bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of Siltuximab and Tocilizumab Analytical Interference on Interleukin 6 Measurements
Authors: Wang Qian , Kian Susan Ashrafzadeh , Deters Rebecca , Irvine Clayton , Algeciras-Schimnich Alicia , Bornhorst Joshua 
Published: November 2023

Abstract

Background
Interleukin 6 (IL-6) plays important roles in both innate and adaptive immunity, while dysregulated persistent production of IL-6 is involved in pathological development of various diseases associated with inflammation. Targeting the IL-6 pathway has led to many innovative treatment approaches. Siltuximab and Tocilizumab are monoclonal antibodies targeting IL-6 and IL-6 receptors respectively and have been FDA-approved for treatment of Castleman disease (Siltuximab), a rare lymphoproliferative disorder characterized by hyperproduction of IL-6 with an unknown prevalence, autoimmune diseases such as rheumatoid arthritis (Tocilizumab), and both shown potential as treatment for cytokine release syndrome in hospitalized COVID-19 patients. However, the presence of siltuximab can interfere with IL-6 assays, leading to the use of C-reactive protein (CRP) as a surrogate marker to monitor its efficacy.

Aim
To evaluate potential Siltuximab and Tocilizumab antibody interference on IL-6 measurements in three different IL-6 protein immunoassays. Method: Serum or EDTA plasma sample pools with different IL-6 concentrations ranging from low (2.3 – 11.1 pg/mL, around the reference interval cut-off for each assay) to high (18.5 – 1142 pg/mL), above reference interval cut-off for each assay) were utilized. Various concentrations of Siltuximab or Tocilizumab were spiked into the sample pools (at 10% of total volume) to achieve final concentrations up to 600 µg/mL and up to 300 µg/mL, respectively. Sample spiked with 10% saline were used as no-drug control. Three assays were used to measure IL-6 concentration: Beckman Access IL-6 assay on UniCel DxI 800 (Beckman Coulter), V-PLEX Plus human IL-6 assay on QuickPlex SQ120 (Meso Scale Diagnostics), and a Luminex cytokine panel assay developed in house (R&D systems) with upper reference interval limits of 6.4,1.8 and 5 pg/mL respectively.

Results
Siltuximab interfered with the measurement of IL-6 for all three assays. A significant interference (&gt; 20% reduction) was observed at even a very low siltuximab concentrations in all three assays (0.05 µg/mL). In the presence of 5 µg/mL or greater Siltuximab, a maximum reduction of 93%, 83%, and 40% was observed for Beckman Access, R&D Luminex assay, and V-PLEX Plus Mesoscale assay, respectively. Tocilizumab did not interfere with the measurement of IL-6 in the three assays when serum was spiked with up to 300 µg/mL of the drug.

Conclusion
Siltuximab falsely reduce the measured IL-6 concentration on all three immunoassays tested in this study to differing degrees, whereas Tocilizumab does not. Consider the therapeutic range of Siltuximab (84 to 332 µg/mL) for treatment of Castleman disease, and a half-life of 20.6 days, measurement of IL-6 may not be useful in Siltuximab treated patients for an extended time-period.
Alternative strategies to provide actionable results when supply of urinalysis strips is unavailable
Authors: Guarner Jeannette , Smith Geoffrey , Alter David , Cole Lisa , Williams Cecellitha , Campbell Davette , Elsea Suzanne , Reynolds Stacian , Lawrence Christine 
Published: November 2023

