bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy of filgotinib in patients with rheumatoid arthritis: final results of the DARWIN 3 long-term extension study
Authors: Westhovens Rene , Winthrop Kevin L , Kavanaugh Arthur , Greenwald Maria , Dagna Lorenzo , Cseuz Regina , Besuyen Robin , de Vries Dick , Modgill Vikas , Le Ly Huong , Genovese Mark C , Emery Paul , Verschueren Patrick , Alten Rieke 
Published: January 2025

ObjectivesDARWIN 3 (ClinicalTrials.gov:NCT02065700) assessed the safety and efficacy of filgotinib in a long-term extension (LTE) of two phase II randomised controlled rheumatoid arthritis (RA) trials.MethodsEligible patients completing the 24-week DARWIN 1 (filgotinib plus methotrexate) and DARWIN 2 (filgotinib monotherapy) trials could enrol. Patients received filgotinib 200 mg/day, except 15 men who received filgotinib 100 mg/day. The primary endpoints were safety and tolerability, which were assessed by the incidence of treatment-emergent adverse events (TEAEs). Safety and efficacy analyses included all enrolled patients who received ≥1 dose of filgotinib in DARWIN 3.Results739 patients entered the LTE. The total patient-years of exposure (PYE) to filgotinib was 3706.3 years; the mean exposure duration was 259.8 weeks. 497 patients (67.3%) discontinued prematurely (including 266 TEAEs and 172 withdrawals due to the patient’s decision or ‘sponsor request’). Overall exposure-adjusted incidence rate (EAIR) was 67 (95% CI 62 to 72.2)/100 PYE for TEAEs and 3.8 (95% CI 3.2 to 4.5)/100 PYE for serious TEAEs. EAIR of infections was 23.3 (95% CI 21.2 to 25.6)/100 PYE, 1.3 (95% CI 0.9 to 1.7)/100 PYE for serious infections and 1.3 (95% CI 0.9 to 1.7)/100 PYE for herpes zoster. EAIRs of major adverse cardiovascular events (0.19 (95% CI 0.8 to 0.39)/100 PYE) and malignancies (0.6 (95% CI 0.4 to 0.9)/100 PYE) were low. Disease response assessed using non-responder imputation plateaued at LTE week 12 before slowly declining over time, with overall American College of Rheumatology (ACR)20/50/70 response rates of 26.9%/20.2%/14.7% at week 396.ConclusionFilgotinib was well tolerated in patients with RA for up to 8 years. Safety and efficacy profiles were maintained in patients previously receiving either filgotinib plus methotrexate or filgotinib monotherapy.
Efficient finite difference method for two-dimensional diffusion equation in comb structure with fractional derivative boundary conditions
Authors: Bu Weiping , Xu Xiaohong , Zhao Yue 
Published: January 2025

In [Liu L., Chen S., Feng L., Wang J., Zhang S., Chen Y., Si X., Zheng L., Analysis of the anomalous diffusion in comb structure with absorbing boundary conditions, J. Comput. Phys. 490:112315, 2023], an anomalous diffusion model in comb structure is simulated by finite difference method, which exhibits a low convergence rate in time compared to space. It inspires us to enhance temporal convergence accuracy for this interesting problem. In this paper, we first consider the finite difference method of normal diffusion equation in comb structure which can be viewed as a natural generalization of the anomalous diffusion case. Then we use finite difference method to solve the above anomalous diffusion problem. Unlike the existed work which employs L1 method to discrete the fractional derivative of the considered equation, the Crank–Nicolson method is used for integer-order problem and L2-1[Formula: see text] method is used for fractional problem here. For these two proposed numerical schemes, their stability and convergence are discussed, respectively. For the fractional problem, the present convergence result shows that the accuracy in time has been obviously improved compared with the existed work. Finally, the obtained theoretical results are verified by some numerical tests.
Rurality and Outcomes of Patients Undergoing Mechanical Thrombectomy for Acute Ischemic Stroke
Authors: Lavin Cassidy , Epstein Jacob , Chen Alvin Huanwen , Cheema Minahil , Yang Jerry , Aquino Alexa , Chan Angie , Le Nancy , Cooper Gillian , Palushi Ambra , Schrier Chad , Gandhi Dheeraj , Chaturvedi Seemant , Downing Jessica , Tran Quincy K. 
Published: January 2025

