bluuebunny/crossref_metadata_2025 huggingface dataset:
A Rare Case of High grade Epithelioid Malignant Neoplasm with CAM 5.2 Expression and (EML4–ALK) Fusion in a Pediatric Patient
Authors: Aljumaili Z , Zhao B , Tchakarov A
Published: November 2023

Introduction/Objective

ALK (anaplastic lymphoma kinase) fusions have been identified in lymphomas and diverse cancer types including carcinomas, melanomas and mesenchymal neoplasms such as inflammatory myofibroblastic tumors (IMT), epithelioid fibrous histiocytoma (EFH). Herein we present a (non IMT, non EFH) ALK rearranged aggressive epithelioid neoplasm.

Methods/Case Report

We report a 17-year-old male with a 14.0 cm mediastinal mass and extensive metastatic disease involving brain, bones, pleura and lymph nodes. The tumor was made of epithelioid like cell with round nuclei, prominent nucleoli and a moderate amount of cytoplasm, arranged in a nested pattern. Ki-67 showed a high proliferative index, >70%. The tumor cells were positive for CAM 5.2; weakly positive for AE1/3, ALK, CD30; focally positive for p63, p53, S100. Additional stains including CD117, PLAP, OCT-4, Sall-4, glypican-3, synaptophysin, chromogranin, CK5/6, p40, pan-melanoma, myogenin, CD99, WT1, CD34, CD45, CD138, MUM1, CD2, CD4, CD5, CD3, CD7, CD15, CD23, CD31, CD20, CD79a, CD15, PAX8, PAX5, CD43, MPO, desmin, D2-40, Calretinin, ERG,

SOX-10, PD-L1 and NUT-1 were all negative. Both BRG and INI1 were retained. The keratin positivity and the lack of “hallmark” cells made anaplastic large cell lymphoma (ALCL) less likely. The absence of desmin and CD30 excluded the rare epithelioid IMT sarcoma. Next-generation sequencing detected an (EML4–ALK) fusion. A diagnosis of high- grade epithelioid malignant neoplasm with (EML4–ALK) fusion was made.

Most cases of this category were described as low grade-appearing spindled cells within a myxoid stroma arranged in fascicles (+S100, +CD34) and have unaggressive behavior. Only three cases, were characterized by epithelioid high- grade morphology and metastatic nature. They shared features like little collagenous stroma, conspicuous mitotic activity and tumor necrosis.

Results (if a Case Study enter NA)

NA

Conclusion

Identification of kinase fusions was essential for precise classification, better knowledge of this epithelioid high grade malignant neoplasm and for targeted therapy purposes. The significant clinicopathologic heterogeneity of this emerging group requires further investigation.
LC/MS-MS quantification of myo-inositol: a novel biomarker for kidney disease
Authors: Omosule Catherine , Blair Connor , Herries Elizabeth , Ladenson Jack , Farnsworth Christopher , Dietzen Dennis , Gaut Joseph
Published: November 2023

Creatinine is the primary biomarker used for assessing kidney function in patients with suspected acute and chronic kidney injury. However, creatinine, a product of muscle creatine metabolism, is an imperfect proxy for renal function because it is subject to non-renal interferences including muscle mass, diet, and medications. Creatinine is particularly problematic as a biomarker of acute kidney injury (AKI) due to relatively high renal function reserve, requiring considerable kidney damage and time for a clinically significant change in creatinine to be detected. Given that AKI and chronic kidney injury (CKD) are associated with high mortality, morbidity, and contribute significantly to health care costs, there is an unmet need for highly sensitive and specific biomarkers for assessing renal function in patients.

Myo-inositol oxygenase (MIOX) is a novel biomarker limitedly expressed in the proximal renal tubules. MIOX concentrations are elevated in mice with renal injury and in critically ill patients with AKI. Our previously published studies have demonstrated that elevation in MIOX concentrations precedes changes in creatinine concentrations by approximately 54 hours. Importantly, MIOX facilitates the conversion of myo-inositol to glucuronic acid.

We developed a robust LC-MS/MS method to quantify myo-inositol in human plasma, hypothesizing that following renal injury (acute and chronic), plasma concentrations of myo-inositol will increase, and will correlate with increases in serum creatinine concentrations. A healthy outpatient cohort was identified from samples obtained from out-patients with normal plasma creatinine, eGFR>60, as well as normal urine protein: creatinine ratio, albumin: creatinine ratio, or urinalysis results that were pan-negative/pan-normal. Remnant samples from out-patients with clinically staged CKD who have not initiated dialyses were selected for the CKD group.

In healthy adult out-patients with stable renal function, the central 95th% distribution of plasma myo-inositol concentrations was 16.61 - 44.2 uM (Median 27.7uM, 95% CI: 26.7-28-7). No sex-based differences in plasma myo-inositol were observed. We also observed excellent correlation between plasma myo-inositol and serum creatinine concentrations (r=0.84, 95% CI: 80-88), as well as excellent sensitivity (99%) and specificity (100%) at a myo-inositol concentration of 50.22uM for differentiating patients with stable kidney function from those with CKD. Patients with CKD exhibited higher plasma myo-inositol concentrations (p value <0.0001) with a central 95% percentile of 51.2-309.1 uM (Median 104.1 uM, 95% CI: 92.3- 113.6).

