bluuebunny/crossref_metadata_2025_split huggingface dataset:
Teriflunomide in pediatric patients with relapsing multiple sclerosis: Open-label extension of TERIKIDS
Authors: Chitnis Tanuja , Banwell Brenda , Kappos Ludwig , Arnold Douglas L , Gücüyener Kivilcim , Deiva Kumaran , Saubadu Stephane , Hu Wenruo , Benamor Myriam , Le-Halpere Annaig , Truffinet Philippe , Tardieu Marc 
Published: April 2024

Background: The double-blind TERIKIDS study demonstrated the efficacy and safety of teriflunomide. Objective: To evaluate the efficacy, safety, and tolerability of continuous teriflunomide treatment in the TERIKIDS open-label extension. Methods: In the double-blind period, children with relapsing MS were randomized to placebo or teriflunomide (14 mg adult-equivalent dose) for ⩽ 96 weeks. Participants received teriflunomide for ⩽ 192 weeks post-randomization in the open-label extension. Results: The mean age at screening was 14.6 years. For teriflunomide/teriflunomide versus placebo/teriflunomide, estimated clinical relapse risk was reduced by 38% (hazard ratio (HR) 0.62; 95% confidence interval (CI) 0.39–0.98; p = 0.11) and numbers of gadolinium-enhancing T1 and new/enlarging T2 lesions were reduced by 43% (relative risk (RR) 0.570; 95% CI 0.33–0.98; p = 0.043) and 49% (RR 0.511; 95% CI 0.34–0.76; p = 0.001), respectively, in the combined double-blind and open-label periods. There was a trend toward reduced risk of 24-week sustained disability progression for teriflunomide/teriflunomide versus placebo/teriflunomide (HR 0.47; 95% CI 0.23–0.96). During the open-label extension, incidences of safety-related discontinuations were 4.0% (teriflunomide/teriflunomide) and 13.5% (placebo/teriflunomide), including two children who developed pancreatitis in the teriflunomide/teriflunomide group. Conclusion: Teriflunomide reduced the long-term risk of focal inflammatory activity, with generally manageable tolerability and no new safety signals. Further evidence would strengthen clinical efficacy findings. ClinicalTrials.gov: NCT02201108.
Therapeutic lag: Is treatment effect delayed in progressive MS?
Authors: Montobbio Noemi , Bovis Francesca , Signori Alessio , Ponzano Marta , Schiavetti Irene , Sormani Maria Pia 
Published: April 2024

Background: Randomized clinical trials (RCTs) in progressive multiple sclerosis (MS) often revealed non-significant treatment effects on disability progression. Objectives: To investigate whether the failure to detect a significant benefit from treatment may be motivated by a delay in treatment effect, possibly related to baseline characteristics. Methods: We re-analyzed data from two RCTs testing interferon-beta and glatiramer-acetate versus placebo in progressive MS with no significant effect on EDSS progression. We first designed a time-dependent Cox model with no treatment effect up to time = t0, and constant hazard ratio (HR) after time = t0. We selected the best-fitting t0 from 0 (standard Cox model) to 2.5 years. Furthermore, we modeled the delay as a function of baseline EDSS and fitted the resulting Cox model to the merged dataset. Results: The time-dependent Cox model revealed a significant benefit of treatment delayed by t0 = 2.5 years for the SPECTRIMS study (HR = 0.65 (0.43–0.98), p = 0.041), and delayed by t0 = 2 years for the PROMISE study (HR = 0.65, (0.42–0.99), p = 0.044). In the merged dataset, the HR for the EDSS-dependent delayed effect was 0.68 (0.56, 0.82), p < 0.001. Conclusion: The assumption of a delayed treatment effect improved the fit to the data of the two examined RCTs, uncovering a significant, although shifted, benefit of treatment.
Fitusiran reduces bleeding in factor X–deficient mice
Authors: Verhenne Sebastien , McCluskey Geneviève , Maynadié Hortense , Adam Frédéric , Casari Caterina , Panicot-Dubois Laurence , Crescence Lydie , Dubois Christophe , Denis Cécile V. , Lenting Peter J. , Christophe Olivier D. 
Published: April 2024

