bluuebunny/crossref_metadata_2025_split huggingface dataset:
An unbiased approach of individual tissue-specific autoantibody identification using Immunoprecipitation coupled to Mass-Spectrometry (IP-MS)
Authors: Arlt Friederike Antonia , Sánchez-Sendín Elisa , Kirchner Marieluise , De Haas Max-Pelgrom , Mertins Philipp , Pruess Harald 
Published: November 2023

Abstract

Background and aim
Autoreactive antibodies have gained increasing recognition in autoimmune diseases of the central nervous system (CNS) serving as disease drivers and / or biomarkers. Identification of novel autoantibodies therefore is crucial to optimize diagnostic work and therapy of these diseases as well as understanding their pathogenesis. Hence, we aimed to develop an unbiased strategy to identify patients’ individual main autoantibodies directed against brain epitopes.

Methods
We used murine tissue-based assays to screen patients’ sera and cerebrospinal fluids (CSFs) for autoreactive IgGs with known and unknown antibody targets. IgGs from autoreactive patients’ samples were coupled to magnetic beads and used as a bait to pull down potential targets from homogenized brain tissue of wildtype mice. After precipitation and several washes to reduce unspecific binding, beads were subjected to on-bead tryptic digestion followed by mass spectrometry based proteomic analyses using liquid chromatography tandem mass-spectrometry (LC-MS/MS). For antibody targets identification the fold change enrichment compared to a negative control or to all other pulldown samples, as well as the protein abundance was used. Antibody target validation was done via recombinant expression of the target protein in HEK-293 cells and neutralization with the respective antigen in tissue-based immunofluorescence assays.

Results
As proof of principle, we were able to identify Grin1 Caspr2, Trim46 and Nf-h [MOU1] as main targets of patients’ sera or CSF with autoimmune encephalopathy. All four antigens showed highest enrichment and/or highest protein abundance in the respective samples and have been confirmed in cell-based assays. In addition, we identified one novel anti-neuronal antibody target in serum and CSF of a patient showing a speckled staining of the granular cerebellar layer. Preabsorbance of the serum and CSF with the recombinant protein fully neutralized the signal of the tissue-based immunofluorescence.

Conclusions
Our IP-MS approach is suitable to identify the main autoantibody targets in patients’ serum and CSF within murine CNS tissue thereby providing an unbiased and scalable technique allowing for tissue-specific autoantibody determination.
Comparing Refrigeration to Immediate Room Temperature Testing for Uric Acid Monitoring in Rasburicase-Treated Patients
Authors: Lin Leo , Filtz Michael , Wilson Jeffrey , Errigo Roscoe , Sorenson Anh Nguyen , Zuromski Lauren , Young Brittany 
Published: November 2023