These results imply that myo-inositol concentrations increase in accord with renal injury and MIOX buildup in patients with kidney dysfunction, making it a potential biomarker for renal impairment.
Evaluation of different microbead volumes in a single antigen bead assay for HLA antibody detection
Authors: Frick Robert , Wetter Lauren , Phelan Donna , Liu Chang , Tang Mei San
Published: November 2023

OBJECTIVE

S: The multiplexed single antigen bead (SAB) assay is now commonly used for detection of antibodies to human leukocyte antigens (HLA) in the management of solid organ transplantation. Serum is incubated with microbeads individually coated with unique HLA antigens and the presence of antibody is detected using a secondary antibody. Due to its cost, laboratories may use a lower-than-recommended volume of reagent microbeads, although the impact of microbead volume on assay performance has not been reported. The present study seeks to determine the concordance of an SAB assay when different microbead volumes were used. Although this is also a required laboratory practice when modifications are made to an FDA-cleared assay, requirements for the validation of a multiplexed assay are currently not well-standardized. Hence, this study may also serve as an example framework for validating a clinical multiplexed assay.

METHODS

SAB (LabScreen, One Lambda) was performed on 14 patient specimens [Mei San T1] selected to provide a range of class I and II HLA antibody levels. Each specimen was tested using three microbead volumes of 5 μL (manufacturer-recommended), 3 μL and 2.5 μL. All reactions were tested in a single session to minimize sources of variability. A mean fluorescence intensity (MFI) of ≥ 2000 was used to define positive beads, which is also the institutional threshold for defining incompatible antigens in solid organ transplantation. Concordance between different bead volumes was calculated using Cohen’s Kappa. Bland-Altman plots were used to visualize bias. All analyses were performed at individual bead level.

RESULTS

Kappa values were: 0.91 (class I) and 0.95 (class II) for 3 μL vs. 5 μL; 0.90 (class I) and 0.93 (class II) for 2.5 μL vs. 5 µL; 0.97 (class I) and 0.93 (class II) for 2.5 μL vs. 3 μL. Positive bias in MFI values was observed with lower bead volumes and was most pronounced in the 2.5 μL vs. 5 μL comparison; in contrast, MFI values between 2.5 µL and 3 µL were more similar.

CONCLUSION

Lower-than-recommended microbead volume may be used in the SAB assay without significant impact on classification of incompatible antigens. Although positive bias in MFI values was observed with lower microbead volumes, the impact on positive vs. negative beads assignment was minimal. Since the tested microbead volumes represented 12.5-20% of the total reaction volume, such a change could have caused a matrix effect and impacted antibody-bead binding, leading to differences in MFI values. Hence, individual laboratories modifying the SAB assay should validate such modifications before implementation to ensure the accuracy of HLA antibody assignment.
Automated Machine Learning-Based Diagnosis and Molecular Characterization of Acute Leukemias using Flow Cytometry Data
Authors: Lewis Joshua , Cooper Lee , Jaye David , Pozdnyakova Olga
Published: November 2023

Current flow cytometric analysis of blood and bone marrow samples for the diagnosis of acute leukemias relies heavily on manual intervention in both the processing and analysis steps, introducing significant subjectivity into the resulting diagnosis and increasing diagnostic turn-around time. Additionally, concurrent molecular characterization of these samples via cytogenetics and targeted sequencing panels can take multiple days, thereby delaying patient diagnosis and treatment. Attention-based multi-instance learning models are machine learning models that can make accurate predictions and generate interpretable insights regarding the classification of a sample from multiple events/cells; while these models have been developed for anatomic pathology applications, they have yet to be applied to flow cytometry data. By utilizing 1,820 flow cytometry samples from 2019-2022 at Brigham and Women’s Hospital, we developed attention-based multi-instance machine learning models for automated diagnosis of acute leukemia, including differentiation of acute myeloid leukemia (AML) from B-lymphoblastic leukemia/lymphoma (B-ALL). Additionally, using concurrent cytogenetic and targeted sequencing data from 674 acute leukemia samples, machine learning models for prediction of molecular aberrancies from flow cytometry data were developed. Machine learning models were created using the TabNet deep learning architecture and VIME self-supervised training algorithm, which are state-of-the-art approaches towards machine learning from tabular data including flow cytometry data. Attention-based multi-instance models demonstrated strong performance for the automated diagnosis of acute leukemia versus non-leukemia samples (AUROC 0.869), as well as the separation of AML from B-ALL samples (AUROC 0.971). These models also accurately predicted cytogenetic aberrancies among AML samples, including t(15;17);PML::RARA (AUROC 1.00), as well as mutations including NPM1 (AUROC 0.725). These models do not require any manual intervention including compensation or gating, and additionally provide quantitative scores for the relative importance of different flow cytometry events and markers for the diagnosis of a particular sample. These importance scores can be integrated into flow cytometry analysis software for visualization and interpretation by hematopathologists. In this study, we have demonstrated the capability of machine learning models to provide automated diagnoses of acute leukemia, as well as accurately predict cytogenetic and molecular aberrancies in blood and bone marrow samples using flow cytometry data. This automated workflow can significantly decrease diagnostic turn-around time and ultimately improve patient outcomes.
Optimized method to enhance the limit of detection for large FLT3 internal tandem duplications
Authors: Hubler Zita , Ficor Tracy , Stroup Brooke , Parikh Bijal
Published: November 2023

