bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intensity-modulated radiotherapy combined with systemic atezolizumab and bevacizumab in treatment of hepatocellular carcinoma with extrahepatic portal vein tumor thrombus: A preliminary multicenter single-arm prospective study
Authors: Wang Kang , Xiang Yan-Jun , Yu Hong-Ming , Cheng Yu-Qiang , Liu Zong-Han , Zhong Jing-Ya , Feng Shuang , Ni Qian-Zhi , Zhu Hong-Fei , Pan Wei-Wei , Li Jing-Jing , Liang Chao , Zhou Hong-Kun , Meng Yan , Lau Wan Yee , Cheng Shu-Qun 
Published: February 2023

Background and aimsThe efficacy and safety of systemic atezolizumab and bevacizumab (atezo/bev) in treatment of patients with unresectable hepatocellular carcinoma (HCC) have been demonstrated. However, the efficacy of this treatment in patients with HCC and extrahepatic portal vein tumor thrombus (ePVTT) is not satisfactory. This study aimed to study the efficacy and safety of combining intensity-modulated radiotherapy (IMRT) with systemic atezo/bev in treatment of these patients.MethodsThis multicenter prospective study included patients with ePVTT treated with IMRT combined with atezo/bev from March to September 2021 in three centers in China. The outcomes of this study included objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to progression (TTP), and association between response and tumor mutational burden (TMB). Treatment-related adverse events (TRAEs) were analyzed to assess safety.ResultsOf 30 patients in this study, the median follow-up was 7.4 months. Based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, the ORR was 76.6%, the median OS for the entire cohort was 9.8 months, the median PFS was 8.0 months, and the median TTP was not reached. This study failed to establish a significant correlation between TMB with any of the following outcomes, including ORR, OS, PFS or TTP. The most common TRAEs at all levels were neutropenia (46.7%), and the most common grade 3/4 TRAE was hypertension (16.7%). There was no treatment-related deaths.ConclusionsIMRT combined with atezo/bev showed encouraging treatment efficacy with an acceptable safety profile, making this treatment to be a promising option for HCC patients with ePVTT. Further studies are required to support the findings of this preliminary study.Clinical trial registrationhttp://www.chictr.org.cn, Identifier ChiCTR2200061793.
Brief report: Assessment of mucosal barrier integrity using serological biomarkers in preclinical stages of rheumatoid arthritis
Authors: Gilbert Benoît Thomas P. , Lamacchia Céline , Amend Lena , Strowig Till , Rodriguez Emiliana , Palmer Gaby , Finckh Axel 
Published: February 2023

BackgroundThe pathogenesis of rheumatoid arthritis (RA) is believed to initiate at mucosal sites. The so-called ‘mucosal origin hypothesis of RA’ postulates an increased intestinal permeability before disease onset. Several biomarkers, including lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (I-FABP), have been proposed to reflect gut mucosa permeability and integrity, while serum calprotectin is a new inflammation marker proposed in RA.MethodsWe analyzed serum samples of individuals genetically at increased risk of RA in a nested-case-control study. Participants from a longitudinal cohort of first-degree relatives of RA patients (SCREEN-RA cohort) were divided into three pre-clinical stages of RA, based on the presence of risk factors for subsequent RA onset: 1) low-risk healthy asymptomatic controls; 2) intermediate-risk individuals without symptoms, but with RA-associated auto-immunity; 3) high-risk individuals with clinically suspect arthralgias. Five patients with newly diagnosed RA were also sampled. Serum LBP, I-FABP and calprotectin were measured using commercially available ELISA kits.ResultsWe included 180 individuals genetically at increased risk for RA: 84 asymptomatic controls, 53 individuals with RA-associated autoimmunity and 38 high risk individuals. Serum LBP, I-FAPB or calprotectin concentrations did not differ between individuals in different pre-clinical stages of RA.ConclusionBased on the serum biomarkers LBP, I-FABP and calprotectin, we could not detect any evidence for intestinal injury in pre-clinical stages of RA.
Developing a novel tool to assess the ability to self-administer medication – A systematic evaluation of patients’ video recordings in the ABLYMED study
Authors: Luegering Anneke , Langner Robert , Wilm Stefan , Doeppner Thorsten R. , Hermann Dirk M. , Frohnhofen Helmut , Gronewold Janine 
Published: February 2023

