bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of a test bench for biomechanical simulation—a preliminary study of mandibular forces
Authors: Ben Achour Anas , Apfeld Florian , Lauer Günter , Bräuer Christian , Leonhardt Henry , Franke Adrian , Lipphaus Andreas , Teicher Uwe , Witzel Ulrich , Schröder Tom Alexander 
Published: February 2024

Purpose: The aim of this study is to develop a test bench, which integrates different complexity levels and enables in that way a flexible and dynamic testing for mid and long term intervals as well as testing of maximum loads till implant failure of different osteosynthesis systems on the mandible.Material and Methods: For this purpose, an analysis of the state of the art regarding existing test benches was combined with interviews of clinical experts to acquire a list of requirements. Based on these requirements a design for a modular test bench was developed. During the implementation of the test stand, functional tests were continuously carried out and improvements made. Depending on the level of complexity, the test bench can be used either as an incorporated variant or as a standalone solution. In order to verify the performance and the degree of fulfilment of the requirements of these two variants of the test bench, preliminary studies were carried out for all levels of complexity. In these preliminary studies, commercially available osteosynthesis and reconstruction plates were investigated for their biomechanical behaviour and compared with data from the literature.Results: In total, fourteen test runs were performed for the different levels of complexity. Firstly, five test runs were executed to test the simplified load scenario in the incorporated variant of the test bench. High forces could be transmitted without failure of the miniplates. Secondly a quasi-static test scenario was examined using the incorporated variant with simplified load insertion. Five experiments with a number of cycles between 40,896 and 100,000 cycles were carried out. In one case the quasi-static testing resulted in a fracture of the tested reconstruction plate with a failure mode similar to the clinical observations of failure. The last four test runs were carried out using the standalone variant of the test bench simulating complex load patterns via the insertion of forces through imitated muscles. During the test runs joint forces were measured and the amplitude and vector of the resulting joint forces were calculated for both temporomandibular joints. Differences in the force transmission depending on the implant system in comparison to the zero sample could be observed.Conclusion: The presented modular test bench showed to be applicable for examination of the biomechanical behavior of the mandible. It is characterized by the adjustability of the complexity regarding the load patterns and enables the subsequent integration of further sensor technologies. Follow-up studies are necessary to further qualify and optimize the test bench.
Plasmid-encoded gene duplications of extended-spectrum β-lactamases in clinical bacterial isolates
Authors: Sobkowiak Annika , Scherff Natalie , Schuler Franziska , Bletz Stefan , Mellmann Alexander , Schwierzeck Vera , van Almsick Vincent 
Published: February 2024

IntroductionThe emergence of extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae is an urgent and alarming One Health problem. This study aimed to investigate duplications of plasmid-encoded ESBL genes and their impact on antimicrobial resistance (AMR) phenotypes in clinical and screening isolates.MethodsMulti-drug-resistant bacteria from hospitalized patients were collected during routine clinical surveillance from January 2022 to June 2023, and their antimicrobial susceptibility patterns were determined. Genotypes were extracted from long-read whole-genome sequencing data. Furthermore, plasmids and other mobile genetic elements associated with ESBL genes were characterized, and the ESBL genes were correlated to ceftazidime minimal inhibitory concentration (MIC).ResultsIn total, we identified four cases of plasmid-encoded ESBL gene duplications that match four genetically similar plasmids during the 18-month surveillance period: five Escherichia coli and three Klebsiella pneumoniae isolates. As the ESBL genes were part of transposable elements, the surrounding sequence regions were duplicated as well. In-depth analysis revealed insertion sequence (IS)-mediated transposition mechanisms. Isolates with duplicated ESBL genes exhibited a higher MIC for ceftazidime in comparison to isolates with a single gene copy (3–256 vs. 1.5–32 mg/L, respectively).ConclusionESBL gene duplications led to an increased phenotypic resistance against ceftazidime. Our data suggest that ESBL gene duplications by an IS-mediated transposition are a relevant mechanism for how AMR develops in the clinical setting and is part of the microevolution of plasmids.
Droplet digital PCR as alternative to microbiological culture for Mycobacterium tuberculosis complex detection in bovine lymph node tissue samples
Authors: Sánchez-Carvajal José María , Vera-Salmoral Eduardo , Huerta Belén , Galán-Relaño Ángela , Ruedas-Torres Inés , Larenas-Muñoz Fernanda , Luque Inmaculada , Carrasco Librado , Gómez-Laguna Jaime 
Published: February 2024