Internal tandem duplications (ITDs) in the fms-related tyrosine kinase 3 gene (FLT3) are recurrently detected in acute myeloid leukemia (AML) and are associated with a poor prognosis. Evaluation for the presence of ITDs in AML is considered standard of care; detection alters risk stratification and therapeutic selection. ITDs can range in size, being a minimum of three base pairs to over 300 base pairs. Larger ITDs are considered rare; however, it is unclear whether this represents true prevalence or a consequence of conventional assay design. The FDA-approved companion diagnostic test for the detection of FLT3 ITDs has a six times higher limit of detection for large ITDs (~300 bp) compared to medium or small ITDs. Further, the conventionally used short-read sequencing approaches to detect ITDs can also struggle to detect larger duplications. Therefore, it is unknown how many patients may have large ITDs that have gone undetected. We developed an approach to improve the detection limit for large ITDs that uses polymerase chain reaction (PCR) and capillary electrophoresis (CE) with a spiked-in reference. Larger ITDs undergo a predictable and reproducible negative PCR bias, which can be adjusted once the effect has been quantitatively characterized. FLT3 ITDs are reported as an allele ratio, the ratio of the ITD to the wild-type allele, as a biomarker for prognosis; the spike-in reference allows for quantification of an allele ratio despite distinct CE run conditions for the ITD and wild-type alleles. Using existing commercially available controls and manufactured plasmid controls, sensitivity was optimized, including temperature, injection time, polymerase, and PCR primers. With this method, the detection limit for large ITD variants is comparable to the limit of detection for medium and small ITDs in the FDA-approved companion diagnostic assay. We now have a robust tool to evaluate the accuracy, precision, linearity, and limit of detection at different ITD lengths. Enhanced identification of large FLT3 ITDs may modify the prevalence estimates of large ITDs in AML and ultimately alter patient management.
Residual Component Culture: Application of Standardized Transfusion Reaction Culture Criteria to Reduce Culture Rates
Authors: Hodge Kyle , Khan Jenna
Published: November 2023

Blood products are often cultured as part of a transfusion reaction (TRXN) workup in order to “not miss” a septic TRXN. These cultures are vulnerable to secondary contamination and are often challenging to interpret due to the lack of a corresponding patient blood culture. Although bacterial contamination of blood products remains a leading cause of transfusion related fatalities, the actual prevalence of primary contamination of blood components is quite low, leading to a low positive predictive value (PPV) for component culture. Given recently mandated mitigation strategies to reduce bacterial contamination of platelets, the PPV of component culture is likely to further decline, making appropriate selection criteria for culture even more critical to conserve laboratory resources and maximize clinical utility. At our institution the decision to culture is at the discretion of the pathology resident and/or transfusion medicine physician. We sought to review our current culture rates and determine if applying standardized indications for component culture could reduce culture rates without impacting diagnostic utility. Clinical symptoms and vital signs were reviewed for the 24-hour period after the reaction for all TRXNs reported from July 2021 to June 2022. Of the 105 reactions reported during the study timeframe, 39 (37%) were cultured, with one positive culture involving a platelet unit. This was deemed a true septic reaction given concordant cultures in the patient. Modified forms of the AABB and BEST culture criteria were then applied to the reported reactions. Modifications were made to provide specific definitions for tachycardia (heart rate > 100bpm and at least 15% increase) and hypotension (SBP < 80mmhg and at least a 30mmHg decrease). Application of the AABB criteria reduces the number of cultures to 22 (21% of reactions) whereas the BEST criteria increases the number of cultures to 51 (49% of reactions). Both criteria captured the true positive septic reaction. Neither criteria were completely concordant with our current practice. Of the 39 reactions selected for culture by our institution, 26 (67%) did not meet AABB criteria and 11 (28%) did not met BEST criteria; 9 and 22 different reactions would have been cultured based on AABB and BEST criteria respectively. Although we are not able to confirm if culturing of the discrepant units would have yielded additional positive cultures, retrospective chart review did not reveal any additional cases of clinically significant sepsis. The modified AABB criteria decreased the culture rate by 56% while still capturing the true positive septic TRXN suggesting that it would be the best option to reduce the cost/burden of culturing products without reducing diagnostic accuracy. Both published criteria do not take into consideration duration of symptoms and clinical interventions, thus clinical judgement remains critical to the decision to culture.
Utility of Vizient Clinical Data Base as a benchmarking tool for laboratory stewardship programs
Authors: Krishnan Subhashree Mallika , Smith Ross , Mathias Patrick , Owens Scott , Schroeder Lee
Published: November 2023