BackgroundOlder people often experience medication management problems due to multimorbidity, polypharmacy and medication complexity. There is often a large gap between patients’ self-reported and actual abilities to handle the self-administration of their medication. Here we report on the development and evaluation of a new tool to assess the ability of non-demented hospitalized patients to self-administer medication in different dosage forms. To this end, we video-recorded the patients’ medication management performance and implemented a novel assessment scheme, which was applied by several independent raters.MethodsSixty-seven in-patients ≥70 years of age and regularly taking ≥5 different drugs autonomously of the ABLYMED study agreed to the video recording of their medication management performance with five different dosage forms. All raters underwent a training and applied a standardized assessment form and written guide with rating rules for evaluation. In a pilot phase, video recordings of three patients were rated by 19 raters (15 medical students, two expert raters to determine a reference standard, and two main raters who later rated the total sample). In the rating phase, based on the ratings obtained from the two main raters, we determined interrater (assessed every section of 20 patients as agreement between the raters at one point of time) and intrarater (assessed as consistency within each rater across three points of time) agreement by intraclass correlation analysis.ResultsIn the pilot phase we obtained an overall sufficient agreement pattern, with an adjustment of the rating rules for patches. In the rating phase we achieved satisfactory agreement between the two raters (interrater reliability) and across different points of time (intrarater reliability). For two dosage forms (eye-drops and pen), rater training needed to be repeated to reach satisfactory levels.DiscussionOur novel rating procedure was found to be objective, valid and reproducible, given appropriate training of the raters. Our findings are an important part of a larger research project to implement a novel assessment for the ability to self-administer medication in different dosage forms. Further, they can support the development of patient trainings to improve medication management and secure independent living.
Objective response to immune checkpoint inhibitor therapy in NRAS-mutant melanoma: A systematic review and meta-analysis
Authors: Jaeger Zachary J. , Raval Neel S. , Maverakis Natalia K. A. , Chen David Y. , Ansstas George , Hardi Angela , Cornelius Lynn A. 
Published: February 2023

IntroductionNRAS mutations are common in melanoma and confer a worse prognosis. Although most patients with metastatic melanoma receive immune checkpoint inhibitors (ICIs), the impact of NRAS mutational status on their efficacy remains under debate.MethodsWe performed a comprehensive literature search across several large databases. Inclusion criteria were trials, cohorts, and large case series that analyzed the primary outcome of objective response rate by NRAS mutational status in patients with melanoma treated with any line of ICI. At least two reviewers independently screened studies using Covidence software, extracted data, and assessed risk of bias. Standard meta-analysis was performed in R with sensitivity analysis and tests for bias.ResultsData on 1770 patients from ten articles were pooled for meta-analysis, and the objective response rate to ICIs was calculated to compare NRAS-mutant and NRAS-wildtype melanoma. The objective response rate was 1.28 (95% confidence interval: 1.01–1.64). Sensitivity analysis identified the study by Dupuis et al. with influential impact on the pooled effect size and heterogeneity, favoring NRAS-mutant melanoma.DiscussionIn this meta-analysis evaluating the impact of NRAS mutational status on objective response to ICIs in metastatic melanoma, NRAS-mutant cutaneous melanoma demonstrated an increased likelihood of partial or complete tumor response, relative to NRAS-wildtype cutaneous melanoma. Genomic screening for NRAS mutations in patients with metastatic melanoma may improve predictive ability when initiating ICIs.
lncRNA-associated ceRNA network revealing the potential regulatory roles of ferroptosis and immune infiltration in Alzheimer’s disease
Authors: Tan Yejun , Tang Wang , Xiao Wenbiao , Huang Roujie , Li Xin , Peng Weijun , Yan Kuipo , Cao Yuan , Zeng Yi , Kang Jin 
Published: February 2023