Abstract
Urinalysis “dip strips” offer physicians qualitative results of 6 analytes which are immediately actionable: protein, glucose, leukocyte esterase, nitrates, blood, and ketones; however, the strips are instrument specific such that they are at the mercy of supply chain shortages. Due to vendor supply issues, we implemented a strategy that would continue to support clinical decision making in the absence of supplies for protein, glucose, white blood cells (WBC) and blood (RBC) detection. Method: In supply shortage situations, an automated algorithm triggered such that urine samples would be sent to the automation chemistry line to run quantification of protein and glucose and make sure an automated urine microscopy was performed for RBC and WBC detection. The algorithm triggered printing two labels so nursing would collect two specimens. We monitored the turn-around time from the specimen being received in the laboratory to results, made sure that the culture reflex order was triggered, and tracked complaints by physicians regarding not having all usual urinalysis results provided by the strips. Prior to implementation, correlation between sample types for protein and glucose measurement was found acceptable.
RESULTS: When we put in place the algorithm, the turn-around time of urine microscopic study was identical to that obtained when the urinalysis was done with the strips; however, the quantification of glucose and protein took approximately 30 minutes more. Urine reflex cultures were triggered correctly with the algorithm as they derive entirely from a WBC count &gt;20. During the period we had the algorithm in place we only had one complaint by a physician wanting to have results of nitrates.
Conclusion: The successful implementation of the algorithm allowed the laboratory to provide actionable urinalysis analytes in a timely manner with minimal complaints from physicians.
An organization-wide analysis of laboratory test cost variables and costs as displayed in the electronic health record: first steps
Authors: Fang Karen , Hoffman Noah , Krumm Niklas , Mathias Patrick 
Published: November 2023

Abstract
Displaying the cost of laboratory tests and medications in the electronic health record (EHR) at the time of order may influence ordering practices. Our organization’s EHR was configured to display a semi-quantitative value adjacent to laboratory orders: “$” tests imply relatively little cost and “$$$$” tests imply resource intensive tests. Cost display is associated with charges from hospital or clinic fee schedules by default but can also be configured to reflect direct laboratory costs. To understand our system’s configuration and potentially improve the information being provided to our clinicians upon ordering, all the test ordering data was compiled and analyzed for all individual “orderable” tests within the year of 2021 (Jan 1st 2021 – Dec 31st 2021). Variables analyzed included frequency of test ordering, average test turnaround time, and each of the various possible measures of “cost”: direct costs based on labor and reagents/supplies (when available), reimbursement from the Clinical Laboratory Fee Schedule, and pricing from the fee schedule of the largest hospital in our organization (chargemaster). Results showed an extensive rightward skew in each of the “cost” variables, with most routine tests, like the complete blood count (CBC) or complete metabolic panel (CMP), falling in the lower price range and a number of outlier tests with much higher costs (newer forms of molecular testing). There was minimal linearity in correlations between the various price variables. Correlation between chargemaster price by quintile and actual dollar signs displayed in the EHR showed that the two often disagree. No definitive discernable logic was thus identified for the number of dollar signs shown in the EHR based on the possible “cost” variables analyzed here. Between the lab’s best estimate for direct costs and chargemaster pricing, a rough correlation with slope greater than 1 was identified, suggesting that chargemaster pricing is systematically higher than the cost of running each test. Between the cost of running each test and reimbursement via the Clinical Laboratory Fee Schedule, a rough correlation with slope less than 1 was identified, suggesting that lab costs are systematically higher than reimbursement. The current lack of strong correlations between these various “cost” variables is helpful as a first step in examining how to improve our organization’s EHR system, assessing our laboratory’s cost effectiveness, and discussing potential future considerations for hospital chargemaster pricing as well as the US system of reimbursement. Further work is needed to clarify the relationship between cost displays in EHR and physician ordering practices.
Treatment of Chin Retrusion With Botulinum Toxin Plus Hyaluronic Acid Filler in Comparison With Hyaluronic Acid Filler Alone: A Randomized, Evaluator-Blinded, Controlled Study
Authors: Guo Yanping , Wang Ji , Wei Wuhan , Zhang Aijun , Li Qiang , Tao Changbo , Shen Caiqi , Wei Hanxiao , Jin Peisheng 
Published: November 2023

Abstract

Background
Hyaluronic acid (HA) has already been widely administered for chin augmentation. Patients with chin retrusion frequently present with increased chin hypertonia. Monotherapy with HA falls short in addressing the multifaceted cosmetic concerns associated with chin retrusion.

Objectives
This study aimed to investigate the clinical efficacy and safety of the combination therapy involving botulinum toxin (BTX) and HA in the treatment of chin retrusion.