Establishing an effective laboratory stewardship program across healthcare systems to improve patient care has been of growing interest. Despite general guidelines from various organizations, clear definitions for these laboratory-based quality measures, and associated benchmarks, are still lacking. Hence, we utilized Vizient® Clinical Data Base (CDB) as a tool to benchmark our institution against U.S. News and World Reports’ Honor Roll (USNW) healthcare organizations 2021-2022. We focused on inpatient laboratory testing with specific targets including mean laboratory resource units used per patient per day to obtain an overview of our institution’s overall performance, daily basic metabolic panel and CBC test ordering patterns across various service lines, and C-reactive protein (CRP) to erythrocyte sedimentation rate (ESR) order ratios compared to USNW hospitals. As one of the five institutions with the highest mean laboratory resource units used per case per day (12.7) from January 1, 2021-January 31, 2022, we investigated this further to identify tests driving this result. Of all the laboratory tests ordered, blood gas was identified at the 99th percentile compared to peers. Stratifying by service, we found cardiac surgery (17%), general medicine (15%), pulmonary/critical care (11%), neonatology (10%) and transplant (9%) services at our institution were the major contributors to blood gas orders. Investigating daily laboratory test orders (BMP, CBC) showed that our institution was at the 46th and 71st percentile overall, respectively. Further CBC analysis showed that general medicine (28%) and oncology (11%) services were the major contributors for the test volume and highest total resource units used per quarter in 2021. Assessing CRP to ESR ratio depicted that our institution’s ratio of 2.2 was lower compared to USNW hospitals’ average of 2.9, meaning ESR is likely overutilized. In conclusion, Vizient CDB can be used as a resource for benchmarking laboratory utilization patterns. It can be helpful in developing road maps and prioritizing interventions for lab stewardship programs. This study identified a general overuse of laboratory resources at the hospital compared to peers, and identified some intervention targets including blood gas testing and ESR.
Assessing the Reliability of Creatinine-Estimated Glomerular Filtration Rate in Living Kidney Donor Candidates: Does it Measure up to the Measured Rate?
Authors: Lahorewala Sarrah , Xin Yi Xin Yi , Roger Bertholf Roger Bertholf
Published: November 2023

A living donor kidney transplant is the best therapy option for patients with end stage renal disease (ESRD); however, it is associated with an increased risk of ESRD development in the donor. Thorough evaluation of the donor candidate’s kidney function status is essential for the appropriate selection of candidates with minimal risk of post-donation kidney dysfunction.

In this study, glomerular filtration rate (GFR) values measured by iohexol plasma clearance (mGFR) and estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) creatinine equations (eGFR), with and without the race factor (2009 and 2021 CKD-Epi equations, respectively), were compared in a cohort of 303 kidney donor candidates. GFR values were analyzed using Bland-Altman plots, linear regression, Mann-Whitney U tests, and p10 and p30 values.

Bland-Altman analysis revealed a lack of agreement between the 2009 and 2021 CKD-Epi eGFR and corresponding mGFR values, with both equations showing a negative bias of 10 – 11 mL/min/1.73m2 and indicating an underestimation of creatinine-eGFR. eGFR underestimation was confirmed by Mann-Whitney U analysis; median GFR values were significantly lower for both CKD-Epi equations as compared to corresponding iohexol-measured values (2009: 85.86; 2021: 87.29; mGFR: 96.58). Despite the overall underestimation, over 14% of donor candidates with eGFR >90 mL/min/1.73m2 had an mGFR value <90 mL/min/1.73m2. Conversely, 36% - 38% of donors with normal kidney function of >90 mL/min/1.73m2 as determined by iohexol-mGFR had corresponding eGFR values <90 mL/min/1.73m2. eGFR showed a significant but poor correlation with mGFR, with R2 values of 0.2775 and 0.2803, respectively. While the 2021 eGFR equation had better accuracy as compared to the 2009 equation (p30 of 81% versus 76%), it displayed low overall accuracy with a p10 of <43%. Separate analysis of Black donor candidates’ eGFR and mGFR values revealed similar trends as observed for the total cohort. While exclusion of the race factor in the 2021 CKD-Epi equation slightly improved accuracy (p30 of 77% versus 72%), the correlation with mGFR remained poor for both equations (R2: 0.1455 and 0.1377 for the 2009 and 2021 equations, respectively).

The results of this study confirmed that creatinine-eGFR values, regardless of the race factor, differ significantly from iohexol-mGFR. Our data shows that even potential kidney donors with eGFR >90 mL/min/1.73m2 cannot be presumed to have normal kidney function, while eGFR <90 mL/min/1.73m2 cannot accurately exclude donor candidates. We conclude that creatinine-eGFR cannot reliably serve as a substitute for mGFR in the context of living donor kidney function evaluation.
Evaluating the effectiveness of pseudothrombocytopenia (PTCP) panel with alternative anticoagulants on clinically suspicious EDTA-dependent PTCP: a single tertiary hospital experience
Authors: Sheikh Fahad , Malik Preeti , Agustin Arnel , Fang Yanan
Published: November 2023

