐regulated in MIA‐injected rats. This effect was male‐specific.Conclusion and ImplicationsVortioxetine may be effective against the development of chronic pain in OA. Its antihyperalgesic effect may be mediated, at least in part, by normalization of NGF expression in the affected joint. Decrease of localized oxidative stress and of expression of pain‐related mediators that contribute to central sensitization are also involved in vortioxetine's antihyperalgesic effect, in a sex‐specific pattern.
Epithelial Interleukin‐1 Receptor‐Like‐1 Activation Is Contingent on Interleukin‐33 Isoforms and Asthma‐Related Receptor Variation
Authors: Portelli Michael A. , Ketelaar Maria E. , Bates Stewart , Csomor Eszter , Shaw Dominick , Emsley Jonas , Brightling Christopher , Hall Ian , Affleck Karen , Edwards Matthew , Nawijn Martijn C. , Koppelman Gerard H. , Van Oosterhout Antoon J. , Sayers Ian 
Published: September 2024

ABSTRACTIntroductionThe interleukin‐33/interleukin‐1 receptor‐like‐1 (IL‐33/IL1RL1) signalling pathway is implicated in asthma pathogenesis, with IL1RL1 nonsynonymous genetic polymorphisms associated with disease risk. We aimed to determine these variants' effect on IL1RL1 signalling induced by different IL33 isoforms thought to be elevated in the asthmatic airway.MethodIn a project funded by GSK plc, which has developed an IL‐33 receptor inhibitor for asthma treatment, human embryonic kidney 293 (HEK293) cells expressing secreted embryonic alkaline phosphatase (SEAP) driven by a nuclear factor kappa‐beta (NF‐κB) promoter, were transiently transfected with IL1RL1, containing one of four extracellular and Toll/interleukin 1 receptor (TIR) domain haplotypes. Cells were stimulated with seven different splice and proteolytic‐generated IL‐33 isoforms (0.001–50 ng/mL) for 24 h. Supernatant SEAP activity and interleukin‐8 (IL‐8) levels were determined. Primary human bronchial epithelial cells (HBECs) representing different genotype carriers were stimulated with IL‐33112–270 (50 ng/mL) and induced IL‐8 mRNA expression measured.ResultsHEK293 cells carrying both asthma extracellular and TIR domain IL1RL1 risk haplotypes presented maximal IL33‐driven signalling, with minimal signalling after IL‐33 activation in other protective haplotypes. All IL‐33 isoforms activated IL1RL1 but with differing magnitudes. Proteolytically cleaved IL3395–270 and IL33106–270 had the greatest effect and the IL33113–270, and Exon 3,4 deletion isoform exhibited the lowest. The effect of extracellular and TIR domain genetic variants on receptor signalling was replicated in primary HBECs. Maximal IL1RL1 signalling was observed in cells carrying both extracellular and TIR signalling domain risk haplotypes.ConclusionsOverall, our study suggests asthma patients carrying the extracellular and TIR domain risk haplotype and have a lung microenvironment that promotes elevated levels of cleaved IL33, particularly where IL3395–270 and IL33106–270 may be more amenable to IL33/IL1RL1 targeting.
Use of autologous micrografts associated with xenogeneic anorganic bone in vertical bone augmentation procedures with Barbell Technique®
Authors: Cosmo Luiz Antonio Mazzucchelli , Coutinho Reginaldo Machado , de Macedo Luís Guilherme Scavone , Aloise Antonio Carlos , Jayme Sérgio Jorge , Zeferino João Pedro Grandini , Graziano Antonio , Martinez Elizabeth Ferreira , Moy Peter Karyen , Pelegrine André Antonio 
Published: September 2024

AbstractIntroductionBidirectional vertical ridge augmentation in the posterior maxilla is very challenging.PurposeTo evaluate the regenerative potential of micrografts, derived from periosteum or bone tissue, added to an anorganic xenograft in vertical reconstruction of the posterior maxilla, by a prospective, controlled study.Materials and methodsAfter clinical selection and the analysis of CBCT scans, 24 posterior maxillary sites, in 19 patients, were treated by using Barbell Technique®. Sites requiring both inlay and onlay reconstruction were enrolled in the study. In the Control Group (CG, n = 8), a xenograft was used in the inlay site and for the onlay site, a 1:1 mix of xenograft and an autograft was used. In Test Group 1 (TG1, n = 8), both inlay and onlay sites were grafted with the xenograft associated with the micrografts derived from periosteum. In Test Group 2 (TG2, n = 8), both inlay and onlay sites were grafted with the xenograft associated with the micrografts derived from bone. Six months after the procedures, CBCT scans were obtained, and bone biopsy samples were harvested during implant placement surgery. The bone specimens were analyzed histomorphometrically, by measuring the percentages of vital mineralized tissue (VMT), non vital mineralized tissue (NVMT) and non mineralized tissue (NMT). Immunohistochemically, the levels of VEGF were categorized by a score approach.ResultsHistomorphometric analysis revealed, for the inlay grafts, no significant difference among the groups for VMT, NVMT and NMT. However, for onlay grafts, CG achieved a higher amount of VMT in comparison with TG2, and the opposite occurred for NMT values. In this regard, no statistical difference was observed between CG and TG1. Concerning immunohistochemistry, the VEGF values for CG and TG1 were slightly higher than those obtained by TG2 for both inlay and onlay grafts, but without statistical significance. CBCT analysis showed a similar level of gain for all groups, for both inlay and onlay bone augmentation sites. Clinically, one implant (in CG) within a total of 50 implants installed, had early failure and was replaced after 3 months. All patients received implant supported prosthesis.ConclusionThis study indicated that the clinical use of micrograft derived from periosteum may have some potential to increase bone formation in onlay reconstructions, unlike the micrograft derived from bone tissue.
Comparison of surface micro‐roughness and adaptation of titanium and cobalt chrome implant abutment fabricated by selective laser melting and conventional techniques
Authors: Albaijan Refal , Vohra Fahim , Alnassar Talal M. , Robaian Ali , Alnafaiy Sarah M. , Murayshed Mohammed S. , Alnasser Abdullah H. , Alshehri Abdullah , Gufran Khalid 
Published: September 2024