Objective: To investigate differences in outcomes among patients with acute ischemic stroke from large vessel occlusion (AIS‐LVO) transferred from rural and urban hospitals to University of Maryland Medical Center (UMMC) for mechanical thrombectomy (MT).Methods: We identified patients with AIS‐LVO transferred to UMMC for MT from July 2016 to June 2023. Primary outcome was good neurologic outcome, defined as 90‐day modified Rankin score 0–2. Multivariable logistic regression was used to identify predictors for the primary outcome.Results: We analyzed 526 patients, 233 (44%) transferred from rural hospitals in Maryland. Median NIHSS was 17 [IQR 14–20] and was similar between groups. Patients from state‐designated rural hospitals were transferred from a longer distance (difference of 57.8 km, p = 0.001), but had shorter intervals from last known well time to recanalization (difference 19 min, p = 0.24). They had similar odds of good neurologic outcome (OR 0.88, 95% CI 0.43–1.78, p = 0.72).Conclusions: Patients transferred from rural areas for MT for AIS‐LVO, at our institution, had a similar likelihood of achieving 90‐day mRS 0–2 as those transferred from urban areas.
Uniportal Robotic‐Assisted Tracheal Resection and Reconstruction Under Spontaneous Ventilation
Authors: Guido Guerra Ricardo Eli , Bolaños Morales Francina Valezka , Silva Gómez Oscar Francisco , Olvera Prado Hector , Ibáñez Barzalobre Sarahí , Bosinceanu Mugurel , Gonzalez-Rivas Diego 
Published: January 2025

Background: Tracheal resection and reconstruction for airway tumors are traditionally performed using general anesthesia, tracheal intubation, and thoracotomy. Modern techniques, such as tubeless tracheal surgery and robotic uniportal approaches, offer several advantages including better surgical conditions, reduced postoperative complications, and faster recovery.Case Report: A 42‐year‐old woman with a tracheal neuroendocrine tumor underwent nonintubated uniportal robotically assisted tracheal resection and reconstruction. Thoracic epidural anesthesia, airway topicalization, and intravenous anesthesia with laryngeal mask airway allowed the procedure to be performed under nonintubated spontaneous ventilation, through a single 3‐cm incision. Postoperative recovery was uneventful, with the patient experiencing minimal pain and no nausea or vomiting.Conclusions: Nonintubated uniportal robotically assisted tracheal resection and reconstruction is a feasible, less invasive technique that offers significant benefits in terms of recovery and patient comfort when performed by experienced surgeons.
The Effect of a Video‐Based Game Exercise Program on Motor Skills, Proprioception, and Cognitive Functions in Individuals With Intellectual Disabilities
Authors: Diril Elif , Menek Burak , Emir Ahmet , Tarakci Devrim , Tarakci Ela 
Published: January 2025