EDTA is considered the most common anticoagulant to induce pseudothrombocytopenia (PTCP). PTCP panel with alternative anticoagulants (heparin and citrate) has been ordered by clinicians in our hospital for suspicious EDTA-dependent PTCP cases to obtain the correct platelet count (PC). In this study, we aimed to evaluate the effectiveness of alternative anticoagulants on clinically suspicious EDTA-PTCP. We retrospectively identified cases for which PTCP panel (EDTA, heparin, and citrate) was performed from June 2021 to March 2022 using the SAP business intelligence tool. PC was considered significantly different when the difference is more than 25% comparing heparin or citrate to EDTA tubes. Representative cases were chosen for chart review and/or peripheral blood smear review. 200 cases were included in the study. 76 cases had similar PCs in all 3 tubes which represent either true thrombocytopenia or PTCP in all 3 tubes. 17 cases had higher PC on heparin and/or citrate than EDTA which are EDTA-PTCP corrected by alternative anticoagulants (confirmed by smear review). Among those 17 cases: 6/17 had high PC on citrate only, 2/17 on heparin only and 9/17 had higher PC on citrate/heparin. 82 cases had lower PC on heparin only compared to EDTA and 62/82 had heparin exposure. There was 1 case with lower PC on citrate only (no heparin tube) compared to EDTA. 24 cases had lower PC in both heparin and citrate than EDTA tubes (lowest PC on Heparin) and 21/24 have heparin exposure. Peripheral blood smears were reviewed in 39 representative cases. Platelet clumps were identified in the corresponding tubes of all cases. Our study shows that heparin-PTCP is common in hospitalized patients and confirms that heparin is not a suitable alternative anticoagulant for EDTA-PTCP as shown by previous literature. However, many laboratories still use it for EDTA-PTCP. Heparin is known to promote platelet activation which may cause PTCP. The low PC in the heparin tube also seems to be associated with prior heparin exposure. Citrate is a better alternative to EDTA-PTCP. Among cases with low PCs on citrate, nearly all have low PCs on heparin as well. It is interesting to note those cases usually have lower PCs on heparin versus citrate and have prior exposure to heparin. The low PCs on citrate might be partially due to insufficient correction (110%) of PC by the dilution factor of the anticoagulant. Literature showed that a higher corrective factor of PCs is required for citrate. Therefore, a correlation study of PCs in EDTA versus citrate in each lab is needed to establish the corrective factor. Furthermore, delayed processing might be contributing as PCs on citrate are less stable and must be processed within 3 hours.
CytogeneticsRapid Resolution of Medically Relevant Polyunsaturated, Very Long-, Odd-, and Branched-Chain Fatty Acid Methyl Esters
Authors: Nelson Andrew T , McDonald Jeffrey G
Published: November 2023

Fatty acids play an important role in human health and disease. Nearly 100 years ago, the Burrs demonstrated that polyunsaturated fatty acids (PUFAs) were essential for development; subsequent work uncovered the role of PUFAs as precursors to important signaling molecules such as prostaglandins, leukotrienes, and thromboxanes. Very long chain fatty acids (VLCFAs) originally sparked interest over 40 years ago for being elevated in humans with peroxisomal disorders. More recent studies have shown that VLCFAs are elevated in healthy human controls, compared to their diabetic counterparts. In a similar vein, odd chain fatty acids (OCFAs) and branched-chain fatty acids (BCFAs) of the iso and anteiso variety are higher in humans with insulin sensitivity than in insulin resistant individuals. These families of fatty acids are most frequently analyzed as their fatty acid methyl esters (FAMEs) by gas chromatography (GC). Regrettably, even recently published methods resolving BCFAs from their linear correlates have run-times in excess of an hour and, in some cases, over 100 minutes.

Objective: The goal of this study was to decrease the GC run-time for the analysis of FAMEs relevant to human health and disease.

Methods: Baseline resolution of FAMEs required careful combination of the right gas chromatograph, column dimensions, stationary phase, carrier gas, and temperature programming.

Results: We cleanly resolved the FAMEs of all common polyunsaturated, very long-, odd-, and branched-chain fatty acids with baseline separation in only ~15 minutes – a 4-fold improvement over many existing methods.

Conclusion: This method will significantly improve analysis of fatty acids in health and disease, especially in large-scale, clinical studies, by quartering the run time necessary to resolve PUFAs, VLCFAs, OCFAs, and BCFAs.
Association of over the counter “hangover remedy” use with alcohol use problems and consumption patterns among young adults
Authors: Han Dae-Hee , Davis Jordan P , Davies Daryl L , Clapp John D , Pedersen Eric R , Leventhal Adam M
Published: November 2023

This cross-sectional study of young adults examined associations of hangover remedy use with alcohol use problems. Results suggest that ever-use of hangover remedy products was positively associated with alcohol use problem score, drinks per typical drinking day, and alcohol use disorder symptom count. Use of hangover remedies among young adults merits further scientific and regulatory attention.
Characterization of a novel L-fuconate dehydratase involved in the non-phosphorylated pathway of L-fucose metabolism from bacteria
Authors: Watanabe Seiya
Published: November 2023

A sugar acid dehydratase from Paraburkholderia mimosarum, potentially involved in the non-phosphorylated L-fucose pathway, was functionally characterized. A biochemical analysis revealed its unique heterodimeric structure and higher specificity toward L-fuconate than D-arabinonate, D-altronate, and L-xylonate, which differed from homomeric homologs. This unique L-fuconate dehydratase has a poor phylogenetic relationship with other functional members of the D-altronate dehydratase/galactarate dehydratase protein family.
Drug repositioning based on weighted local information augmented graph neural network
Authors: Meng Yajie , Wang Yi , Xu Junlin , Lu Changcheng , Tang Xianfang , Peng Tao , Zhang Bengong , Tian Geng , Yang Jialiang
Published: November 2023

