bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Midbrain Organoids Enriched With Dopaminergic Neurons for Long‐Term Functional Evaluation
Authors: Wang Xinyue , Sun Gaoying , Tang Mingming , Li Da , Qi Jianhuan , Wang Chuanyue , Wang Yukai , Hu Baoyang 
Published: February 2025

ABSTRACTHuman midbrain organoids with functional dopaminergic (DA) neurons are invaluable for the therapeutic development of Parkinson's disease (PD). However, current methods face significant limitations, including challenges in generating pint‐sized organoids enriched with DA neurons and the lack of robust functional assays for efficiently evaluating neural networks over extended periods. Here we present an innovative approach that combines developmental patterning with mechanical cutting to produce small midbrain organoids, with diameters less than 300 μm, suitable for long‐term evaluation, along with a comprehensive functional assay system consisting of calcium transient assay, neurite extension assay, and multielectrode array (MEA) assay. Radial cutting of organoids into four to eight portions according to their sizes at the appropriate developmental stage significantly increases the yield of viable organoids while reducing necrotic cell regions. Using the functional assay system, we demonstrate that DA neurons within the organoids extend long projections, respond to dopamine stimulation, and form neural networks characterised by giant depolarising potential‐like events. Our approach supports the generation of midbrain organoids and PD models that can be used for long‐term functional testing.
The Risk Factors and Predictors of Chronic Obstructive Pulmonary Disease in Patients With Obstructive Sleep Apnea–Hypopnea Syndrome at Plateau
Authors: Geng Yumei , Hu Yu , Li Bin , Dawa Zhuoma , Zhang Fang 
Published: February 2025

ABSTRACTBackgroundOSAHS patients with COPD (i.e., overlap syndrome) have a significantly worse prognosis than those with OSAHS alone, and the role of plateau hypoxia in the occurrence of the disease is still unclear. This underscores the urgent need to explore the risk factors for the incidence of COPD in patients with OSAHS and to identify predictors for the occurrence of overlap syndrome at plateau.MethodsFifty patients with OSAHS and 34 patients with overlap syndrome were enrolled in this study. Demographic, auxiliary examination, and laboratory data were collected.ResultsAll patients enrolled were obstructive sleep apnea–hypopnea syndrome. The apnea–hypopnea index (AHI), the number of hypopnea, and the oxygen desaturation index were higher in the group of patients with overlap syndrome than in the group of patients with OSAHS. The mean pulse oxygen saturation was lower than that in the group of patients with OSAHS (p < 0.05). The right heart structure and function indexes (PASP, right atrial transverse diameter, RVTD, BNP, TNI) in patients with overlap syndrome were worse than those in patients with OSAHS (p < 0.05), and this worse cardiovascular status was positively correlated with inflammatory factors such as high‐sensitivity C‐reactive protein, IL‐6, and PCT (p < 0.05). Binary logistic regression analysis indicated that PASP, smoking index, and AHI were independent risk factors for OSAHS developing into overlap syndrome. ROC curve showed that the area under the curve of the combination of the three markers for predicting overlap syndrome was 0.908 (95% CI 0.843–0.974, p = 0.000), with a sensitivity of 0.882 and a specificity of 0.820. The optimal cutoff values for PASP were 42.5 mmHg, 15 for the smoking index, and 25.65 for the AHI based on the Youden index.ConclusionsOur study reveals that overlap syndrome has more frequent nighttime hypopnea and hypoxia than OSAHS alone. The cardiovascular complications of overlapping syndromes at plateau are more pronounced, possibly due to the exacerbation of the systemic inflammatory response. The combination of PASP, smoking index, and AHI can be a powerful tool for predicting and assessing the occurrence of COPD in OSAHS patients from plateau populations in China. These findings have the potential to significantly improve the management and prognosis of patients with overlap syndrome.
Decentralized Clinical Trials in the Era of Real‐World Evidence: A Statistical Perspective
Authors: Chen Jie , Di Junrui , Daizadeh Nadia , Lu Ying , Wang Hongwei , Shen Yuan‐Li , Kirk Jennifer , Rockhold Frank W. , Pang Herbert , Zhao Jing , He Weili , Potter Andrew , Lee Hana 
Published: February 2025