Abstract
Rasburicase (Rb) is a uric acid (UA) degrading enzyme important for treating tumor lysis syndrome. Rb retains activity at room temperature (RT), so specimens collected for UA-level monitoring require cooling protocols: collecting samples in pre-chilled tubes, transporting on ice, centrifuging at 4°C, and testing within 4 hours. In our laboratory, specimens are tested within ~45 minutes of collection. Our clinical study objective was to determine if we could ease these pre-analytical requirements to improve compliance while maintaining accuracy. 50 pairs of specimens were transported and stored either on ice or at RT. All were tested at 3 time points post-collection: immediately upon arrival to the laboratory (~45 minutes), 90 minutes, and 135 minutes. Linear regression analysis of iced versus RT specimens showed a high correlation with R2= 0.99 (p&lt; .0001) and bias of -2.4%, which indicate no clinical differences observed in UA concentrations between 1-12 mg/dL, at the immediate testing time point. UA levels did not significantly decrease in the iced specimens at any time point. However, UA levels had decreased by &gt;10% in 16 of the 50 RT specimens after 90 minutes. Linear regression analysis of specimens tested immediately on ice versus RT specimens tested after 135 minutes yielded an R2= 0.84 (p&lt; .0001) and bias of -17.5%. The best model from a stepwise regression was composed of the number of binned Rb half-lives (0-2 or &gt;2) that had passed since the patients’ Rb infusion (Rb half-life= 1080 minutes; p&lt; .0001) and the Rb dose (3 mg versus 6 mg, p&lt; .0001), which explained ~50% of the UA variation (R2= 0.48, p&lt; .0001). Keeping Rb dose constant, RT specimens tested within 0-2 half-lives post-infusion had an additional 24% average decrease in UA concentration compared to those tested after &gt;2 half-lives. Similarly, keeping Rb half-life constant, RT specimens from patients given a 6-mg dose had an 18% decrease in UA concentration compared to patients given a 3-mg dose. Using a total allowable error (TEA) of 17% as a threshold, 96%, 60%, and 38% of RT specimens tested within 0-2 half-lives were within TEA at the immediate (45-minute), 90-minute, and 135-minute time points, respectively. In contrast, 100%, 96%, and 88% of RT specimens tested after &gt;2 half-lives were within TEA at the immediate (45-minute), 90-minute, and 135-minute time points, respectively. UA concentrations are not clinically different in RT or iced specimens, as long as tested within ~45 minutes post-collection. Specimens tested within 2 Rb half-lives post-infusion have significantly decreased UA levels if kept at RT for &gt;90 minutes. Laboratories that can test UA levels rapidly after specimen collection may be able to validate alternative pre-analytical methods to transporting and testing on ice.
Development and Validation of a Liquid Chromatography Mass Spectrometry Method to Measure Highly Concentrated Tacrolimus and Cyclosporine Specimens Prepared from Commercial Pharmaceutical Products to Assess Administration Through Feeding Tubes
Authors: Xiao Yi , Gabra Mari Ishak , Leung Edward 
Published: November 2023

Abstract

Background
Tacrolimus and cyclosporine are common immunosuppressive drugs used in the prevention and treatment of solid-organ transplant rejection (e.g., kidney, liver, heart). Other indications include several autoimmune diseases such as Crohn’s disease, autoimmune hepatitis, and rheumatoid arthritis. To prevent toxicity while achieving therapeutic efficacy, tacrolimus and cyclosporine in whole blood specimens are commonly measured in medical centers so that their dosages can be precisely adjusted. Different from adult patients, pediatric patients often require smaller doses and the use of feeding tubes for drug administration. In order to assess nonspecific adsorption by feeding tubes, we modified our in-house clinical method to measure highly concentrated tacrolimus and cyclosporine specimens prepared from clinical pharmaceutical products. Method: Highly concentrated tacrolimus and cyclosporine specimens were serially diluted with dimethyl sulfoxide (2,000 times for tacrolimus and 20,000 times for cyclosporine) before measurements by our clinical method using liquid chromatography mass spectrometry. The method for highly concentrated tacrolimus and cyclosporine was validated, with analytical measurement range determined with in-house prepared concentrated specimens at varying concentrations, precision (repeatability and reproducibility) assessed by multiple measurements of concentrated specimens at three different concentrations, accuracy assessed by recovery studies, and matrix effect assessed by post-column infusion and by matrix dilution with dimethyl sulfoxide.

Results
The method was linear from 10 ug/mL to 80 ug/mL for tacrolimus, and 1 mg/mL to 8 mg/mL for cyclosporine with r2 &gt; 0.99. Repeatability and reproducibility were &lt;10% CV. Minimal matrix effect was observed. Recovery studies using commercial calibrators to measure specimens prepared from reference materials and dimethyl sulfoxide identified no significant bias for tacrolimus but an average positive bias of 20% for cyclosporine, and a correction factor was used to finalize cyclosporine results for specimens prepared from clinical pharmaceutical products. The positive bias was eliminated when calibrators were prepared in dimethyl sulfoxide.