Drug repositioning, the strategy of redirecting existing drugs to new therapeutic purposes, is pivotal in accelerating drug discovery. While many studies have engaged in modeling complex drug–disease associations, they often overlook the relevance between different node embeddings. Consequently, we propose a novel weighted local information augmented graph neural network model, termed DRAGNN, for drug repositioning. Specifically, DRAGNN firstly incorporates a graph attention mechanism to dynamically allocate attention coefficients to drug and disease heterogeneous nodes, enhancing the effectiveness of target node information collection. To prevent excessive embedding of information in a limited vector space, we omit self-node information aggregation, thereby emphasizing valuable heterogeneous and homogeneous information. Additionally, average pooling in neighbor information aggregation is introduced to enhance local information while maintaining simplicity. A multi-layer perceptron is then employed to generate the final association predictions. The model’s effectiveness for drug repositioning is supported by a 10-times 10-fold cross-validation on three benchmark datasets. Further validation is provided through analysis of the predicted associations using multiple authoritative data sources, molecular docking experiments and drug–disease network analysis, laying a solid foundation for future drug discovery.
Test-retest reliability of spectral parameterization by 1/f characterization using SpecParam
Authors: McKeown Daniel J , Finley Anna J , Kelley Nicholas J , Cavanagh James F , Keage Hannah A D , Baumann Oliver , Schinazi Victor R , Moustafa Ahmed A , Angus Douglas J
Published: November 2023

SpecParam (formally known as FOOOF) allows for the refined measurements of electroencephalography periodic and aperiodic activity, and potentially provides a non-invasive measurement of excitation: inhibition balance. However, little is known about the psychometric properties of this technique. This is integral for understanding the usefulness of SpecParam as a tool to determine differences in measurements of cognitive function, and electroencephalography activity. We used intraclass correlation coefficients to examine the test-retest reliability of parameterized activity across three sessions (90 minutes apart and 30 days later) in 49 healthy young adults at rest with eyes open, eyes closed, and during three eyes closed cognitive tasks including subtraction (Math), music recall (Music), and episodic memory (Memory). Intraclass correlation coefficients were good for the aperiodic exponent and offset (intraclass correlation coefficients > 0.70) and parameterized periodic activity (intraclass correlation coefficients > 0.66 for alpha and beta power, central frequency, and bandwidth) across conditions. Across all three sessions, SpecParam performed poorly in eyes open (40% of participants had poor fits over non-central sites) and had poor test-retest reliability for parameterized periodic activity. SpecParam mostly provides reliable metrics of individual differences in parameterized neural activity. More work is needed to understand the suitability of eyes open resting data for parameterization using SpecParam.
Impact of Concomitant Thiopurine on the Efficacy and Safety of Filgotinib in Patients with Ulcerative Colitis: Post Hoc Analysis of the Phase 2b/3 SELECTION Study
Authors: Watanabe Kenji , Peyrin-Biroulet Laurent , Danese Silvio , Fujitani Yasushi , Faes Margaux , Oortwijn Alessandra , Lindsay James O , Rogler Gerhard , Hibi Toshifumi
Published: November 2023

Background and Aims

SELECTION is the first study to assess the impact of concomitant thiopurine and other immunomodulator [IM] use on the efficacy and safety of a Janus kinase inhibitor, filgotinib, in patients with ulcerative colitis.

Methods

Data from the phase 2b/3 SELECTION study were used for this post hoc analysis. Patients were randomised [2:2:1] to two induction studies [biologic-naive, biologic-experienced] to filgotinib 200 mg, 100 mg, or placebo. At Week 10, patients receiving filgotinib were re-randomised [2:1] to continue filgotinib or to switch to placebo until Week 58 [maintenance]. Outcomes were compared between subgroups with and without concomitant IM use.

Results

At Week 10, similar proportions of patients in the +IM and −IM groups treated with filgotinib 200 mg achieved Mayo Clinic Score [MCS] response [biologic-naive: 65.8% vs 66.9%; biologic-experienced: 61.3% vs 50.5%] and clinical remission [biologic-naive: 26.0% vs 26.2%; biologic-experienced: 11.3% vs 11.5%]. At Week 58, similar proportion of patients in the +IM and −IM groups treated with filgotinib 200 mg achieved MCS response [biologic-naive: 74.2% vs 75.0%; biologic-experienced: 45.5% vs 61.4%] and clinical remission [biologic-naive: 51.6% vs 47.4%; biologic-experienced: 22.7% vs 24.3%]. The probability of protocol-specified disease worsening during the maintenance study in patients treated with filgotinib 200 mg did not differ between +IM and −IM groups [p = 0.6700]. No differences were observed in the incidences of adverse events between +IM and −IM groups in the induction/maintenance studies.

Conclusions

The efficacy and safety profiles of filgotinib treatment in SELECTION did not differ with or without concomitant IM use.