Abstract
Factor X (FX) deficiency is a rare bleeding disorder manifesting a bleeding tendency caused by low FX activity levels. We aim to explore the use of fitusiran (an investigational small interfering RNA that silences antithrombin expression) to increase thrombin generation and the in vivo hemostatic potential under conditions of FX deficiency. We therefore developed a novel model of inducible FX deficiency, generating mice expressing &lt;1% FX activity and antigen (f10low mice). Compared with control f10WT mice, f10low mice had sixfold and fourfold prolonged clotting times in prothrombin time and activated partial prothrombin time assays, respectively (P &lt; .001). Thrombin generation was severely reduced, irrespective of whether tissue factor or factor XIa was used as an initiator. In vivo analysis revealed near-absent thrombus formation in a laser-induced vessel injury model. Furthermore, in 2 distinct bleeding models, f10low mice displayed an increased bleeding tendency compared with f10WT mice. In the tail-clip assay, blood loss was increased from 12 ± 16 μL to 590 ± 335 μL (P &lt; .0001). In the saphenous vein puncture (SVP) model, the number of clots generated was reduced from 19 ± 5 clots every 30 minutes for f10WT mice to 2 ± 2 clots every 30 minutes (P &lt; .0001) for f10low mice. In both models, bleeding was corrected upon infusion of purified FX. Treatment of f10low mice with fitusiran (2 × 10 mg/kg at 1 week interval) resulted in 17 ± 6% residual antithrombin activity and increased thrombin generation (fourfold and twofold to threefold increase in endogenous thrombin potential and thrombin peak, respectively). In the SVP model, the number of clots was increased to 8 ± 6 clots every 30 minutes (P = .0029). Altogether, we demonstrate that reduction in antithrombin levels is associated with improved hemostatic activity under conditions of FX deficiency.
Optimized cytogenetic risk-group stratification of KMT2A-rearranged pediatric acute myeloid leukemia
Authors: van Weelderen Romy E. , Harrison Christine J. , Klein Kim , Jiang Yilin , Abrahamsson Jonas , Alonzo Todd , Aplenc Richard , Arad-Cohen Nira , Bart-Delabesse Emmanuelle , Buldini Barbara , De Moerloose Barbara , Dworzak Michael N. , Elitzur Sarah , Fernández Navarro José M. , Gamis Alan , Gerbing Robert B. , Goemans Bianca F. , de Groot-Kruseman Hester A. , Guest Erin , Ha Shau-Yin , Hasle Henrik , Kelaidi Charikleia , Lapillonne Hélène , Leverger Guy , Locatelli Franco , Miyamura Takako , Norén-Nyström Ulrika , Polychronopoulou Sophia , Rasche Mareike , Rubnitz Jeffrey E. , Stary Jan , Tierens Anne , Tomizawa Daisuke , Zwaan C. Michel , Kaspers Gertjan J. L. 
Published: April 2024

Abstract
A comprehensive international consensus on the cytogenetic risk-group stratification of KMT2A-rearranged (KMT2A-r) pediatric acute myeloid leukemia (AML) is lacking. This retrospective (2005-2016) International Berlin-Frankfurt-Münster Study Group study on 1256 children with KMT2A-r AML aims to validate the prognostic value of established recurring KMT2A fusions and additional cytogenetic aberrations (ACAs) and to define additional, recurring KMT2A fusions and ACAs, evaluating their prognostic relevance. Compared with our previous study, 3 additional, recurring KMT2A-r groups were defined: Xq24/KMT2A::SEPT6, 1p32/KMT2A::EPS15, and 17q12/t(11;17)(q23;q12). Across 13 KMT2A-r groups, 5-year event-free survival probabilities varied significantly (21.8%-76.2%; P &lt; .01). ACAs occurred in 46.8% of 1200 patients with complete karyotypes, correlating with inferior overall survival (56.8% vs 67.9%; P &lt; .01). Multivariable analyses confirmed independent associations of 4q21/KMT2A::AFF1, 6q27/KMT2A::AFDN, 10p12/KMT2A::MLLT10, 10p11.2/KMT2A::ABI1, and 19p13.3/KMT2A::MLLT1 with adverse outcomes, but not those of 1q21/KMT2A::MLLT11 and trisomy 19 with favorable and adverse outcomes, respectively. Newly identified ACAs with independent adverse prognoses were monosomy 10, trisomies 1, 6, 16, and X, add(12p), and del(9q). Among patients with 9p22/KMT2A::MLLT3, the independent association of French-American-British–type M5 with favorable outcomes was confirmed, and those of trisomy 6 and measurable residual disease at end of induction with adverse outcomes were identified. We provide evidence to incorporate 5 adverse-risk KMT2A fusions into the cytogenetic risk-group stratification of KMT2A-r pediatric AML, to revise the favorable-risk classification of 1q21/KMT2A::MLLT11 to intermediate risk, and to refine the risk-stratification of 9p22/KMT2A::MLLT3 AML. Future studies should validate the associations between the newly identified ACAs and outcomes and unravel the underlying biological pathogenesis of KMT2A fusions and ACAs.
Converting IMPROVE bleeding and VTE risk assessment models into a fast-and-frugal decision tree for optimal hospital VTE prophylaxis
Authors: Djulbegovic Benjamin , Boylan Alice , Kolo Shelby , Scheurer Danielle Bowen , Anuskiewicz Sydney , Khaledi Flora , Youkhana Kimberley , Madgwick Sarah , Maharjan Neema , Hozo Iztok 
Published: April 2024