AbstractPurposeThe objective of this study was to assess the surface micro‐roughness and abutment adaptation of selective laser melting (SLM) implant abutments in comparison to cast and machined implant abutments.MethodsForty abutment specimens were divided equally into four groups according to the fabrication technique as follows (n = 10), Machined Ti alloy abutments (Control), Cast CoCr abutments, SLM‐CoCr abutments, and SLM‐Ti alloy abutments. Forty internal connection implants (Ø 4.0 ×10 mm, Superline™, Dentium Co., Seoul, Korea) were mounted in clear acrylic resin. Fabricated abutments were assessed for surface micro‐roughness using a 3D optical noncontact surface microscope. Vertical and horizontal adaptation of the abutment with implant interface was assessed by using Bruker micro‐CT. Data was assessed using analysis of variance and Tukey post hoc comparison tests for all the variables except vertical misfit was assessed using Kruskal–Wallis test. Pearson correlation was used to assess dependence between independent variable (surface roughness) and dependent variables (Horizontal misfit and vertical misfit).ResultsSLM‐Ti abutments showed significantly rougher surface (p < 0.05) among the study groups. While SLM‐CoCr abutments were smoother than Cast abutments with mean Ra of 1.30 ± 0.11 and 1.58 ± 0.17 μm, respectively (p < 0.05). For abutment adaptation, SLM‐Ti abutments showed the highest horizontal misfit among the groups (p < 0.05). While, SLM‐CoCr abutments (29.24 ± 11.11 μm) showed comparable (p > 0.05) horizontal misfit results with Cast (26.08 ± 3.93 μm) and machined (26.45 ± 7.33 μm) abutments. Comparable (p > 0.05) vertical misfit values between Cast CoCr (487.01 ± 40.34 μm), SLM‐CoCr (358.38 ± 114.93 μm) and SLM‐Ti (299.85 ± 172.88 μm) abutments were observed. A positive correlation was found between the surface roughness of the mating surfaces and abutment adaptation.ConclusionSLM CoCr abutments exhibited low roughness and comparable abutment adaptation (vertically and horizontally) than cast (control) abutments. Therefore, SLM CoCr abutments should be clinically investigated as potential implant abutments for clinical use.
Dynamic functional network connectivity and its association with lipid metabolism in Alzheimer's disease
Authors: Zang Feifei , Liu Xinyi , Fan Dandan , He Cancan , Zhang Zhijun , Xie Chunming ,   for the Alzheimer's Disease Neuroimaging Initiative,   for the Alzheimer's Disease Metabolomics Consortium
Published: September 2024

AbstractAimsThe study aims to examine the changing trajectory characteristics of dynamic functional network connectivity (dFNC) and its correlation with lipid metabolism‐related factors across the Alzheimer's disease (AD) spectrum populations.MethodsData from 242 AD spectrum subjects, including biological, neuroimaging, and general cognition, were obtained from the Alzheimer's Disease Neuroimaging Initiative for this cross‐sectional study. The study utilized a sliding‐window approach to assess whole‐brain dFNC, investigating group differences and associations with biological and cognitive factors. Abnormal dFNC was used in the classification of AD spectrum populations by support vector machine. Mediation analysis was performed to explore the relationships between lipid‐related indicators, dFNC, cerebrospinal fluid (CSF) biomarkers, and cognitive performance.ResultsSignificant group difference concerning were observed in relation to APOE‐ε4 status, CSF biomarkers, and cognitive scores. Two reoccurring connectivity states were identified: state‐1 characterized by frequent but weak connections, and state‐II characterized by less frequent but strong connections. Pre‐AD subjects exhibited a preference for spending more time in state‐I, whereas AD patients tended remain in state‐II for longer periods. Group difference in dFNC was primarily found between AD and non‐AD participants within each state. The dFNC of state‐I yielded strong power to distinguish AD from other groups compared with state‐II. APOE‐ε4+, high polygenic score, and high serum lipid group were strongly associated with network disruption between association cortex system and sensory cortex system that characterized elevation of cognitive function, which may suggest a compensatory mechanism of dFNC in state‐I, whereas differential connections of state‐II mediated the relationships between APOE‐ε4 genotype and CSF biomarkers, and cognitive indicators.ConclusionThe dysfunction of dFNC temporal–spatial patterns and increased cognition in individuals with APOE‐ε4, high polygenic score, and higher serum lipid levels shed light on the lipid‐related mechanisms of dynamic network reorganization in AD.
Long‐term outcomes after cleft lift surgery for pilonidal sinus disease in post‐pubertal adolescents: data from a prospective Danish cohort
Authors: Ankersen J. L. , Faurschou I. K. , Hougaard H. T. , Doll D. , Oetzmann von Sochaczewski C. , Sørensen M. , Pedersen A. G. , Haas S. 
Published: September 2024