ClinicalTrials.gov identifier

NCT02914522.
ERS/ESTS/ESTRO/ESR/ESTI/EFOMP statement on management of incidental findings from low dose CT screening for lung cancer
Authors: O'Dowd Emma L , Tietzova Ilona , Bartlett Emily , Devaraj Anand , Biederer Jürgen , Brambilla Marco , Brunelli Alessandro , Chorostowska Joanna , Decaluwe Herbert , Deruysscher Dirk , De Wever Walter , Donoghue Matthew , Fabre Aurelie , Gaga Mina , van Geffen Wouter , Hardavella Georgia , Kauczor Hans-Ulrich , Kerpel-Fronius Anna , van Meerbeeck Jan , Nagavci Blin , Nestle Ursula , Novoa Nuria , Prosch Helmut , Prokop Mathias , Putora Paul Martin , Rawlinson Janette , Revel Marie-Pierre , Snoeckx Annemiek , Veronesi Giulia , Vliegenthart Rozemarijn , Weckbach Sabine , Blum Torsten G , Baldwin David R
Published: November 2023

Background

Screening for lung cancer with low radiation dose computed tomography has a strong evidence base, is being introduced in several European countries and is recommended as a new targeted cancer screening programme. The imperative now is to ensure that implementation follows an evidence-based process that will ensure clinical and cost effectiveness. This European Respiratory Society (ERS) task force was formed to provide an expert consensus for the management of incidental findings which can be adapted and followed during implementation.

Methods

A multi-European society collaborative group was convened. 23 topics were identified, primarily from an ERS statement on lung cancer screening, and a systematic review of the literature was conducted according to ERS standards. Initial review of abstracts was completed and full text was provided to members of the group for each topic. Sections were edited and the final document approved by all members and the ERS Science Council.

Results

Nine topics considered most important and frequent were reviewed as standalone topics (interstitial lung abnormalities, emphysema, bronchiectasis, consolidation, coronary calcification, aortic valve disease, mediastinal mass, mediastinal lymph nodes and thyroid abnormalities). Other topics considered of lower importance or infrequent were grouped into generic categories, suitable for general statements.

Conclusions

This European collaborative group has produced an incidental findings statement that can be followed during lung cancer screening. It will ensure that an evidence-based approach is used for reporting and managing incidental findings, which will mean that harms are minimised and any programme is as cost-effective as possible.
The Evolution of Temperature and Desiccation-Related Protein Families in Tardigrada Reveals a Complex Acquisition of Extremotolerance
Authors: Fleming James F , Pisani Davide , Arakawa Kazuharu
Published: November 2023

Tardigrada is an ecdysozoan lineage famed for its resilience. Tardigrades can tolerate high doses of radiation, low-oxygen environments, desiccation, and both high and low temperatures under a dormant state called “anhydrobiosis”, which is a reversible halt of metabolism upon almost complete desiccation. A large amount of research has focused on the genetic pathways related to these capabilities, and a number of genes have been identified and linked to the extremotolerant response of tardigrades. However, the history of these genes is unclear, and the origins and history of extremotolerant genes within Tardigrada remain a mystery. Here, we generate the first phylogenies of six separate protein families linked with desiccation and radiation tolerance in Tardigrada: cytosolic abundant heat-soluble protein, mitochondrial abundant heat-soluble protein, secretory abundant heat-soluble protein, meiotic recombination 11 homolog, and the newly discovered Echiniscus testudo abundant heat-soluble proteins (alpha and beta). The high number of independent gene duplications found amongst the six gene families studied suggests that tardigrades have a complex history with numerous independent adaptations to cope with aridity within the limnoterrestrial environment. Our results suggest that tardigrades likely transitioned from a marine environment to a limnoterrestrial environment only twice, once in stem Eutardigrada and once in Heterotardigrada, which explains the unique adaptations to anhydrobiosis present in both classes.
Revised set of equations describing the seismo-electromagnetic coupled wavefield in an ambient geomagnetic field
Authors: Yamazaki Ken'ichi
Published: November 2023

Temporal variations in the electromagnetic field generated by seismic waves are accounted for mainly by electrokinetic (EK) and motional induction (MI) effects. Currently, these effects are considered in terms of different sets of equations, even though both mechanisms are assumed in data interpretation. In principle, however, they should be described by a single set of equations, possibly including a new type of coupling effect. This inconsistency suggests that the deviation of conventional equations was somewhat incorrect, with some coupling mechanisms having been overlooked. Here, the derivation of the conventional equations was reconsidered, and necessary revisions were applied. The revised equations describe both EK and MI effects and include a previously unrecognized coupling effect (although its effect is negligible). The solution of the new equations is well approximated by a simple sum of EK and MI effects determined by conventional equations. In conclusion, it was confirmed that the conventional procedure for estimation of seismically induced EM variations in terms of the EK and MI effects is sufficiently accurate, in spite of the conventional governing equations missing some of coupling terms related to the EK and MI effects.
Factors influencing community-facility linkage for case management of possible serious bacterial infections among young infants in Kenya
Authors: Odwe George , Liambila Wilson , K’Oduol Kezia , Nyangacha Zipporah , Gwaro Helen , Kamberos Alexandra Haake , Hirschhorn Lisa R
Published: November 2023