Conclusion
s: We have developed and validated a LC-MS/MS method for the measurement of highly concentrated tacrolimus and cyclosporine in specimens prepared from clinical pharmaceutical products. We hypothesize that one or more components in the commercial calibrators have contributed to the positive bias of cyclosporine in those specimens. Our method can be used to support studies that assess nonspecific adsorption by feeding tubes.
CytogeneticsTissue Fixation Significantly Impacts MLH1 Promoter Methylation Analysis: A Quality Improvement Study
Authors: Park Yongsang , Yeboah Bettie , Rosti Ozgur , Williams Eli , Fan Jinbo 
Published: November 2023

Abstract
MLH1 promoter methylation (MPM) analysis is an invaluable tool for distinguishing sporadic from inherited colorectal and endometrial cancers. At our institutional clinical genomics lab, we observed an unusually high failure rate of MPM testing in endometrial (EM) cancers. This triggered a quality improvement (QI) project to identify the underlying cause and improve the success rate of our MPM assay. We retrospectively identified all MPM cases (EM and non-endometrial (NEM) cancers) between January 2019 and October 2022 through querying our departmental database. The failure rates of these two groups were juxtaposed with the following variables: DNA concentration, performing technologists, operating surgeons, and specimen collection day (Monday through Saturday). A subsequent fishbone analysis was performed to evaluate the impact of specimen handling, fixation, and embedding procedure/timeline in the gross room and histology labs. We identified one-hundred thirty-one EM cases and eighty-two NEM cases that underwent MPM testing. Thirty-one EM cases (24%) and seven NEM cases (9%) failed, re-demonstrating the higher failure rate (X2=7.9, P-value=0.005) of EM cases. There was no significant difference in DNA concentration, performing technologists, and operating surgeons when compared to passed cases, however, a highly significant difference was seen concerning day of specimen collection (X2=53, P-value&lt;0.0001). Most notably, all failed EM (n=31) and NEM cases (n=7) were collected on either Thursday or Friday (failure rate of 26% and 59%, respectively, 44% jointly). Our fishbone analysis revealed that specimens accessioned Thursday afternoon and Friday were fixed throughout the weekend before embedding on Monday, resulting in prolonged fixation (one extra day). This is consistent with previous studies’ conclusions showing DNA quality (but not quantity) significantly worsened with longer formalin fixation. Upon presenting these data to lab personnel, workflow changes were implemented. Cancer tissue that would have originally fixed over the weekend was instead processed on Saturday starting December 2022. This QI project revealed that prolonged formalin fixation of specimens over the weekend dramatically reduces the success rate of MPM analysis of EM cancer cases. Subsequently, we expanded our investigation to include other molecular assays at our institution that have returned similar results. Since the implementation of the revised workflow in December 2022, a preliminary prospective analysis showed the MLH1 failure rate of EM cancer tissues collected on Thursday and Friday has decreased from 44% to 11% in the past three months (December 2022 – February 2023). The current findings have important implications for the use of FFPE specimens in genetic analysis and highlight the need for careful consideration of fixation workflows, especially over the weekend, in sample processing protocols.
survex: an R package for explaining machine learning survival models
Authors: Spytek Mikołaj , Krzyziński Mateusz , Langbein Sophie Hanna , Baniecki Hubert , Wright Marvin N , Biecek Przemysław 
Published: November 2023

Abstract

Summary
Due to their flexibility and superior performance, machine learning models frequently complement and outperform traditional statistical survival models. However, their widespread adoption is hindered by a lack of user-friendly tools to explain their internal operations and prediction rationales. To tackle this issue, we introduce the survex R package, which provides a cohesive framework for explaining any survival model by applying explainable artificial intelligence techniques. The capabilities of the proposed software encompass understanding and diagnosing survival models, which can lead to their improvement. By revealing insights into the decision-making process, such as variable effects and importances, survex enables the assessment of model reliability and the detection of biases. Thus, transparency and responsibility may be promoted in sensitive areas, such as biomedical research and healthcare applications.

Availability and implementation
survex is available under the GPL3 public license at https://github.com/modeloriented/survex and on CRAN with documentation available at https://modeloriented.github.io/survex.
Miriam Toews’Women Talkingand the Embodied Life of Feminist Nonviolence
Authors: Glista Victoria 
Published: November 2023