Methods
We enrolled patients with moderate to severe chin retrusion for 9 months of follow-up after they received either combined treatment with BTX plus HA or monotreatment with HA. We also calculated the surface-volume coefficient with 3-dimensional digital scanning technique, and evaluated outcomes based on the Allergan Chin Retrusion Scale (ACRS), the Global Aesthetic Improvement Scale (GAIS), and treatment-related adverse events (TRAEs).

Results
A total of 50 patients were recruited and randomized to the treatment group (BTX plus HA) or control group (HA alone) in a 1:1 ratio. Patients in the treatment group exhibited significantly higher surface-volume coefficients during the first 6 months (P &lt; .05). ACRS scores and responder rates in the 2 groups remained similar throughout the follow-up (P &gt; .05). Within the initial 3 months, the GAIS responder rate in the treatment group was significantly higher than that in the control group (P &lt; .05). Mild TRAEs were observed in both groups, and subsided within 7 days. There was no increase in adverse effects with the combined treatment.

Conclusions
In comparison to monotherapy, the combined treatment not only improved the surface-volume coefficient of hyaluronic acid but also achieved similar ACRS scores with less HA volume. Furthermore, the combination treatment yielded superior treatment outcomes for individuals with chin retrusion.

Level of Evidence: 2
Cryolipolysis of the Arms and Inner Thighs Shows Similar Treatment Outcomes in Chinese Individuals Compared to White Individuals Treated in a Prior Study: The XinCOOL Study
Authors: Rivers Jason K , McGillivray William , Braun Martin , Bhogal Meetu , Zheng Suzanne , Hickling Matthew 
Published: November 2023

Abstract

Background
Studies of predominantly White participants show that cryolipolysis reduces subcutaneous fat in the arms and inner thighs, but none have specifically tested for similar outcomes in participants of Chinese descent.

Objectives
This study assessed the safety and effectiveness of cryolipolysis treatment for noninvasive subcutaneous fat reduction of arms and inner thighs in participants of Chinese descent to assess equivalence to results seen in a prior study of White participants.

Methods
Replicating a similar study design, participants of first- or second-generation Chinese descent underwent cryolipolysis treatment of arms and/or inner thighs. Effectiveness was assessed using pretreatment and posttreatment photographic review by blinded, independent experts, investigator-assessed caliper measurements, and participant satisfaction 12 weeks posttreatment. Safety was assessed throughout.

Results
Among 50 enrolled participants, 48 completed the study. The majority of participants (97.9%) were female, with a mean age of 36.0 years and mean BMI of 24.16 kg/m2 (range 19.3-29.9 kg/m2). Overall, 76.4% and 70.0% of pretreatment photographs of arms and pairs of inner thighs, respectively, were correctly identified by at least 2 of 3 reviewers. The mean reduction from baseline in caliper-measured fat thickness was 6.5 mm for arms and 6.6 mm for inner thighs, and the majority of participants (&gt;60%) were satisfied with the treatment. No adverse events were reported.

Conclusions
Cryolipolysis is a well-tolerated, effective means of noninvasive fat reduction of arms and inner thighs in participants of Chinese descent. The results from this study show similar effectiveness and safety in Chinese participants compared with White participants treated in a prior study.

Level of Evidence: 2
Pretarsal Augmentation of the Lower Eyelids Using Fat Grafts in Asian Patients
Authors: Mizuno Tsutomu , Yamamoto Atsushi 
Published: November 2023

Abstract

Background
Surgical procedures are required to achieve long-term pretarsal roll fullness of the lower eyelids with a satisfactory appearance.

Objectives
To assess the efficacy of a surgical method using fat grafts for pretarsal augmentation of the lower eyelids.

Methods
We conducted a retrospective clinical study that included 12 Japanese patients (24 lower eyelids) who underwent pretarsal augmentation of the lower eyelids using fat grafts and were followed up for more than 6 months. Morphometric measurements of the projection, width, and area of the pretarsal roll fullness of the lower eyelids were performed. Additionally, surgical outcomes and complications were assessed.