Background: Individuals with intellectual disability (ID) exhibit various problems, such as attention, learning, and physical–motor difficulties. The study is aimed at investigating the effects of video game–based therapy programs on cognitive and physical functions in individuals with ID.Methods: The study, conducted through a three‐arm randomized trial, involved 45 adults aged 18–30 with mild to moderate ID. Participants were divided into three groups: Group 1 received home‐based video game–based therapy, supervised video game–based therapy, and occupational therapy–based activity training. Group 2 received video game–based therapy supervised by a therapist and an occupational therapy–based activity training program. Group 3 received occupational therapy–based activity training only. MOXO d‐CPT was used to evaluate attention; sit‐to‐stand test, joint position sense, and nine‐hole peg test were used to assess physical–motor functionality.Results: Results showed significant improvements in attention, functional performance, proprioception, and fine motor skills in all groups (p < 0.05). Group 1 was superior to Group 3 in nondominant JPS‐flexion, sit‐to‐stand test, and nondominant JPS‐abduction parameters (p < 0.017). When comparing Group 1 and Group 2, Group 1 was found to be more effective in the sit‐to‐stand test parameter compared to Group 2 (p < 0.017), while the other parameters of the two groups were similar to each other (p > 0.017). There were no significant differences between groups for different outcome measures (p > 0.017).Conclusion: The study suggests that video‐based game exercises combined with occupational therapy interventions can effectively enhance cognitive functions, functional performance, proprioception, and fine motor skills in adults with ID.Trial Registration: ClinicalTrials.gov identifier: NCT06097819
XOR-Derived ROS in Tie2-Lineage Cells Including Endothelial Cells Promotes Aortic Aneurysm Progression in Marfan Syndrome
Authors: Yagi Hiroki , Akazawa Hiroshi , Liu Qing , Yamamoto Kimiko , Nawata Kan , Saga-Kamo Akiko , Umei Masahiko , Kadowaki Hiroshi , Matsuoka Ryo , Shindo Akito , Okamura Shun , Toko Haruhiro , Takeda Norifumi , Ando Masahiko , Yamauchi Haruo , Takeda Norihiko , Fini Mehdi A. , Ono Minoru , Komuro Issei 
Published: January 2025

BACKGROUND:

Marfan syndrome (MFS) is an inherited disorder caused by mutations in the
FBN1
gene encoding fibrillin-1, a matrix component of extracellular microfibrils. The main cause of morbidity and mortality in MFS is thoracic aortic aneurysm and dissection, but the underlying mechanisms remain undetermined.

METHODS:

To elucidate the role of endothelial XOR (xanthine oxidoreductase)–derived reactive oxygen species in aortic aneurysm progression, we inhibited in vivo function of XOR either by endothelial cell (EC)–specific disruption of the
Xdh
gene or by systemic administration of an XOR inhibitor febuxostat in MFS mice harboring the
Fbn1
missense mutation p.(Cys1041Gly). We assessed the aberrant activation of mechanosensitive signaling in the ascending aorta of
Fbn1
C1041G/+
mice. Further analysis of human aortic ECs investigated the mechanisms by which mechanical stress upregulates XOR expression.

RESULTS:

We found a significant increase in reactive oxygen species generation in the ascending aorta of patients with MFS and
Fbn1
C1041G/+
mice, which was associated with a significant increase in protein expression and enzymatic activity of XOR protein in aortic ECs. Genetic disruption of
Xdh
in ECs or treatment with febuxostat significantly suppressed aortic aneurysm progression and improved perivascular infiltration of macrophages. Mechanistically, mechanosensitive signaling involving FAK (focal adhesion kinase)–p38 MAPK (p38 mitogen-activated protein kinase) and Egr-1 (early growth response-1) was aberrantly activated in the ascending aorta of
Fbn1
C1041G/+
mice, and mechanical stress on human aortic ECs upregulated XOR expression through Egr-1 upregulation. Consistently, EC-specific knockout of XOR or systemic administration of febuxostat in
Fbn1
C1041G/+
mice suppressed reactive oxygen species generation, FAK–p38 MAPK activation, and Egr-1 upregulation.