AbstractAimPilonidal sinus disease (PSD) is a common condition. Despite a relatively large proportion of patients presenting as post‐pubertal adolescents, only small cohorts focusing on this PSD subcategory have been published, and surgical treatment remains challenging.MethodThe study is based on a prospective database established at Randers Regional Hospital in 2016. All patients undergoing Bascom's cleft lift (BCL) surgery from June 2016 until June 2020 were included in this study, focusing on patients ≤18 years of age comparing them to adult patients. Indications for BCL surgery were primary extensive manifestation, non‐healing disease after previous elective surgery or disease recurrence.ResultsIn total, n = 380 PSD patients were operated, of which n = 79 were post‐pubertal adolescents with a median age at time of surgery of 17.2 years (interquartile range 16.3, 18.0). Sixty‐six (84%) were boys. Twenty‐seven (34%) presented with primary extensive manifestation, 34 (43%) due to non‐healing wounds and 18 (23%) due to recurrence. Fifty‐four patients (69%) healed uneventfully. There was no difference between the indications of surgery groups in terms of overall healing or time to healing if prolonged (P = 0.6). The median follow‐up was 62 months (interquartile range 48, 73), with a 5‐year recurrence rate of 19%, compared to 17% (P = 0.6) in the adult population.ConclusionOur study is the first to investigate long‐term clinical outcomes of BCL surgery for PSD in post‐pubertal adolescent patients. Recurrences seem to occur more frequently compared to adults. However, we demonstrate that post‐pubertal adolescent patients with advanced PSD can be treated with BCL surgery with acceptable outcomes.
Diabetes mellitus and adverse clinical events in patients with atrial fibrillation: A report from the GLORIA‐AF registry phase III
Authors: Liu Yang , Chen Yang , Lam Steven H. M. , Huang Bi , Romiti Giulio F. , Alam Uazman , Chao Tze Fan , Olshansky Brian , Hong Kui , Huisman Menno V. , Lip Gregory Y. H. ,   the GLORIA‐AF Investigators
Published: September 2024

AbstractAimsAtrial fibrillation (AF) and diabetes mellitus (DM) are both associated with adverse clinical events, but the associations have not been fully elucidated, particularly with concomitant insulin use. This study aimed to analyse the associations between adverse events and DM, as well as adverse events and sole insulin use.Materials and MethodsOur analysis included individuals with AF from the prospective Global Registry on Long‐Term Oral Anti‐Thrombotic Treatment in Patients with Atrial Fibrillation (GLORIA‐AF) registry with 3‐year follow‐up. Outcomes included all‐cause death, major bleeding, cardiovascular (CV) death, myocardial infarction (MI), stroke, thromboembolism and major adverse cardiovascular events (MACE).ResultsA total of 15 861 AF individuals were included (age 70.0 ± 10.2 years; 55% male, 20% Asian), of whom, 3666 had DM (age 70.0 ± 9.5 years ; 59% male, 21% Asian). After adjustment, those with DM had higher risks of all‐cause death (hazard ratio [HR]: 1.46, 95% confidence interval [CI]: 1.28–1.66), CV death (HR: 1.53 95% CI: 1.27–1.86), major bleeding (HR: 1.23, 95% CI: 1.01–1.48), MI (HR: 1.50, 95% CI: 1.17–1.94) and MACE (HR: 1.42, 95% CI: 1.23–1.63). Compared to individuals with DM receiving oral hypoglycaemic agents, those receiving insulin alone were associated with increased risks of all‐cause death (HR: 2.16, 95% CI: 1.61–2.91), CV death (HR: 2.24, 95% CI: 1.45–3.47), major bleeding (HR: 1.89, 95% CI: 1. 21–2.95), MI (HR: 2.24, 95% CI: 1.31–3.82) and MACE (HR: 2.11, 95% CI: 1.54–2.88).ConclusionsDM was independently associated with higher risks of all‐cause death, CV death, MI, major bleeding and MACE in AF individuals. Individuals receiving insulin alone were associated with higher risks of all‐cause death, CV death, MI, major bleeding and MACE.