Results
Pretarsal roll fullness of the lower eyelids was achieved for more than 6 months postoperatively. The surgery resulted in enlarged eyes with sufficient pretarsal roll fullness, and all patients were satisfied with the aesthetic outcomes. The mean projection (1.6 ± 1.0 vs 0.5 ± 0.6 mm), width (7.4 ± 1.5 vs 4.4 ± 3.6 mm), and area (143.5 ± 42.2 vs 32.8 ± 39.6 mm2) of the pretarsal roll fullness of the lower eyelids were significantly greater postoperatively than preoperatively (P &lt; .05). No early postoperative complications were observed during the 6- to 12-month follow-up period. However, overcorrections were observed in 2 cases (16.7%) due to late-onset fat overgrowth, which was corrected by revision surgery.

Conclusions
Fat grafting can help achieve sufficient pretarsal roll fullness of the lower eyelids. The technique presented herein is a simple and reliable alternative surgical procedure for creating pretarsal roll fullness of the lower eyelids.

Level of Evidence: 4
An in-depth comparison of linear and non-linear joint embedding methods for bulk and single-cell multi-omics
Authors: Makrodimitris Stavros , Pronk Bram , Abdelaal Tamim , Reinders Marcel 
Published: November 2023

AbstractMulti-omic analyses are necessary to understand the complex biological processes taking place at the tissue and cell level, but also to make reliable predictions about, for example, disease outcome. Several linear methods exist that create a joint embedding using paired information per sample, but recently there has been a rise in the popularity of neural architectures that embed paired -omics into the same non-linear manifold. This work describes a head-to-head comparison of linear and non-linear joint embedding methods using both bulk and single-cell multi-modal datasets. We found that non-linear methods have a clear advantage with respect to linear ones for missing modality imputation. Performance comparisons in the downstream tasks of survival analysis for bulk tumor data and cell type classification for single-cell data lead to the following insights: First, concatenating the principal components of each modality is a competitive baseline and hard to beat if all modalities are available at test time. However, if we only have one modality available at test time, training a predictive model on the joint space of that modality can lead to performance improvements with respect to just using the unimodal principal components. Second, -omic profiles imputed by neural joint embedding methods are realistic enough to be used by a classifier trained on real data with limited performance drops. Taken together, our comparisons give hints to which joint embedding to use for which downstream task. Overall, product-of-experts performed well in most tasks and was reasonably fast, while early integration (concatenation) of modalities did quite poorly.
Characterization on the oncogenic effect of the missense mutations of p53 via machine learning
Authors: Pan Qisheng , Portelli Stephanie , Nguyen Thanh Binh , Ascher David B 
Published: November 2023

Abstract
Dysfunctions caused by missense mutations in the tumour suppressor p53 have been extensively shown to be a leading driver of many cancers. Unfortunately, it is time-consuming and labour-intensive to experimentally elucidate the effects of all possible missense variants. Recent works presented a comprehensive dataset and machine learning model to predict the functional outcome of mutations in p53. Despite the well-established dataset and precise predictions, this tool was trained on a complicated model with limited predictions on p53 mutations. In this work, we first used computational biophysical tools to investigate the functional consequences of missense mutations in p53, informing a bias of deleterious mutations with destabilizing effects. Combining these insights with experimental assays, we present two interpretable machine learning models leveraging both experimental assays and in silico biophysical measurements to accurately predict the functional consequences on p53 and validate their robustness on clinical data. Our final model based on nine features obtained comparable predictive performance with the state-of-the-art p53 specific method and outperformed other generalized, widely used predictors. Interpreting our models revealed that information on residue p53 activity, polar atom distances and changes in p53 stability were instrumental in the decisions, consistent with a bias of the properties of deleterious mutations. Our predictions have been computed for all possible missense mutations in p53, offering clinical diagnostic utility, which is crucial for patient monitoring and the development of personalized cancer treatment.
BannMI deciphers potential n-to-1 information transduction in signaling pathways to unravel message of intrinsic apoptosis
Authors: Schmidt Bettina , Sers Christine , Klein Nadja 
Published: November 2023

Abstract

Motivation
Cell fate decisions, such as apoptosis or proliferation, are communicated via signaling pathways. The pathways are heavily intertwined and often consist of sequential interaction of proteins (kinases). Information integration takes place on the protein level via n-to-1 interactions. A state-of-the-art procedure to quantify information flow (edges) between signaling proteins (nodes) is network inference. However, edge weight calculation typically refers to 1-to-1 interactions only and relies on mean protein phosphorylation levels instead of single cell distributions. Information theoretic measures such as the mutual information (MI) have the potential to overcome these shortcomings but are still rarely used.