BackgroundAlzheimer’s disease (AD) is the most common form of dementia characterized by a prominent cognitive deterioration of sufficient magnitude to impair daily living. Increasing studies indicate that non-coding RNAs (ncRNAs) are involved in ferroptosis and AD progression. However, the role of ferroptosis-related ncRNAs in AD remains unexplored.MethodsWe obtained the intersection of differentially expressed genes in GSE5281 (brain tissue expression profile of patients with AD) from the GEO database and ferroptosis-related genes (FRGs) from the ferrDb database. Least absolute shrinkage and selection operator model along with weighted gene co-expression network analysis screened for FRGs highly associated with AD.ResultsA total of five FRGs were identified and further validated in GSE29378 (area under the curve = 0.877, 95% confidence interval = 0.794–0.960). A competing endogenous RNA (ceRNA) network of ferroptosis-related hub genes (EPT1, KLHL24, LRRFIP1, CXCL2 and CD44) was subsequently constructed to explore the regulatory mechanism between hub genes, lncRNAs and miRNAs. Finally, CIBERSORT algorithms were used to unravel the immune cell infiltration landscape in AD and normal samples. M1 macrophages and mast cells were more infiltrated whereas memory B cells were less infiltrated in AD samples than in normal samples. Spearman’s correlation analysis revealed that LRRFIP1 was positively correlated with M1 macrophages (r = -0.340, P &lt; 0.001) whereas ferroptosis-related lncRNAs were negatively correlated with immune cells, wherein miR7-3HG correlated with M1 macrophages and NIFK-AS1, EMX2OS and VAC14-AS1 correlated with memory B cells (|r| &gt; 0.3, P &lt; 0.001).ConclusionWe constructed a novel ferroptosis-related signature model including mRNAs, miRNAs and lncRNAs, and characterized its association with immune infiltration in AD. The model provides novel ideas for the pathologic mechanism elucidation and targeted therapy development of AD.
Bifurcation analysis of motoneuronal excitability mechanisms under normal and ALS conditions
Authors: Moustafa Muhammad , Mousa Mohamed H. , Saad Mohamed S. , Basha Tamer , Elbasiouny Sherif M. 
Published: February 2023

IntroductionBifurcation analysis allows the examination of steady-state, non-linear dynamics of neurons and their effects on cell firing, yet its usage in neuroscience is limited to single-compartment models of highly reduced states. This is primarily due to the difficulty in developing high-fidelity neuronal models with 3D anatomy and multiple ion channels in XPPAUT, the primary bifurcation analysis software in neuroscience.MethodsTo facilitate bifurcation analysis of high-fidelity neuronal models under normal and disease conditions, we developed a multi-compartment model of a spinal motoneuron (MN) in XPPAUT and verified its firing accuracy against its original experimental data and against an anatomically detailed cell model that incorporates known MN non-linear firing mechanisms. We used the new model in XPPAUT to study the effects of somatic and dendritic ion channels on the MN bifurcation diagram under normal conditions and after amyotrophic lateral sclerosis (ALS) cellular changes.ResultsOur results show that somatic small-conductance Ca2+-activated K (SK) channels and dendritic L-type Ca2+ channels have the strongest effects on the bifurcation diagram of MNs under normal conditions. Specifically, somatic SK channels extend the limit cycles and generate a subcritical Hopf bifurcation node in the V-I bifurcation diagram of the MN to replace a supercritical node Hopf node, whereas L-type Ca2+ channels shift the limit cycles to negative currents. In ALS, our results show that dendritic enlargement has opposing effects on MN excitability, has a greater overall impact than somatic enlargement, and dendritic overbranching offsets the dendritic enlargement hyperexcitability effects.DiscussionTogether, the new multi-compartment model developed in XPPAUT facilitates studying neuronal excitability in health and disease using bifurcation analysis.
Leg restlessness and hyperparathyroidism in Parkinson's disease, a further clue to RLS pathogenesis?
Authors: Marano Massimo , Pozzilli Valeria , Magliozzi Alessandro , Tabacco Gaia , Naciu Anda Mihaela , Palermo Andrea , Di Lazzaro Vincenzo 
Published: February 2023