ABSTRACTThere has been a growing trend that activities relating to clinical trials take place at locations other than traditional trial sites (hence decentralized clinical trials or DCTs), some of which are at settings of real‐world clinical practice. Although there are numerous benefits of DCTs, this also brings some implications on a number of issues relating to the design, conduct, and analysis of DCTs. The Real‐World Evidence Scientific Working Group of the American Statistical Association Biopharmaceutical Section has been reviewing the field of DCTs and provides in this paper considerations for decentralized trials from a statistical perspective. This paper first discusses selected critical decentralized elements that may have statistical implications on the trial and then summarizes regulatory guidance, framework, and initiatives on DCTs. More discussions are presented by focusing on the design (including construction of estimand), implementation, statistical analysis plan (including missing data handling), and reporting of safety events. Some additional considerations (e.g., ethical considerations, technology infrastructure, study oversight, data security and privacy, and regulatory compliance) are also briefly discussed. This paper is intended to provide statistical considerations for decentralized trials of medical products to support regulatory decision‐making.
Effect of a Supratherapeutic Dose of Omaveloxolone on the Corrected QT Interval in Healthy Participants: A Randomized, Double‐Blind, Placebo‐ and Active‐Controlled, Three‐Way Crossover Study
Authors: Zahir Hamim , Murai Masako , Wu Lucy , Valentine Michelle , Hynes Scott M. 
Published: February 2025

ABSTRACTOmaveloxolone is approved for the treatment of Friedreich ataxia (FA) in patients aged ≥ 16 years at a dose of 150 mg once daily. This double‐blind, randomized, placebo‐ and active‐controlled, three‐way crossover, thorough corrected QT interval (QTc) study (NCT05927649) evaluated the effect of supratherapeutic omaveloxolone exposure on QTc to exclude a clinically significant prolongation (defined as > 10 ms). Healthy adults were randomized to one of six sequences of three single oral doses (omaveloxolone 450 mg, placebo, or moxifloxacin 400 mg [open‐label positive control]) administered with an FDA high‐fat meal. Serial pharmacokinetic blood sampling and time‐matched electrocardiogram assessments were performed. The primary endpoint was placebo‐corrected change from baseline in QTcF (ΔΔQTcF) following omaveloxolone administration. Secondary endpoints included pharmacokinetic parameters of omaveloxolone and its major plasma metabolites (M17 and M22) and safety. All 30 enrolled participants completed the study. The mean omaveloxolone Cmax was 319 ng/mL in this study (4.5‐fold the mean steady‐state Cmax [71.5 ng/mL] with the approved dose). The mean QTcF intervals were < 450 ms, and mean changes from baseline were < 10 ms at all timepoints following all doses. The upper limit of the 90% CIs of ΔΔQTcF following omaveloxolone administration was < 10 ms at all timepoints. At the Cmax of omaveloxolone, M17, and M22, alone or combined, the upper limits of the 90% CIs of the model‐predicted ΔΔQTcF were all < 10 ms. No safety concerns were identified. Supratherapeutic omaveloxolone exposure that covers the worst‐case clinical exposure did not cause a clinically significant QTc prolongation and was generally well tolerated.
National Prescribing Practices for Pediatric Dystonia Among Providers in the United States
Authors: Davis Sarah Paige W. , Kane Natalie , Botteron Haley E. , Gelineau‐Morel Rose 
Published: February 2025