CONCLUSIONS:
Aberrant activation of mechanosensitive signaling in vascular ECs triggered endothelial XOR activation and reactive oxygen species generation, which contributes to the progression of aortic aneurysms in MFS. These findings highlight a drug repositioning approach using a uric acid–lowering drug febuxostat as a potential therapy for MFS.
Abstract TP338: Functional recovery during the chronic phase after cerebral infarction via CSF-derived microRNA
Authors: Xu Hai-Bin , Kenichiro Hira , INABA TOSHIKI , Kijima Chikage , Yoshifumi Miyauchi , Ueno Yuji , Miyamoto Nobukazu , Hattori Nobutaka 
Published: January 2025

(Background):
Stroke has become a leading cause of mortality and disability worldwide. However, except rehabilitation, there is no effective therapy during chronic phase after ischemic stroke.

Interestingly, it has been reported that young cerebrospinal fluid (CSF) restores oligodendrogenesis and memory in aged mice. However, if specific components in CSF could contribute to functional recovery during chronic phase of ischemic stroke remains unclear. We tried to distinguish a specific microRNA in CSF and identify its potential therapeutic functions.

(Method):
Rats were subjected to permanent left middle cerebral artery occlusion (pMCAO). Brains and CSF were collected at 3, 7, 14, 28 days after pMCAO. MicroRNA in CSF was evaluated by microRNA Array. A specific microRNA was selected based on heatmap and volcano plot. IPA analysis was used to distinguish possibly related signaling pathways.

Mimic/ inhibitor of this microRNA was applied respectively to primary cultured astrocytes and neurons soon after 3 hours’ oxygen glucose deprivation (OGD). Associated proteins were tested through western blot at 96 hours after OGD.
In vivo, time course of pStat3 was assessed in peri-infarct cortical area. At 7 days after pMCAO, mimic of this microRNA was applied to CSF through Cisterna Magna. behavioral tests were assessed at 7, 14, 21, 28 days after pMCAO. At 28 days after pMCAO, brains were harvested for ischemia volume calculation and immunofluorescence.

(Result):
miR-204-5p was significantly upregulated in CSF at 7 days after pMCAO and selected as target microRNA. According to IPA analysis, miR-204-5p might be associated with Stat3 signaling pathway.

Based on results of astrocyte culture, GFAP was significantly decreased by applying miR-204-5p mimic. Regarding neuron culture, pStat3, MAP2 showed a tendency to increase by applying miR-204-5p mimic.
In vivo, pStat3 significantly increased at 3 days and began to decrease from 7 days after pMCAO. miR-204-5p mimic group showed a tendency of ameliorated functional dysfunction, smaller ischemia volume at 28 days after pMCAO. In peri-infarct area, compared with non-treatment group, GFAP was significantly decreased, and pStat3 showed tendency to increase in miR-204-5p mimic group.

(Conclusion):
Applying miR-204-5p mimic into CSF contributed to functional recovery via activating Stat3 signalling pathway and reducing astrocytosis, which might be a candidate of exosome or liposome preparation for future clinical trials.
Abstract TP396: Effects of low-intensity pulsed focal ultrasound-mediated delivery of endothelial progenitor-derived exosomes in MCAo stroke
Authors: Alptekin Ahmet , Khan Mohammad B. , Parvin Mahrima , Chowdhury Hasanul , Kashif Sawaiz , Selina Fowzia , Williams Dylan , Blumling Emily , Frank Joseph A. , DHANDAPANI Krishnan , Arbab Ali 
Published: January 2025