AbstractIn Miriam Toews’ novel Women Talking (2018), the women of a remote Mennonite colony discover that they have been serially raped in their sleep, and so they meet to plot a nonhierarchical community of their own. I argue that this transformation relies on gestures, postures, and reorientations that spur liberatory new ways of perceiving and participating in the world; consequently, their bodily comportment is essential to revolutionary worldmaking, as well as to how we might approach the novel beyond its titular emphasis on speech. The women’s rechoreography of the colony’s norms also revivifies nonviolence as agonistic and egalitarian—a tentpole of the Mennonite faith. My reading works across the entanglement of movement and transformation in Women Talking before thinking through its rehearsal of bodily relations or set of gestural and postural ethics that ultimately dispose these women and survivors toward radical forms of care and interdependence, or what Judith Butler might call “aggressive nonviolence.”
A Core Outcome Set for Inflammatory Bowel Diseases: Development and Recommendations for Implementation in Clinical Practice Through an International Multi-stakeholder Consensus Process
Authors: Fierens Liselotte , Carney Nicholas , Novacek Gottfried , van der Woude C Janneke , Siegmund Britta , Casellas Francesc , Borruel Natalia , Huberts Anouk S , Sonnenberg Elena , Gerold Nathalie , Primas Christian , Hedin Charlotte R H , Stamm Tanja , Julsgaard Mette , Fiorino Gionata , Radice Simona , Zini Michela Luciana Luisa , Gross Evelyn , Sander Cornelia , Arijs Ingrid , Vakouftsi Vasiliki-Rafaela , Koltai Tunde , Charlafti Iliàs , Ferrante Marc 
Published: November 2023

Abstract

Background and Aims
Standardising health outcome measurements supports delivery of care and enables data-driven learning systems and secondary data use for research. As part of the Health Outcomes Observatory [H2O] initiative, and building on existing knowledge, a core outcome set [COS] for inflammatory bowel diseases [IBD] was defined through an international modified Delphi method.

Methods
Stakeholders rated 90 variables on a 9-point importance scale twice, allowing score modification based on feedback displayed per stakeholder group. Two consecutive consensus meetings were held to discuss results and formulate recommendations for measurement in clinical practice. Variables scoring 7 or higher by ≥80% of the participants, or based on consensus meeting agreement, were included in the final set.

Results
In total, 136 stakeholders (45 IBD patients [advocates], 74 health care professionals/researchers, 13 industry representatives, and four regulators) from 20 different countries participated. The final set includes 18 case-mix variables, three biomarkers [haemoglobin to detect anaemia, C-reactive protein and faecal calprotectin to detect inflammation] for completeness, and 28 outcomes (including 16 patient-reported outcomes [PROs] and one patient-reported experience). The PRO-2 and IBD-Control questionnaires were recommended to collect disease-specific PROs at every contact with an IBD practitioner, and the Subjective Health Experience model questionnaire, PROMIS Global Health and Self-Efficacy short form, to collect generic PROs annually.

Conclusions
A COS for IBD, including a recommendation for use in clinical practice, was defined. Implementation of this set will start in Vienna, Berlin, Barcelona, Leuven, and Rotterdam, empowering patients to better manage their care. Additional centres will follow worldwide.
Associations of omega-3 fatty acids vs. fenofibrate with adverse cardiovascular outcomes in people with metabolic syndrome: propensity matched cohort study
Authors: Kim Nam Hoon , Kim Ji Yoon , Choi Jimi , Kim Sin Gon 
Published: November 2023

Abstract

Aims
Omega-3 fatty acids and fenofibrates have shown some beneficial cardiovascular effects; however, their efficacy has not been compared. This study aimed to compare the effectiveness of currently available omega-3 fatty acids and fenofibrate for reducing major adverse cardiovascular events (MACE).

Methods and results
From a nationwide population-based cohort in South Korea (2008–2019), individuals with metabolic syndrome (≥30 years) who received statin with omega-3 fatty acids and those receiving statin with fenofibrate were matched by propensity score (n = 39 165 in both groups). The primary outcome was MACE, including ischaemic heart disease (IHD), ischaemic stroke (IS), and death from cardiovascular causes. The risk of MACE was lower [hazard ratio (HR), 0.79; 95% confidence interval (CI), 0.74–0.83] in the fenofibrate group than in the omega-3 fatty acid group. Fenofibrate was associated with a lower incidence of IHD (HR, 0.72; 95% CI, 0.67–0.77) and hospitalization for heart failure (HR, 0.90; 95% CI, 0.82–0.97), but not IS (HR, 0.90; 95% CI, 0.81–1.00) nor death from cardiovascular causes (HR, 1.07; 95% CI, 0.97–1.17). The beneficial effect of fenofibrate compared to omega-3 fatty acids was prominent in patients with preexisting atherosclerotic cardiovascular disease and those receiving lower doses of omega-3 fatty acids (≤2 g per day).