ABSTRACTWhile multiple oral medications are used to treat dystonia, limited information exists on current prescribing practices. This study analyzes real‐world prescribing practices for pediatric dystonia in the United States, evaluating prescription frequency, dosing, and the impact of comorbidities. Oracle electronic health record real‐world data were queried from 2014 to 2019 for encounters of patients under age 18 with a dystonia diagnosis and available medication records. Information was extracted on prescriptions for dystonia medications (baclofen, clonidine, carbidopa‐levodopa, gabapentin, tetrabenazine, trihexyphenidyl, and select benzodiazepines), dosing, and comorbid diagnoses of cerebral palsy (CP), epilepsy, or spasticity. A total of 4010 pediatric patients with dystonia were included. Benzodiazepines were most commonly prescribed (midazolam in 53.5% of patients, diazepam 46.7%, lorazepam 41.9%, clonazepam 28.3%). This was followed by baclofen (33.4%), clonidine (26.3%), and gabapentin (19.7%). Dystonia patients with epilepsy were more commonly prescribed benzodiazepines than patients without epilepsy (diazepam 79.1% vs. 29%; clonazepam 50.9% vs. 16%) and baclofen was more often prescribed in patients with CP (59.4%) or spasticity (63.8%) than those without (17%). All medications showed decreased milligram per kilogram dosage as patient weight increased. Benzodiazepines, baclofen, and clonidine were the most common medications prescribed to pediatric patients with dystonia in the United States, although medical comorbidities impact prescribing practices. There was significant variability in weight‐based dosing of all medications. There remains a need to determine which dystonia medications are most effective for each patient and the necessary drug exposure to maximize therapeutic efficacy and minimize adverse effects.
Widespread and Diverging Patterns of Change in Local Phylogenetic Diversity
Authors: Fernandez‐Fournier Philippe , Carroll Tadhg , Dornelas Maria , Mooers Arne Ø. 
Published: February 2025

ABSTRACTAimEcosystems are witnessing drastic changes in biodiversity worldwide. However, it is still unclear whether changes in phylogenetic diversity—a measure of the evolutionary relationships among species—reflect observed changes in species richness. Specifically, we ask whether changes in local phylogenetic diversity correlate with changes in species richness and examine if major taxonomic groups show diverging trends.LocationGlobal.MethodsWe estimate how local phylogenetic diversity has changed compared to species richness and whether there were diverging patterns across taxonomic groups. We use a database of compiled assemblage time series from around the world, BioTIME. We use assemblage total evolutionary history (Faith's phylogenetic diversity; PD) as well as average relatedness (mean pairwise distance and mean nearest taxon distance; MPD and MNTD, respectively) as measures of phylogenetic diversity and report taxon‐level and assemblage‐level posterior slope estimates from a Bayesian hierarchical model. We report trends in four major taxonomic groups: fish, birds, terrestrial mammals and terrestrial plants.ResultsWe found strong evidence of widespread increases in MPD across fish and bird assemblages, reflecting decreases in average relatedness and strong evidence of a decrease of MPD in mammals, indicating the opposite. Conversely, we did not find consistent directional change in MNTD, though null average trends included notable positive and negative trends across studies and regions. We also found moderate evidence that SR and PD were increasing in fish assemblages, while they were decreasing in mammals.Main ConclusionsOur findings suggest that changes in species composition are significantly altering the evolutionary makeup of assemblages at the local scale and that overall patterns diverge within and across taxonomic groups. We suggest potential drivers of these changes but highlight that our results are more generalisable for fish and birds than for mammals and plants, given the variation in geographical coverage and sample size.
Analysis of patient characteristics and safety of insulin glargine U300 use in 21 359 patients with type‐2 diabetes and chronic kidney disease: DPV registry study
Authors: Vijayan Anjaly , Lanzinger Stefanie , Forestier Nicole , Hess Gregor , Rottmann Marcus , Wosch Frank J. , Seufert Jochen , Holl Reinhard W. , Bramlage Peter ,   for the DPV
Published: February 2025