Results
This work proposes a Bayesian nearest neighbor-based MI estimator (BannMI) to quantify n-to-1 kinase dependency in signaling pathways. BannMI outperforms the state-of-the-art MI estimator on protein-like data in terms of mean squared error and Pearson correlation. Using BannMI, we analyze apoptotic signaling in phosphoproteomic cancerous and noncancerous breast cell line data. Our work provides evidence for cooperative signaling of several kinases in programmed cell death and identifies a potential key role of the mitogen-activated protein kinase p38.

Availability and implementation
Source code and applications are available at: https://github.com/zuiop11/nn_info and can be downloaded via Pip as Python package: nn-info.
Improving the filtering of false positive single nucleotide variations by combining genomic features with quality metrics
Authors: Eren Kazım Kıvanç , Çınar Esra , Karakurt Hamza U , Özgür Arzucan 
Published: November 2023

Abstract

Motivation
Technical errors in sequencing or bioinformatics steps and difficulties in alignment at some genomic sites result in false positive (FP) variants. Filtering based on quality metrics is a common method for detecting FP variants, but setting thresholds to reduce FP rates may reduce the number of true positive variants by overlooking the more complex relationships between features. The goal of this study is to develop a machine learning-based model for identifying FPs that integrates quality metrics with genomic features and with the feature interpretability property to provide insights into model results.

Results
We propose a random forest-based model that utilizes genomic features to improve identification of FPs. Further examination of the features shows that the newly introduced features have an important impact on the prediction of variants misclassified by VEF, GATK-CNN, and GARFIELD, recently introduced FP detection systems. We applied cost-sensitive training to avoid errors in misclassification of true variants and developed a model that provides a robust mechanism against misclassification of true variants while increasing the prediction rate of FP variants. This model can be easily re-trained when factors such as experimental protocols might alter the FP distribution. In addition, it has an interpretability mechanism that allows users to understand the impact of features on the model’s predictions.

Availability and implementation
The software implementation can be found at https://github.com/ideateknoloji/FPDetect.
ROCCO: a robust method for detection of open chromatin via convex optimization
Authors: Hamilton Nolan H , Furey Terrence S 
Published: November 2023

Abstract

Motivation
Analysis of open chromatin regions across multiple samples from two or more distinct conditions can determine altered gene regulatory patterns associated with biological phenotypes and complex traits. The ATAC-seq assay allows for tractable genome-wide open chromatin profiling of large numbers of samples. Stable, broadly applicable genomic annotations of open chromatin regions are not available. Thus, most studies first identify open regions using peak calling methods for each sample independently. These are then heuristically combined to obtain a consensus peak set. Reconciling sample-specific peak results post hoc from larger cohorts is particularly challenging, and informative spatial features specific to open chromatin signals are not leveraged effectively.

Results
We propose a novel method, ROCCO, that determines consensus open chromatin regions across multiple samples simultaneously. ROCCO employs robust summary statistics and solves a constrained optimization problem formulated to account for both enrichment and spatial dependence of open chromatin signal data. We show this formulation admits attractive theoretical and conceptual properties as well as superior empirical performance compared to current methodology.

Availability and implementation
Source code, documentation, and usage demos for ROCCO are available on GitHub at: https://github.com/nolan-h-hamilton/ROCCO. ROCCO can also be installed as a stand-alone binary utility using pip/PyPI.
An accurate spectrophotometric method for chitosan quantification
Authors: González-Davis Oscar , Betanzo Itandehui , Vazquez-Duhalt Rafael 
Published: November 2023

Abstract
Chitosan is a biopolymer obtained from chitin, one of the most abundant biopolymers in nature. Numerous applications of chitosan are well known in the biomedical, environmental, and industrial fields, and the potential applications are considerable. This work reports a new spectrophotometric method to determine chitosan concentration accurately. The method is based on the deamination of chitosan by nitrite in acidic conditions, followed by a carbohydrate determination by the anthrone reagent.