Abstract
Current hospital venous thromboembolism (VTE) prophylaxis for medical patients is characterized by both underuse and overuse. The American Society of Hematology (ASH) has endorsed the use of risk assessment models (RAMs) as an approach to individualize VTE prophylaxis by balancing overuse (excessive risk of bleeding) and underuse (risk of avoidable VTE). ASH has endorsed IMPROVE (International Medical Prevention Registry on Venous Thromboembolism) risk assessment models, the only RAMs to assess short-term bleeding and VTE risk in acutely ill medical inpatients. ASH, however, notes that no RAMs have been thoroughly analyzed for their effect on patient outcomes. We aimed to validate the IMPROVE models and adapt them into a simple, fast-and-frugal (FFT) decision tree to evaluate the impact of VTE prevention on health outcomes and costs. We used 3 methods: the “best evidence” from ASH guidelines, a “learning health system paradigm” combining guideline and real-world data from the Medical University of South Carolina (MUSC), and a “real-world data” approach based solely on MUSC data retrospectively extracted from electronic records. We found that the most effective VTE prevention strategy used the FFT decision tree based on an IMPROVE VTE score of ≥2 or ≥4 and a bleeding score of &lt;7. This method could prevent 45% of unnecessary treatments, saving ∼$5 million annually for patients such as the MUSC cohort. We recommend integrating IMPROVE models into hospital electronic medical records as a point-of-care tool, thereby enhancing VTE prevention in hospitalized medical patients.
Production and recovery system for furan compounds from rice straw using an ionic liquid (1-methylimidazolium hydrogen sulfate) and vacuum steam distillation
Authors: Enomoto Kota , Hosoya Takashi , Miyafuji Hisashi 
Published: April 2024

AbstractFuran compounds, including 5-hydroxymethylfurfural and furfural, can be synthesized from biomass and have garnered attention for their potential applications in biofuels and resin precursors. In this study, the synthesis of the furan compounds from rice straw was explored using a combined approach of ionic liquid treatment, specifically 1-methylimidazolium hydrogen sulfate ([MIM]HSO4), and vacuum steam distillation. Through the optimization of various processing parameters, we established that the best conditions for the furan compound production include: a cold trap cooling temperature of – 196 ℃, a system pressure of 10 hPa, a treatment temperature of 180 ℃, a reaction duration of 30 min, a sample loading of 1wt%, and a particle size range of 45–90 µm. Under these conditions, the resultant yield of the furan compounds was quantified at 27.9wt%. Additionally, the recyclability of the utilized ionic liquid was evaluated. Notably, even after four recycling cycles (encompassing a total of five reactions), the yield of the furan compounds remained consistent, underscoring the viability of ionic liquid reuse.
Functionalization of niobium nitrogen-doped titanium dioxide (TiO2) nanoparticles with ethanolic extracts of Mentha arvensis
Authors: Farooqi Muhammad Awais , Farooqi Hafiz Muhammad Umer , Bhatti Theophilus , Siddiqui Ghayas Uddin , Kausar Farzana , Kang Chul Ung 
Published: April 2024