BackgroundNon-motor manifestations are the main features of Parkinson's disease (PD). These have been associated with vitamin D abnormalities, but the role of parathormone (PTH) is still obscure. Among the non-motor symptoms of PD, the pathogenesis of restless leg syndrome (RLS) is still debated, but it has been associated with the vitamin D/PTH axis in other disease models. Our study deepens the association between vitamin D and PTH with the prevalence of non-motor symptoms of PD and explores such a relationship in patients reporting leg restlessness.MethodsFifty patients with PD were extensively investigated with motor and non-motor scales. Data on serum levels of vitamin D, PTH, and related metabolites were obtained, and patients were stratified as having vitamin D deficiency or hyperparathyroidism according to standardized criteria.ResultsOverall, 80% of patients with PD exhibited low vitamin D levels, and hyperparathyroidism was diagnosed in 45%. The analysis of the non-motor symptoms profile using the non-motor symptom questionnaire (NMSQ) revealed 36% of leg restlessness, a main feature of RLS. This was significantly associated with worse motor symptoms, quality of sleep, and quality of life. Moreover, it was associated with hyperparathyroidism (OR: 3.48) and with PTH levels, independent of vitamin D, calcium/phosphate levels, and motor status.ConclusionOur results suggest a significant association between the vitamin D/PTH axis and leg restlessness in PD. PTH has a putative role in nociceptive modulation, and previous evidence on hyperparathyroidism has suggested a possible interrelation with RLS. Further investigations are necessary to add PTH to the non-dopaminergic non-motor landscape of PD.
Development of running is not related to time since onset of independent walking, a longitudinal case study
Authors: Bach Margit M. , Zandvoort Coen S. , Cappellini Germana , Ivanenko Yury , Lacquaniti Francesco , Daffertshofer Andreas , Dominici Nadia 
Published: February 2023

IntroductionChildren start to run after they master walking. How running develops, however, is largely unknown.MethodsWe assessed the maturity of running pattern in two very young, typically developing children in a longitudinal design spanning about three years. Leg and trunk 3D kinematics and electromyography collected in six recording sessions, with more than a hundred strides each, entered our analysis. We recorded walking during the first session (the session of the first independent steps of the two toddlers at the age of 11.9 and 10.6 months) and fast walking or running for the subsequent sessions. More than 100 kinematic and neuromuscular parameters were determined for each session and stride. The equivalent data of five young adults served to define mature running. After dimensionality reduction using principal component analysis, hierarchical cluster analysis based on the average pairwise correlation distance to the adult running cluster served as a measure for maturity of the running pattern.ResultsBoth children developed running. Yet, in one of them the running pattern did not reach maturity whereas in the other it did. As expected, mature running appeared in later sessions (&gt;13 months after the onset of independent walking). Interestingly, mature running alternated with episodes of immature running within sessions. Our clustering approach separated them.DiscussionAn additional analysis of the accompanying muscle synergies revealed that the participant who did not reach mature running had more differences in muscle contraction when compared to adults than the other. One may speculate that this difference in muscle activity may have caused the difference in running pattern.
From childhood trauma to hyperarousal in adults: The mediating effect of maladaptive shame coping and insomnia
Authors: Schalkwijk Frans , Van Someren Eus J. W. , Nicolai Nelleke J. , Uijttewaal Julia L. , Wassing Rick 
Published: February 2023

IntroductionA new line of insomnia research focuses on the developmental trajectories from early live stress to insomnia in adulthood. Adverse childhood experiences (ACE’s) might create a vulnerability for later maladaptive coping with distress, as seen in chronic hyperarousal or insomnia. In an functional magnetic resonance imaging (fMRI) study, failure to dissociate the neurobiological components of shame from autobiographical shameful memories in insomnia was reflected by continued activation of the dorsal anterior cingulate cortex (dACC), which may be a result of maladaptive coping in the wake of ACE’s. Following up on that study, the current pilot study explores the relation between ACE’s, shame coping-styles, adult insomnia, hyperarousal, and neurobiology of autobiographical memory.MethodsWe used existing data (N = 57) from individuals with insomnia (N = 27) and controls (N = 30), and asked these participants to complete the childhood trauma questionnaire (CTQ). Two structural equation models were used to test the hypotheses that shame-coping styles and insomnia symptom severity mediate the association between ACE’s and (1) self-rated hyperarousal symptoms and (2) dACC activation to recall of autobiographical memories.ResultsFor the association between ACE’s and hyperarousal, there was a significant mediation of shame-coping style (p &lt; 0.05). This model also indicated worse shame coping with more ACE’s (p &lt; 0.05) and worse insomnia symptoms with more ACES’s (p &lt; 0.05), but no association between shame coping and insomnia symptoms (p = 0.154). In contrast, dACC activation to recall of autobiographical memories could only be explained by its direct association with ACE’s (p &lt; 0.05), albeit that in this model more ACE’s were also associated with worse insomnia symptoms.DiscussionThese findings could have an implication for the approach of treatment for insomnia. It could be focused more on trauma and emotional processing instead of conventional sleep interventions. Future studies are recommended to investigate the relationship mechanism between childhood trauma and insomnia, with additional factors of attachment styles, personality, and temperament.
Object stiffness recognition and vibratory feedback without ad-hoc sensing on the Hannes prosthesis: A machine learning approach
Authors: Bruni Giulia , Marinelli Andrea , Bucchieri Anna , Boccardo Nicolò , Caserta Giulia , Di Domenico Dario , Barresi Giacinto , Florio Astrid , Canepa Michele , Tessari Federico , Laffranchi Matteo , De Michieli Lorenzo 
Published: February 2023