IntroductionBovine tuberculosis (bTB) caused by Mycobacterium tuberculosis complex (MTC) remains a significant concern for public health. Direct real-time PCR and droplet digital PCR (ddPCR) are proposed as alternative tools to enhance diagnostic precision and efficiency. This study aims to assess the diagnostic performance of a ddPCR assay targeting IS6110 for the detection of MTC DNA in both microbiological culture and fresh lymph node (LN) tissue samples obtained from cattle, in comparison with the established reference standard, the microbiological culture followed by real-time PCR. MethodsThe fresh LNs (N=100) were collected each from a different cattle carcass at the slaughterhouse. The limit of detection of ddPCR-IS6110 was set to 101 copies per 20 μl reaction.ResultsDdPCR-IS6110 detected 44 out of 49 reference-standard positive samples and yielded negative results in 47 out of 51 reference-standard negative samples, resulting in adjusted sensitivity (Se) and specificity (Sp) of 90.76% [95% confidence interval (CI): 82.58 - 98.96%)], and 100% (95% CI: 100%) respectively. The estimated adjusted false negative rate (FNR) was 9.23% (95% CI: 1.04 - 17.42%) and the false positive rate (FPR) was 0% (95% CI: 0%). When directly applied from fresh bovine LN tissues, ddPCR-IS6110 identified 47 out of 49 reference-standard positive samples as ddPCR-IS6110-positive and 42 out of 51 reference-standard negative samples as ddPCR-IS6110-negative, resulting in adjusted Se and Sp values of 94.80% [95% (CI): 88.52 - 100%] and 100% (95% CI: 100%), respectively. The adjusted FNR was 5.20% (95% CI: 0 - 11.50%) and the FPR was 0% (95% CI: 0%). Noteworthy, ddPCR-IS6110 disclosed as positive 9 samples negative to reference-standard. DiscussionDdPCR-IS6110 proved to be a rapid, highly sensitive, and specific diagnostic tool as an alternative to reference-standard method.
Operator decision-making in angiography-only guided revascularization for lesions not indicated for FFR: a QFR-based functional assessment in chronic coronary syndrome
Authors: Kanoun Schnur Sadeek S. , Pranevičius Robertas , Stark Cosima , Prunea Dan , Andreka Judit , Schmidt Albrecht , Harb Stefan , Ruzsa Zoltan , Zweiker Robert , Kane Jesse , Toth Gabor G. 
Published: February 2024

BackgroundDiscordance between coronary angiographic findings and invasive functional significance is well-established. Yet, the prevalence of this mismatch in an era increasingly utilizing invasive functional assessments, such as fractional flow reserve (FFR), remains unclear. This study examines the extent of such discrepancies in current clinical practice.MethodsThis single-center prospective registry included consecutive patients with chronic coronary syndrome (CCS) who underwent elective coronary angiography, with or without revascularization. Coronary angiograms deemed not requiring FFR due to clear anatomical distinctions, either anatomically severe indicating a need for revascularization or mild suggesting no need for intervention, were selected for evaluation. These were then subjected to post-hoc analysis by three independent operators who were blinded to the definitive treatment strategies. Importantly, the post-hoc analysis was conducted in two distinct phases: firstly, a re-evaluation of coronary stenosis, and secondly, a separate functional assessment, each carried out independently. Coronary stenosis severity was assessed visually, while functional relevance was determined by quantitative flow ratio (QFR), calculated using a computational fluid dynamics algorithm applied to angiographic images. Analysis focused on discrepancies between QFR-based functional indications and revascularization strategies actually performed.ResultsIn 191 patients, 488 vessels were analyzed. Average diameter stenosis (DS) was 37 ± 34%, and QFR was 0.87 ± 0.15, demonstrating a moderate correlation (r = −0.84; 95% CI: −0.86 to −0.81, p &lt; 0.01). Agreement with QFR at conventional anatomical cutoffs was 88% for 50% DS and 91% for 70% DS. Mismatches between revascularization decisions and QFR indications occurred in 10% of cases. Discrepancies were more frequent in the left anterior descending artery (14%) compared to the left circumflex (6%) and the right coronary artery (9%; p = 0.07).ConclusionIn a cardiac-center where FFR utilization is high, discordance between coronary angiography and functional significance persists, even when operators are confident in their decisions not to use functional interrogation. This gap, most evident in the left anterior descending artery, highlights the potential need for integrated angiography-based functional assessments to refine revascularization decisions in CCS.
Transcriptome profiling reveals superovulation with the gonadotropin-releasing hormone agonist trigger impaired embryo implantation in mice
Authors: Li Meng , Han Jingmei , Yang Nana , Li Xiangyun , Wu Xinglong 
Published: February 2024