AbstractAimsManaging type‐2 diabetes (T2D) in chronic kidney disease (CKD) patients requires consideration of kidney function, and many drugs have not been investigated thoroughly. Clinical studies have demonstrated Glargine U300 (Gla‐300) supports achievement of adequate glycemic control at low hypoglycemia risk.Materials and MethodThis cross‐sectional study analysed routine data of 21 359 T2D patients with CKD (1786 using Gla‐300; 19 568 without any insulin) from the prospective Diabetes‐Patienten‐Verlaufsdokumentation (DPV) registry to evaluate patient characteristics and safety of Gla‐300 use across different CKD stages.ResultsPatients on Gla‐300 had T2D onset at an earlier age (median age 55.1 vs. 62.3 years), longer diabetes duration (17.3 vs. 11.3 years), higher body weight (91.3 vs. 83.9 kg) and HbA1c levels (7.3% vs. 6.7%) than non‐insulin patients (all p < 0.001). Gla‐300 usage increased from CKD stage 1–4 (median dose 44 vs. 55 units) with higher baseline HbA1c levels (7.2% vs. 7.4%). Although severe hypoglycemia rates were low, a slight increase (0.01%/PY vs. 0.04%/PY) was observed with decreasing estimated glomerular filtration rate levels. Compared to others, stage 5 CKD patients had a distinct profile with lower HbA1c levels (6.9%), body weight (90 kg) and higher Gla‐300 usage (50 units). Metformin, SGLT‐2 inhibitors and GLP‐1 RA were common concomitant drugs with diminished usage in advanced CKD stages, while Gla‐300 was common at all stages.ConclusionDespite variations in patient profiles, Gla‐300 is widely used across all CKD stages, particularly in advanced stages with a low rate of severe hypoglycemia, suggesting its safe administration in CKD patients.
Efficacy and safety of a bio‐absorbable antibiotic delivery in calcium sulphate granules for the treatment of osteomyelitis in patients with diabetic foot: A randomized, double blinded, controlled clinical study The BIG D‐FOOT study
Authors: Monami Matteo , Bordoni Laura , Ragghianti Benedetta , Silverii Giovanni Antonio , Mannucci Edoardo 
Published: February 2025

AbstractBackgroundDiabetic foot osteomyelitis (DFO) is associated with a considerably high risk of incident major amputations, disability and mortality. To assess the effects of a local antibiotic delivery system on the incidence of post‐surgical infective complications in patients with DFO.MethodsThis is a double‐blind, placebo‐controlled, parallel series, randomized controlled trial (RCT) aimed at verifying the efficacy and safety of a local calcium‐sulphate bio‐absorbable antibiotic delivery (either with tobramycin or vancomycin) in patients with DFO treated with surgical procedures. The trial enrolled adult patients with diabetes and Texas 3 grade ulcers complicated by osteomyelitis and accompanied by deep tissues infection. The primary end‐point was the percentage of infective complications (composite end‐point of dehiscence, infection, DFO recurrence and new DFO in adjacent sites) at 12 weeks.ResultsThe study was prematurely terminated after the completion of the first 20 cases, because of the significant superiority of the active treatment arm. After 12 weeks of treatment, five of 20 wounds (25%) achieved the primary composite end‐point. All post‐surgical infective complications occurred in the placebo group, with a significant between‐group difference (unadjusted p = 0.010). No between‐group differences in overall costs were observed.ConclusionsThis is the first RCT in patients with DFO showing that the use of antibiotic‐impregnated calcium‐sulphate granules is economically sustainable and has the potential of improving the prognosis of DFO.
A Mechanistic Approach to Animal Dispersal—Quantifying Energetics and Maximum Distances
Authors: Wilkinson Caitlin , Brose Ulrich , Dyer Alexander , Hirt Myriam R. , Ryser Remo 
Published: February 2025

ABSTRACTDispersal is a fundamental process driving many ecological patterns. During transfer, species often make large‐scale displacements resulting in significant energy losses with implications for fitness and survival, however generalising these losses across different taxonomic groups is challenging. We developed a bioenergetic dispersal model based on fundamental processes derived from species traits. By balancing energy storage and energy loss during active dispersal, our mechanistic model can quantify energy expenditures depending on landscape configuration and the species in focus. Moreover, it can be used to predict the maximum dispersal capacity of animals, which we compare with recorded maximum dispersal distances (n = 1571). Due to its foundation in bioenergetics it can easily be integrated into various ecological models, such as food‐web and meta‐community models. Furthermore, as dispersal is integral to ecological research, the quantification of dispersal capacities provides valuable insight into landscape connectivity, species persistence, and distribution patterns with implications for conservation research.
Cytomegalic parvalbumin neurons in fetal cases of hemimegalencephaly
Authors: Gelot Antoinette‐Bernabe , Draia‐Nicolau Tangra Ondina , Mathieu Rémi , Silvagnoli Lucas , Watrin Françoise , Cardoso Carlos , Manent Jean‐Bernard , de Chevigny Antoine , Represa Alfonso 
Published: February 2025