AbstractTitanium dioxide (TiO2) nanoparticles have gained significant attention due to their wide-ranging applications. This research explores an approach to functionalize Niobium Nitrogen Titanium Dioxide nanoparticles (Nb-N-TiO2 NPs) with Mentha arvensis ethanolic leaf extracts. This functionalization allows doped NPs to interact with the bioactive compounds in extracts, synergizing their antioxidant activity. While previous studies have investigated the antioxidant properties of TiO2 NPs synthesized using ethanolic extracts of Mentha arvensis, limited research has focused on evaluating the antioxidant potential of doped nanoparticles functionalized with plant extracts. The characterization analyses are employed by Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and Ultraviolet–visible (UV–Vis) spectroscopy to evaluate these functionalized doped nanoparticles thoroughly. Subsequently, the antioxidant capabilities through the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric-reducing antioxidant power (FRAP) assays have been assessed. Within functionalized Nb-N-TiO2, the FTIR has a distinctive peak at 2350, 2010, 1312, 1212, and 1010 cm−1 with decreased transmittance associated with vibrations linked to the Nb-N bond. SEM revealed a triangular aggregation pattern, 500 nm to 2 µm of functionalized Nb-N-TiO2 NPs. Functionalized doped Nb-N-TiO2 NPs at 500 µg mL−1 exhibited particularly robust antioxidant activity, achieving an impressive 79% efficacy at DPPH assessment; meanwhile, ferric reduction efficiency of functionalized doped Nb-N-TiO2 showed maximum 72.16%. In conclusion, doped Nb-N-TiO2 NPs exhibit significantly enhanced antioxidant properties when functionalized with Mentha arvensis ethanolic extract compared to pure Nb-N-TiO2 manifested that doped Nb-N-TiO2 have broad promising endeavors for various biomedicine applications.
Recent advances in membrane technologies applied in oil–water separation
Authors: Huang Jialu , Ran Xu , Sun Litao , Bi Hengchang , Wu Xing 
Published: April 2024

AbstractEffective treatment of oily wastewater, which is toxic and harmful and causes serious environmental pollution and health risks, has become an important research field. Membrane separation technology has emerged as a key area of investigation in oil–water separation research due to its high separation efficiency, low costs, and user-friendly operation. This review aims to report on the advances in the research of various types of separation membranes around emulsion permeance, separation efficiency, antifouling efficiency, and stimulus responsiveness. Meanwhile, the challenges encountered in oil–water separation membranes are examined, and potential research avenues are identified.
Many purported pseudogenes in bacterial genomes are bona fide genes
Authors: Cooley Nicholas P. , Wright Erik S. 
Published: April 2024

Abstract
Background
Microbial genomes are largely comprised of protein coding sequences, yet some genomes contain many pseudogenes caused by frameshifts or internal stop codons. These pseudogenes are believed to result from gene degradation during evolution but could also be technical artifacts of genome sequencing or assembly.

Results
Using a combination of observational and experimental data, we show that many putative pseudogenes are attributable to errors that are incorporated into genomes during assembly. Within 126,564 publicly available genomes, we observed that nearly identical genomes often substantially differed in pseudogene counts. Causal inference implicated assembler, sequencing platform, and coverage as likely causative factors. Reassembly of genomes from raw reads confirmed that each variable affects the number of putative pseudogenes in an assembly. Furthermore, simulated sequencing reads corroborated our observations that the quality and quantity of raw data can significantly impact the number of pseudogenes in an assembler dependent fashion. The number of unexpected pseudogenes due to internal stops was highly correlated (R2 = 0.96) with average nucleotide identity to the ground truth genome, implying relative pseudogene counts can be used as a proxy for overall assembly correctness. Applying our method to assemblies in RefSeq resulted in rejection of 3.6% of assemblies due to significantly elevated pseudogene counts. Reassembly from real reads obtained from high coverage genomes showed considerable variability in spurious pseudogenes beyond that observed with simulated reads, reinforcing the finding that high coverage is necessary to mitigate assembly errors.

Conclusions
Collectively, these results demonstrate that many pseudogenes in microbial genome assemblies are actually genes. Our results suggest that high read coverage is required for correct assembly and indicate an inflated number of pseudogenes due to internal stops is indicative of poor overall assembly quality.
Genomic characterization and related functional genes of γ- poly glutamic acid producing Bacillus subtilis
Authors: Zhu Jiayue , Wang Xue , Zhao Jianan , Ji Fang , Zeng Jun , Wei Yanwen , Xu LiLi , Dong Guoying , Ma Xingyuan , Wang Chengmin 
Published: April 2024

Abstractγ- poly glutamic acid (γ-PGA), a high molecular weight polymer, is synthesized by microorganisms and secreted into the extracellular space. Due to its excellent performance, γ-PGA has been widely used in various fields, including food, biomedical and environmental fields. In this study, we screened natto samples for two strains of Bacillus subtilis N3378-2at and N3378-3At that produce γ-PGA. We then identified the γ-PGA synthetase gene cluster (PgsB, PgsC, PgsA, YwtC and PgdS), glutamate racemase RacE, phage-derived γ-PGA hydrolase (PghB and PghC) and exo-γ-glutamyl peptidase (GGT) from the genome of these strains. Based on these γ-PGA-related protein sequences from isolated Bacillus subtilis and 181 B. subtilis obtained from GenBank, we carried out genotyping analysis and classified them into types 1–5. Since we found B. amyloliquefaciens LL3 can produce γ-PGA, we obtained the B. velezensis and B. amyloliquefaciens strains from GenBank and classified them into types 6 and 7 based on LL3. Finally, we constructed evolutionary trees for these protein sequences. This study analyzed the distribution of γ-PGA-related protein sequences in the genomes of B. subtilis, B. velezensis and B. amyloliquefaciens strains, then the evolutionary diversity of these protein sequences was analyzed, which provided novel information for the development and utilization of γ-PGA-producing strains.
Outlier detection in spatial error models using modified thresholding-based iterative procedure for outlier detection approach
Authors: Cai Jiaxin , Hu Weiwei , Yang Yuhui , Yan Hong , Chen Fangyao 
Published: April 2024