IntroductionSuperovulation is a critical step in assisted reproductive technology, but the use of human chorionic gonadotropin (hCG) as a trigger for superovulation can result in ovarian hyperstimulation. Thus, the use of Gonadotropin-releasing hormone agonist (GnRHa) trigger has been increasingly adopted, although it has been associated with a higher rate of pregnancy failure compared to natural cycles. This study aimed to investigate the effect of GnRHa trigger on embryo implantation in a mouse model.MethodsMice in the superovulation (PG) group were administered 7.5 IU of PMSG, followed by the injection of 3.5 μg of GnRHa (Leuprorelin) 48 h later, while mice in the control group (CTR) mated naturally. We compared the number of oocytes, blastocysts, and corpus luteum between the two groups and the implantation sites after the transfer of natural blastocysts. Ovaries, uterus, and serum 2 and 4 days after mating were collected for qRT-PCR, transcriptome sequencing, and hormone assays.ResultsThe PG group had more oocytes, blastocysts, and corpus luteum after superovulation than the CTR group. However, the mRNA expression of leukemia inhibitory factor (Lif) and the number of implantation sites were reduced in the PG group. The ELISA assay revealed that superovulation increased ovarian estrogen secretion. The transcriptome analysis showed that superphysiological estrogen led to a response of the uterus to a high estrogen signal, resulting in abnormal endometrium and extracellular matrix remodeling and up-regulation of ion transport and inflammation-related genes.ConclusionOur findings suggest that a combination of PMSG and GnRHa trigger impaired embryo implantation in mice, as the excessive uterine response to superphysiological estrogen levels can lead to the change of gene expression related to endometrial remodeling, abnormal expression of uterine ion transport genes and excessive immune-related genes.
Neutrophil-derived Activin-A moderates their pro-NETotic activity and attenuates collateral tissue damage caused by Influenza A virus infection
Authors: Divolis Georgios , Synolaki Evgenia , Doulou Athanasia , Gavriil Ariana , Giannouli Christina C. , Apostolidou Anastasia , Foster Martyn L. , Matzuk Martin M. , Skendros Panagiotis , Galani Ioanna-Evdokia , Sideras Paschalis 
Published: February 2024

BackgroundPre-neutrophils, while developing in the bone marrow, transcribe the Inhba gene and synthesize Activin-A protein, which they store and release at the earliest stage of their activation in the periphery. However, the role of neutrophil-derived Activin-A is not completely understood.MethodsTo address this issue, we developed a neutrophil-specific Activin-A-deficient animal model (S100a8-Cre/Inhbafl/fl mice) and analyzed the immune response to Influenza A virus (IAV) infection. More specifically, evaluation of body weight and lung mechanics, molecular and cellular analyses of bronchoalveolar lavage fluids, flow cytometry and cell sorting of lung cells, as well as histopathological analysis of lung tissues, were performed in PBS-treated and IAV-infected transgenic animals.ResultsWe found that neutrophil-specific Activin-A deficiency led to exacerbated pulmonary inflammation and widespread hemorrhagic histopathology in the lungs of IAV-infected animals that was associated with an exuberant production of neutrophil extracellular traps (NETs). Moreover, deletion of the Activin-A receptor ALK4/ACVR1B in neutrophils exacerbated IAV-induced pathology as well, suggesting that neutrophils themselves are potential targets of Activin-A-mediated signaling. The pro-NETotic tendency of Activin-A-deficient neutrophils was further verified in the context of thioglycollate-induced peritonitis, a model characterized by robust peritoneal neutrophilia. Of importance, transcriptome analysis of Activin-A-deficient neutrophils revealed alterations consistent with a predisposition for NET release. ConclusionCollectively, our data demonstrate that Activin-A, secreted by neutrophils upon their activation in the periphery, acts as a feedback mechanism to moderate their pro-NETotic tendency and limit the collateral tissue damage caused by neutrophil excess activation during the inflammatory response.
Causal effect of gut microbiota of Defluviitaleaceae on the clinical pathway of “Influenza–Subacute Thyroiditis–Hypothyroidism”
Authors: Zhang Xin , Li Pei-Heng , Wang Dongyue , Li Hancong , Kong Xiangyu , Zhang Gongshuang , Zhao Yue , Liu Jiaye , Wu Wenshuang , Zhang Yuwei , Li Zhi-Hui , Luo Han 
Published: February 2024