Exosomes have been used for therapeutic purposes to target stroke and other disorders. Repeated administration of mesenchymal stem cell (MSC)-derived exosomes in rats showed improved functionality and reduced stroke injury. However, exosomes from endothelial progenitor cells (EPCs) have not been tested in any stroke model, and in vivo bio-distribution study is lacking.
Targeted delivery of IV-administered exosomes has been a great challenge. Modifying the exosomal surface to carry different ligands or peptides has been tried to increase delivery to target tissues. However, the overall results are not encouraging. Delivery of exosomes to the brain is a daunting task, and a blood-brain barrier(BBB)-penetrable peptide is being considered. However, a method that can deliver naïve (unmodified) exosomes to the site of stroke without destroying host tissues, disrupting BBB, or the membranes of the delivery vehicles (such as exosomes) will be a breakthrough.
Low-intensity pulsed ultrasound (LIPUS) is approved for clinical use in musculoskeletal and physiotherapy clinics. The use of focused LIPUS to deliver exosomes has yet to be explored in stroke. The objectives of the proposed studies were to determine whether LIPUS-mediated increased delivery of EPC exosomes enhances stroke recovery and functional improvement in mice with tMCAo stroke. In this study, we used EPC-derived exosomes for stroke treatment. To enhance exosome delivery to the stroke area, we utilized focused LIPUS, which temporarily disrupts BBB. We evaluated stroke volume with MRI at different time points. We also conducted behavioral studies in parallel to MRI to determine the recovery. In the end, we studied the brain tissue with immunohistochemistry studies to evaluate the extent of stroke and tissue regeneration.
In vivo, imaging showed a higher accumulation of EPC exosomes following focused LIPUS without any damage to the underlying brain tissues. Four groups (Vehicle, LIPUS only, EPC-exosomes only, and LIPUS+EPC-exosomes) of aged animals were enrolled in the studies. The focused LIPUS + EPC exosomes group showed a decreased stroke volume (p=0.08) on day 7, decreased FluoroJade+ cells, and significantly higher numbers of neovascularization in and around the stroke areas although rCBF was not increased compared to that of other groups. There were no differences in the white matter tract volumes, ventricular volumes, astrogliosis, or neurobehavioral functions among the treated groups.
Transforming Early Stroke Care Through Mobile Stroke Treatment Unit Rendezvous With Rural Emergency Medical Services
Authors: Davis Nicolle W. , Fayed Mahmoud , Hardee Evan , Lykens David , Hester Jeannette M. , Magnuson Ashley E. , Singh Amita , Peng Teng J. , Khanna Anna 
Published: January 2025

BACKGROUND:
Mobile stroke units, also sometimes called Mobile Stroke Treatment Units (MSTUs) are changing the paradigm of acute stroke care and are considered to be an extension of the time is brain concept. Of the <20 active Mobile Stroke Programs in the United States, most are rooted in urban settings. In July 2023, the first MSTU in Florida was launched in Alachua County, implementing a unique and innovative rendezvous process with rural emergency medical services (EMS). We compared stroke outcome metrics between the MSTU, including rendezvous patients, and the standard process of EMS to the emergency department (ED).

METHODS:
We performed a retrospective analysis of patients with acute stroke evaluated in the MSTU and those transported to the ED by the standard EMS stroke alert process at an academic Comprehensive Stroke Center between July 25, 2023 and May 31, 2024. Patient demographic and acute stroke metrics were extracted to complete univariate and multivariate logistic regression analysis.

RESULTS:

Across all 3 groups, both MSTU patients with (n=76) and without (n=291) rendezvous compared with EMS-to-ED patients (n=807), had significantly shorter mean dispatch-to-door times (29.4 versus 28.5 versus 73.2 minutes, respectively;
P
<0.01), dispatch-to-needle times (41.3 versus 44.6 versus 104.1 minutes, respectively;
P
<0.01), and dispatch-to-puncture (92.7 versus 81.9 versus 138.0 minutes, respectively;
P
<0.01). In rural counties, MSTU rendezvous patients (n=76) compared with EMS-to-ED patients (n=206), had shorter mean dispatch-to-door and dispatch-to-needle times (41.3 versus 97.8 minutes, respectively;
P
<0.001). After adjusting for age and sex, these differences remained significant (odds ratio, 1.21 [95% CI, 1.07–1.37];
P
<0.01 and odds ratio, 1.80 [95% CI, 1.07–3.04];
P
=0.03, respectively).