Conclusion
In a real-world setting, fenofibrate use was associated with a lower risk of MACE compared with low-dose omega-3 fatty acids when added to statins in people with metabolic syndrome.
The Danish-Norwegian randomized trial on beta-blocker therapy after myocardial infarction: Design, rationale, and baseline characteristics
Authors: Kristensen Anna Meta Dyrvig , Munkhaugen John , Halvorsen Sigrun , Olsen Michael Hecht , Bakken Arnhild , Sehested Thomas Steen Gyldenstierne , Ruddox Vidar , Lange Theis , Fagerland Morten Wang , Torp-Pedersen Christian , Prescott Eva , Atar Dan 
Published: November 2023

Abstract

Background and aims
The evidence for beta-blocker therapy after myocardial infarction (MI) is randomized trials conducted more than 30 years ago, and the continued efficacy has been questioned.

Design and methods
The ongoing Danish (DANBLOCK) and Norwegian (BETAMI) randomized beta-blocker trials are joined to evaluate the effectiveness and risks of long-term beta-blocker therapy after MI. Patients with normal or mildly reduced left ventricular ejection fraction (LVEF ≥ 40%) will be randomized to open-label treatment with beta-blockers or no such therapy. The event-driven trial will randomize ∼5700 patients and continue until 950 primary endpoints have occurred. As of July 2023, 5228 patients have been randomized. Of the first 4000 patients randomized, median age was 62 years, 79% were men, 48% had a ST-segment elevation myocardial infarction (STEMI), and 84% had a normal LVEF. The primary endpoint is a composite of adjudicated recurrent MI, incident heart failure (HF), coronary revascularization, ischaemic stroke, all-cause mortality, malignant ventricular arrhythmia, or resuscitated cardiac arrest. The primary safety endpoint includes a composite of recurrent MI, HF, all-cause mortality, malignant ventricular arrhythmia, or resuscitated cardiac arrest 30 days after randomization. Secondary endpoints include each of the components of the primary endpoint, patient-reported outcomes, and other clinical outcomes linked to beta-blocker therapy. The primary analysis will be conducted according to the intention-to-treat principle using a Cox proportional hazards regression model. End of follow-up is expected in December 2024.

Conclusion
The combined BETAMI–DANBLOCK trial will have the potential to affect current clinical practice for beta-blocker therapy in patients with normal or mildly reduced LVEF after MI.
Inonotus obliquus sclerotia epidermis were different from internal tissues in compound composition, antioxidant activity, and associated fungi
Authors: Zhang Yijia , Liu Qiao , Sun Yong , Jiang Jihong 
Published: November 2023

Abstract
Inonotus obliquus is a medicinal fungus with potential for use in various health applications. To better utilize this fungus, this study focused on epidermis and internal tissues of five sclerotia from different regions in Jilin, Inner Mongolia, and Heilongjiang, examining their polyphenols, polysaccharides, flavonoids, and total triterpenes contents. And evaluated the extracts from sclerotia for their total antioxidant capacity and scavenging ability of DPPH free radicals. The study also isolated the associated fungi from the epidermis and internal tissues of three sclerotia. Results revealed that the polyphenol content was higher in the epidermis than in internal tissue of every sclerotium. However, flavonoid and total triterpenoid content was lower in the epidermis of every sclerotium. The polysaccharide content was no significant in different parts of three sclerotia, but the epidermal polysaccharide content in two sclerotia was significantly higher than in internal tissues. The internal tissue extracts from tested sclerotia exhibited better scavenging ability of DPPH free radicals than those from the epidermis. There was no significant difference in total antioxidant capacity among different parts of three sclerotia, and the internal tissues' total antioxidant capacity in two sclerotia was higher than the epidermis. The number and species of associated fungi in the internal tissues were far less than that in the epidermis. The study suggests separating the epidermis and internal tissue for medicinal use. The research provides insights into the bioactive components and associated fungi of I. obliquus to inform its practical application in medicine.