IntroductionHypothyroidism has been found to be influenced by gut microbiota. However, it remains unclear which a taxon of gut microbiota plays a key role in this function. Identifying the key bacteria affects hypothyroidism and through what mechanism will be helpful for the prevention of hypothyroidism through specific clinical pathways.Materials and methodsIn Study A, 35 families and 130 genera of gut microbiota are used as exposures, with hypothyroidism as the outcome. The causal effect of the gut microbiota on hypothyroidism is estimated through two-sample Mendelian randomization. Combining the results of the two taxonomical levels, key taxa are selected, which in Study B are investigated for their causal association with multiple generally admitted causes of hypothyroidism and their more upstream factors. For validating and revealing the potential mechanism, enrichment analyses of the related genes and interacting transcription factors were performed.ResultsIn Study A, Defluviitaleaceae (OR: 0.043, 95% CI: 0.005–0.363, P = 0.018)/Defluviitaleaceae_UCG_011 (OR: 0.385, 95% CI: 0.172–0.865, P = 0.021) are significantly causally associated with hypothyroidism at both taxonomical levels. In Study B, Defluviitaleaceae family and Defluviitaleaceae_UCG_011 genus show the causal association with decreased thyroiditis (Family: OR: 0.174, 95% CI: 0.046–0.653, P = 0.029; Genus: OR: 0.139, 95% CI: 0.029–0.664, P = 0.043), decreased subacute thyroiditis (Family: OR: 0.028, 95% CI: 0.004–0.213, P = 0.007; Genus: OR: 0.018, 95% CI: 0.002–0.194, P = 0.013), decreased influenza (Family: OR: 0.818, 95% CI: 0.676–0.989, P = 0.038; Genus: OR: 0.792, 95% CI: 0.644–0.974, P = 0.027), and increased anti-influenza H3N2 IgG levels (Family: OR: 1.934, 95% CI: 1.123–3.332, P = 0.017; Genus: OR: 1.675, 95% CI: 0.953–2.943, P = 0.073). The results of the enrichment analysis are consistent with the findings and the suggested possible mechanisms.ConclusionDefluviitaleaceae of the gut microbiota displays the probability of causally inhibiting the clinical pathway of “Influenza–Subacute Thyroiditis–Hypothyroidism” and acts as the potential probiotics to prevent influenza, subacute thyroiditis, and hypothyroidism.
Comparative analysis of multimodal biomarkers for amyloid-beta positivity detection in Alzheimer's disease cohorts
Authors: Mehdipour Ghazi Mostafa , Selnes Per , Timón-Reina Santiago , Tecelão Sandra , Ingala Silvia , Bjørnerud Atle , Kirsebom Bjørn-Eivind , Fladby Tormod , Nielsen Mads 
Published: February 2024

IntroductionEfforts to develop cost-effective approaches for detecting amyloid pathology in Alzheimer's disease (AD) have gained significant momentum with a focus on biomarker classification. Recent research has explored non-invasive and readily accessible biomarkers, including magnetic resonance imaging (MRI) biomarkers and some AD risk factors.MethodsIn this comprehensive study, we leveraged a diverse dataset, encompassing participants with varying cognitive statuses from multiple sources, including cohorts from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and our in-house Dementia Disease Initiation (DDI) cohort. As brain amyloid plaques have been proposed as sufficient for AD diagnosis, our primary aim was to assess the effectiveness of multimodal biomarkers in identifying amyloid plaques, using deep machine learning methodologies.ResultsOur findings underscore the robustness of the utilized methods in detecting amyloid beta positivity across multiple cohorts. Additionally, we investigated the potential of demographic data to enhance MRI-based amyloid detection. Notably, the inclusion of demographic risk factors significantly improved our models' ability to detect amyloid-beta positivity, particularly in early-stage cases, exemplified by an average area under the ROC curve of 0.836 in the unimpaired DDI cohort.DiscussionThese promising, non-invasive, and cost-effective predictors of MRI biomarkers and demographic variables hold the potential for further refinement through considerations like APOE genotype and plasma markers.
Proteasome localization and activity in pig brain and in vivo small molecule screening for activators
Authors: Amrein Almira Adriana , Chen May W. , El Demerdash Nagat , Javdan Cameron , Park Dongseok , Lee Jennifer K. , Martin Lee J. 
Published: February 2024