Abstract
Background
Outliers, data points that significantly deviate from the norm, can have a substantial impact on statistical inference and provide valuable insights in data analysis. Multiple methods have been developed for outlier detection, however, almost all available approaches fail to consider the spatial dependence and heterogeneity in spatial data. Spatial data has diverse formats and semantics, requiring specialized outlier detection methodology to handle these unique properties. For now, there is limited research exists on robust spatial outlier detection methods designed specifically under the spatial error model (SEM) structure.

Method
We propose the Spatial-Θ-Iterative Procedure for Outlier Detection (Spatial-Θ-IPOD), which utilizes a mean-shift vector to identify outliers within the SEM. Our method enables an effective detection of spatial outliers while also providing robust coefficient estimates. To assess the performance of our approach, we conducted extensive simulations and applied it to a real-world empirical study using life expectancy data from multiple countries.

Results
Simulation results showed that the masking and JD (Joint Detection) indicators of our Spatial-Θ-IPOD method outperformed several commonly used methods, even in high-dimensional scenarios, demonstrating stable performance. Conversely, the Θ-IPOD method proved to be ineffective in detecting outliers when spatial correlation was present. Moreover, our model successfully provided reliable coefficient estimation alongside outlier detection. The proposed method consistently outperformed other models (both robust and non-robust) in most cases. In the empirical study, our proposed model successfully detected outliers and provided valuable insights in the modeling process.

Conclusions
Our proposed Spatial-Θ-IPOD offers an effective solution for detecting spatial outliers for SEM while providing robust coefficient estimates. Notably, our approach showcases its relative superiority even in the presence of high leverage points. By successfully identifying outliers, our method enhances the overall understanding of the data and provides valuable insights for further analysis.
Determinants of early chronic kidney disease in patients with recently diagnosed type 2 diabetes mellitus: a retrospective study from the Taiwan Diabetes Registry
Authors: Yeh Yun-Kai , Lin Kuan-Hung , Sheu Wayne Huey-Herng , Lo Su-Huey , Yeh Yen-Po , Huang Chien-Ning , Hwu Chii-Min , Lu Chieh-Hsiang 
Published: April 2024

Abstract
Background
We tried to identify the risk factor associate with early chronic kidney disease (CKD) in recently diagnosed type 2 diabetes mellitus patients by utilizing real-world data from Taiwan Diabetes Registry.

Materials and methods
Patients with type 2 diabetes mellitus recently diagnosed within 1 year. We divided the study participants into control group and early CKD group. Early CKD was defined as either CKD stage G1 with albuminuria, CKD stage G2 with albuminuria, or CKD stage G3a regardless of albuminuria (Urine-albumin to creatinine ratio (UACR) ≥ 3 mg/mmol). Control group was defined as CKD G1 or CKD G2 without albuminuria. Logistic regression analyses were used to compare differences in clinical characteristics between the subgroups. Linear regression models were employed to examine the factors predicting estimated glomerular filtration rate (eGFR) and UACR.

Results
Total 2217 patients with recently diagnosed type 2 diabetes mellitus were included. 1545 patients were assigned to control group and 618 patients were assigned to the early CKD group. Age (odds ratio (OR) 1.215, 95% confidence interval [CI] 1.122–1.316), systolic blood pressure (OR 1.203, 95% CI 1.117–1.296), glycated hemoglobin (OR 1.074, 95% CI 1.023–1.129) and triglyceride (OR 2.18, 95% CI 1.485–3.199) were found to be significant risk factors. Further, presence of bidirectional association between UACR and eGFR was found.

Conclusions
We reported factors associated with early CKD in recently diagnosed type 2 diabetes mellitus patients. Variables that associated with eGFR and UACR were identified respectively, included a mutual influence between UACR and eGFR.