IntroductionIn recent years, hand prostheses achieved relevant improvements in term of both motor and functional recovery. However, the rate of devices abandonment, also due to their poor embodiment, is still high. The embodiment defines the integration of an external object – in this case a prosthetic device – into the body scheme of an individual. One of the limiting factors causing lack of embodiment is the absence of a direct interaction between user and environment. Many studies focused on the extraction of tactile information via custom electronic skin technologies coupled with dedicated haptic feedback, though increasing the complexity of the prosthetic system. Contrary wise, this paper stems from the authors' preliminary works on multi-body prosthetic hand modeling and the identification of possible intrinsic information to assess object stiffness during interaction.MethodsBased on these initial findings, this work presents the design, implementation and clinical validation of a novel real-time stiffness detection strategy, without ad-hoc sensing, based on a Non-linear Logistic Regression (NLR) classifier. This exploits the minimum grasp information available from an under-sensorized and under-actuated myoelectric prosthetic hand, Hannes. The NLR algorithm takes as input motor-side current, encoder position, and reference position of the hand and provides as output a classification of the grasped object (no-object, rigid object, and soft object). This information is then transmitted to the user via vibratory feedback to close the loop between user control and prosthesis interaction. This implementation was validated through a user study conducted both on able bodied subjects and amputees.ResultsThe classifier achieved excellent performance in terms of F1Score (94.93%). Further, the able-bodied subjects and amputees were able to successfully detect the objects' stiffness with a F1Score of 94.08% and 86.41%, respectively, by using our proposed feedback strategy. This strategy allowed amputees to quickly recognize the objects' stiffness (response time of 2.82 s), indicating high intuitiveness, and it was overall appreciated as demonstrated by the questionnaire. Furthermore, an embodiment improvement was also obtained as highlighted by the proprioceptive drift toward the prosthesis (0.7 cm).
Uptake of severe acute respiratory syndrome coronavirus 2 spike protein mediated by angiotensin converting enzyme 2 and ganglioside in human cerebrovascular cells
Authors: McQuaid Conor , Solorzano Alexander , Dickerson Ian , Deane Rashid 
Published: February 2023

IntroductionThere is clinical evidence of neurological manifestations in coronavirus disease-19 (COVID-19). However, it is unclear whether differences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/spike protein (SP) uptake by cells of the cerebrovasculature contribute to significant viral uptake to cause these symptoms.MethodsSince the initial step in viral invasion is binding/uptake, we used fluorescently labeled wild type and mutant SARS-CoV-2/SP to study this process. Three cerebrovascular cell types were used (endothelial cells, pericytes, and vascular smooth muscle cells), in vitro.ResultsThere was differential SARS-CoV-2/SP uptake by these cell types. Endothelial cells had the least uptake, which may limit SARS-CoV-2 uptake into brain from blood. Uptake was time and concentration dependent, and mediated by angiotensin converting enzyme 2 receptor (ACE2), and ganglioside (mono-sialotetrahexasylganglioside, GM1) that is predominantly expressed in the central nervous system and the cerebrovasculature. SARS-CoV-2/SPs with mutation sites, N501Y, E484K, and D614G, as seen in variants of interest, were also differentially taken up by these cell types. There was greater uptake compared to that of the wild type SARS-CoV-2/SP, but neutralization with anti-ACE2 or anti-GM1 antibodies was less effective.ConclusionThe data suggested that in addition to ACE2, gangliosides are also an important entry point of SARS-CoV-2/SP into these cells. Since SARS-CoV-2/SP binding/uptake is the initial step in the viral penetration into cells, a longer exposure and higher titer are required for significant uptake into the normal brain. Gangliosides, including GM1, could be an additional potential SARS-CoV-2 and therapeutic target at the cerebrovasculature.