AbstractObjectiveMutations in genes of the mTOR pathway have been identified as a major cause of hemimegalencephaly (HMG), focal cortical dysplasia type II, and tuberous sclerosis, cortical malformations associated with epilepsy. These conditions are characterized at the cellular level by increased size of pyramidal neurons that grow with dysmorphic features and in some cases by the presence of giant balloon cells. Our previous research in tuberous sclerosis has shown that parvalbumin (Pvalb) and calbindin immunoreactive cells in cortical and subcortical tuberal lesions show cytomegalic features, suggesting the involvement of GABAergic cells in mTOR‐related pathologies. In the present report, we propose to deepen our understanding of the role of interneurons in mTOR‐related cortical malformations by analyzing the maturation of Pvalb neurons in fetal samples of HMG.MethodsWe performed immunohistochemical staining of cortical samples from individuals with HMG from 21 gestational weeks to 10 postnatal months. The study focused on Pvalb cells, and pS6 counterstaining was performed to assess the activation of the mTOR pathway. To investigate the pathomechanisms behind the cytomegalic features, we examined mTOR pathway gene expression in Pvalb interneurons and cortical projection neurons using a single‐cell transcriptomic atlas of the human neocortex.ResultsOur results revealed cytomegalic features in Pvalb interneurons, indicating abnormal development in HMG patients compared to controls. This phenotype progressively worsened over time, suggesting ongoing developmental abnormalities associated with mTOR dysregulation, which may underlie the pathology of cortical malformations in HMG. Our transcriptomic data revealed similar expression patterns of mTOR and its upstream regulators in both Pvalb and glutamatergic neurons during development, suggesting that mTOR pathway disorders may induce similar phenotypes in both cell types.SignificanceThe present data suggest that Pvalb interneurons are involved in the development of mTOR‐related cortical dysplasia and that they may be a contributor to the clinical phenotype of these patients.
Metabolomic and proteomic stratification of equine osteoarthritis
Authors: Anderson James R. , Phelan Marie M. , Caamaño‐Gutiérrez Eva , Clegg Peter D. , Rubio‐Martinez Luis M. , Peffers Mandy J. 
Published: February 2025

AbstractBackgroundEquine osteoarthritis (OA) is predominantly diagnosed through clinical examination and radiography, leading to detection only after significant joint pathology. The pathogenesis of OA remains unclear and while many medications modify the disease's inflammatory components, no curative or reversal treatments exist. Identifying differentially abundant metabolites and proteins correlated with osteoarthritis severity could improve early diagnosis, track disease progression, and evaluate responses to interventions.ObjectivesTo identify molecular markers of osteoarthritis severity based on histological and macroscopic grading.Study designCross‐sectional study.MethodsPost‐mortem synovial fluid was collected from 58 Thoroughbred racehorse joints and 83 joints from mixed breeds. Joints were histologically and macroscopically scored and categorised by OA and synovitis grade. Synovial fluid nuclear magnetic resonance metabolomic and mass spectrometry proteomic analyses were performed, individually and combined.ResultsIn Thoroughbreds, synovial fluid concentrations of metabolites 2‐aminobutyrate, alanine and creatine were elevated for higher OA grades, while glutamate was reduced for both Thoroughbreds and mixed breeds. In mixed breeds, concentrations of three uncharacterised proteins, lipopolysaccharide binding protein and immunoglobulin kappa constant were lower for higher OA grades; concentrations of an uncharacterised protein were higher for OA grade 1 only, and apolipoprotein A1 concentrations were higher for OA grades 1 and 2 compared with lower grades. For Thoroughbreds, gelsolin concentrations were lower for higher OA grades, and afamin was lower at a higher synovitis grade. Correlation analyses of combined metabolomics and proteomics datasets revealed 58 and 32 significant variables for Thoroughbreds and mixed breeds, respectively, with correlations from −0.48 to 0.42 and −0.44 to 0.49.Main LimitationsThe study's reliance on post‐mortem assessments limits correlation with clinical osteoarthritis severity.ConclusionsFollowing stratification of equine OA severity through histological and macroscopic grading, synovial fluid metabolomic and proteomic profiling identified markers that may support earlier diagnosis and progression tracking. Further research is needed to correlate these markers with clinical osteoarthritis severity.