IntroductionLoss of proteasome function, proteinopathy, and proteotoxicity may cause neurodegeneration across the human lifespan in several forms of brain injury and disease. Drugs that activate brain proteasomes in vivo could thus have a broad therapeutic impact in neurology.MethodsUsing pigs, a clinically relevant large animal with a functionally compartmental gyrencephalic cerebral cortex, we evaluated the localization and biochemical activity of brain proteasomes and tested the ability of small molecules to activate brain proteasomes.ResultsBy Western blotting, proteasome protein subunit PSMB5 and PSMA3 levels were similar in different pig brain regions. Immunohistochemistry for PSMB5 showed localization in the cytoplasm (diffuse and particulate) and nucleus (cytoplasm &lt; nucleus). Some PSMB5 immunoreactivity was colocalized with mitochondrial (voltage-gated anion channel and cyclophilin D) and cell death (Aven) proteins in the neuronal soma and neuropil in the neocortex of pig and human brains. In the nucleus, PSMB5 immunoreactivity was diffuse, particulate, and clustered, including perinucleolar decorations. By fluorogenic assay, proteasome chymotrypsin-like activities (CTL) in crude tissue soluble fractions were generally similar within eight different pig brain regions. Proteasome CTL activity in the hippocampus was correlated with activity in nasal mucosa biopsies. In pilot analyses of subcellular fractions of pig cerebral cortex, proteasome CTL activity was highest in the cytosol and then ~50% lower in nuclear fractions; ~15–20% of total CTL activity was in pure mitochondrial fractions. With in-gel activity assay, 26S-singly and -doubly capped proteasomes were the dominant forms in the pig cerebral cortex. With a novel in situ histochemical activity assay, MG132-inhibitable proteasome CTL activity was localized to the neuropil, as a mosaic, and to cell bodies, nuclei, and centrosome-like perinuclear satellites. In piglets treated intravenously with pyrazolone derivative and chlorpromazine over 24 h, brain proteasome CTL activity was modestly increased.DiscussionThis study shows that the proteasome in the pig brain has relative regional uniformity, prominent nuclear and perinuclear presence with catalytic activity, a mitochondrial association with activity, 26S-single cap dominance, and indications from small molecule systemic administration of pyrazolone derivative and chlorpromazine that brain proteasome function appears safely activable.
Spasticity-Plus syndrome in multiple sclerosis patients in a tertiary hospital in Spain
Authors: Goicochea Briceño Haydee , Higueras Yolanda , Ruiz Pérez Irene , García Domínguez José Manuel , Cuello Juan Pablo , Meldaña Rivera Ariana , Martínez Ginés María Luisa 
Published: February 2024

IntroductionSpasticity is a common symptom in multiple sclerosis (MS) and it is often associated with other symptoms such as spasms/cramps and pain. The concept of Spasticity-Plus syndrome takes into account that spasticity is accompanied by one or more symptoms (spasms/cramps, pain, bladder dysfunction, sleep disorders, fatigue and/or tremor). As these symptoms share a common cannabinoid control, therapy acting on cannabinoid receptors may be useful. The main study objectives were to determine the number of MS patients who met Spasticity-Plus syndrome criteria and to identify the most common symptoms.MethodsClinical records of MS patients treated with nabiximols in a tertiary hospital from 2002 to 2022 were reviewed retrospectively.ResultsOf the 73 patients included in the study, 53.4% were women, and most had secondary progressive MS (64.4%). All patients met the criteria for Spasticity-Plus syndrome: 100% had spasticity and at least another symptom. Pain was the second most common symptom (91.8%), followed by spasms/cramps (79.4%), and fatigue (76.7%). Sleep disturbances (p &lt; 0.0001) and tremor (p &lt; 0.027) were more frequent in patients with relapsing–remitting MS than in patients with progressive MS. No statistically significant differences were found for spasticity, pain, spasms/cramps, and fatigue between MS phenotypes. Regarding symptoms clusters, 94.4% of the patients had three or more symptoms. Spasticity was more frequently associated with pain (91.8%) and spasms/cramps (79.4%).ConclusionSpasticity-Plus syndrome was present in all the study population of patients with different MS phenotypes, and treated with nabiximols.