CONCLUSIONS:
Our study demonstrates the effectiveness of MSTUs in Florida and establishes that the MSTU rendezvous process significantly improves timely stroke care in underserved rural counties.
Effect of Remote Ischemic Conditioning on the Form and Function of Red Blood Cells in Patients With Acute Ischemic Stroke
Authors: Blauenfeldt Rolf Ankerlund , Waller Jennifer , Drasbek Kim Ryun , Bech Jesper Nørgaard , Hvas Anne-Mette , Larsen Julie Brogaard , Andersen Morten Nørgaard , Nielsen Marlene Christina , Kjølhede Maria , Kjeldsen Mathilde , Gude Martin Faurholdt , Khan Mohammad Badruzzaman , Baban Babak , Andersen Grethe , Hess David Charles 
Published: January 2025

BACKGROUND:
Remote ischemic conditioning (RIC) is a simple and low-cost intervention that is thought to increase collateral blood flow through the vasodilatory effects of nitric oxide (NO) produced by the endothelium and red blood cells (RBCs). This study aims to investigate whether RIC affects RBC deformability and levels of NO and nitrite in patients with ischemic stroke.

METHODS:
This is a predefined substudy to the RESIST (Remote Ischemic Conditioning in Patients With Acute Stroke Trial) randomized clinical trial conducted in Denmark. RIC was started in the ambulance and continued at the hospital for seven days. Blood samples were collected at different time points: prehospital in the ambulance, in-hospital upon arrival, 2 hours postadmission, and 24 hours postadmission. RBC deformability and erythrocyte aggregation rate were assessed using ektacytometry, NO using flowcytometry, and nitrite content using ozone chemiluminescence.

RESULTS:

Of 1500 prehospital randomized patients, 486 patients were included in this study between July 28, 2020, and November 11, 2023, and had blood samples taken. Of these, 249 (51%) had AIS, and here RIC treatment was not associated with increased RBC maximal deformability (RIC, 0.549; sham, 0.548;
P
=0.31), RBC NO (RIC, 35 301 median fluorescence intensity; sham, 34979 median fluorescence intensity;
P
=0.89), or nitrite (RIC, 0.036 µmol/L; sham, 0.034 µmol/L;
P
=0.38), but RIC treatment was associated with a significantly reduced aggregation pressure and a slower erythrocyte aggregation rate (RIC, 323.76 millipascal; sham, 352.74 millipascal;
P
=0.0113).

CONCLUSIONS:
Prehospital and in-hospital RIC significantly reduced erythrocyte aggregation rate in patients with acute ischemic stroke, while there was no change in RBC deformability, NO content, or whole blood nitrite levels.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03481777.
Exploring neuroendocrine influences on the sensorimotor-association
axis in a female and a male individual
Authors: Serio Bianca , Yilmaz Deniz , Pritschet Laura , Grotzinger Hannah , Jacobs Emily G. , Eickhoff Simon B. , Valk Sofie L. 
Published: January 2025

Abstract
Human neuroimaging studies consistently show multimodal patterns of variability along a key principle of macroscale cortical organization—the sensorimotor-association (S-A) axis. However, little is known about day-to-day fluctuations in functional activity along this axis within an individual, including sex-specific neuroendocrine factors contributing to such transient changes. We leveraged data from two densely sampled healthy young adults, one female and one male, to investigate intra-individual daily variability along the S-A axis, which we computed as our measure of functional cortical organization by reducing the dimensionality of functional connectivity matrices. Daily variability was greatest in temporal limbic and ventral prefrontal regions in both participants, and was more strongly pronounced in the male subject. Next, we probed local- and system-level effects of steroid hormones and self-reported perceived stress on functional organization. Beyond shared patterns of effects, our findings revealed subtle and unique associations between neuroendocrine fluctuations and intra-individual variability along the S-A axis in the female and male participants. In sum, our study points to neuroendocrine factors as possible modulators of intra-individual variability in functional brain organization, highlighting the need for further research in larger samples to assess the sex specificity of these effects.