Despite evidence showing the feasibility and acceptability of implementing the World Health Organization’s guidelines on managing possible serious bacterial infection (PSBI) in Kenya, the initial implementation revealed sub-optimal community-facility referrals and follow-up of PSBI cases. This study explores facilitators and barriers of community-facility linkages in implementing PSBI guidelines in Busia and Migori counties, Kenya. We used an exploratory qualitative study design drawing on endline evaluation data from the ‘COVID-19: Mitigating Neonatal Mortality’ project collected between June and July 2022. Data include case narratives with caregivers of sick young infants (0–59 days old) (18), focus group discussions with community health volunteers (CHVs) (6), and in-depth interviews with facility-based providers (18). Data were analysed using an inductive thematic analysis framework. Between August 2021 and July 2022, CHVs assessed 10 187 newborns, with 1176 (12%) identified with PSBI danger signs and referred to the nearest facility, of which 820 (70%) accepted referral. Analysis revealed several factors facilitating community-facility linkage for PSBI treatment, including CHVs’ relationship with community members and facilities, availability of a CHV desk and tools, use of mobile app, training and supportive supervision. However, challenges such as health system-related factors (inadequate providers, stockout of essential commodities and supplies, and lack of transport/ambulance) and individual-related factors (caregivers’ refusal to take referrals) hindered community-facility linkage. Addressing common barriers and fostering positive relationships between community health workers and facilities can enhance acceptance and access to PSBI services at the community level. Combining community health workers’ efforts with a mobile digital strategy can improve the efficiency of the identification, referral and tracking of PSBI cases in the community and facilitate linkage with primary healthcare facilities.
‘I don’t know exactly what that means to do check-ups’: understanding and experiences of primary care among resettled young adult refugees
Authors: Brewer Sarah E , Alsharea Enas , Wah Lah Say
Published: November 2023

Young adult refugees have suboptimal primary care use, including having a regular provider and engaging with a regular source of care for primary and preventive healthcare needs. Our purpose was to understand how young adult refugees (ages 18–29 years) resettled to the United States understand and experience primary care. We conducted 23 semi-structured interviews with young adult refugees and explored their ideas about and experiences of key characteristics of primary care. Emergent themes were synthesized. Young adult refugees reported a lack of an understanding of the idea of primary care. However, they also described the lack of accepted key components of primary care, such as being the first contact and providing continuity, coordination and comprehensiveness. The importance of developing an ability to ask questions, get answers and feel empowered was a facilitator of primary care successes. Young refugees lack access to healthcare that exemplifies quality primary care. Improving understanding of the primary care model and its value as well as increasing access and ease of engagement could improve primary care engagement for young adult refugees.
HLA-DQA1*05 Not Associated With Ustekinumab Loss of Response and Antidrug Antibodies in Ulcerative Colitis and Crohn’s Disease Patients
Authors: Colombel Jean-Frédéric , Martín-Arranz María D , Brinkman Brigitta , Guan Meijian , Hart Amy , Gasink Christopher
Published: November 2023

Lay Summary

It is unknown if inflammatory bowel disease patients carrying the HLA-DQA1*05 allele have a greater risk of immunogenicity to ustekinumab. We observed that ustekinumab-treated patients carrying the allele did not have increased immunogenicity or reduced efficacy/serum ustekinumab concentrations vs noncarriers
Health Care Personnel Exposure Risk Assessment and Management During a Mpox Outbreak in Chicago, Illinois, 17 May to 8 July 2022
Authors: Zelencik Shane , VanDine Alison , Campos-Bovee Maria , Goitia Kimberly , Cela Valbona , Walblay Kelly , Galanto Daniel , Pacilli Massimo , Kim Do Young , Black Stephanie R
Published: November 2023

This report summarizes risk assessment interviews and follow-up with health care personnel (HCP) after exposure to patients with mpox disease during 17 May to 8 July 2022. HCP-case interactions were assessed using a standard questionnaire to categorize the risk associated with patient encounters. We assessed 150 interactions among 142 HCP and 30 cases. Four (2.7%) interactions were defined as high risk, 5 (3.3%) intermediate, 107 (71.3%) low, and 31 (20.7%) no risk. High and intermediate exposures were offered postexposure prophylaxis; 4 accepted. No documented mpox transmission after exposure was identified. These findings suggest transmission risk in health care settings during routine patient care is low.
The Potential Benefits of Delaying Seasonal Influenza Vaccine Selections for the Northern Hemisphere: A Retrospective Modeling Study in the United States
Authors: Lee Kyueun , Williams Katherine V , Englund Janet A , Sullivan Sheena G
Published: November 2023

Background

Antigenic similarity between vaccine viruses and circulating viruses is crucial for achieving high vaccine effectiveness against seasonal influenza. New non-egg-based vaccine production technologies could revise current vaccine formulation schedules. We aim to assess the potential benefit of delaying seasonal influenza vaccine virus selection decisions.

Methods

We identified seasons where season-dominant viruses presented increasing prevalence after vaccine formulation had been decided in February for the Northern Hemisphere, contributing to their antigenic discrepancy with vaccine viruses. Using a SEIR (susceptible-exposed-infectious-recovered) model of seasonal influenza in the United States, we evaluated the impact of updating vaccine decisions with more antigenically similar vaccine viruses on the influenza burden in the United States.

Results

In 2014–2015 and 2019–2020, the season-dominant A(H3N2) subclade and B/Victoria clade, respectively, presented increasing prevalence after vaccine decisions were already made for the Northern Hemisphere. Our model showed that the updated A(H3N2) vaccine could have averted 5000–65 000 influenza hospitalizations in the United States in 2014–2015, whereas updating the B/Victoria vaccine component did not substantially change influenza burden in the 2019–2020 season.

Conclusions

With rapid vaccine production, revising current timelines for vaccine selection could result in substantial epidemiological benefits, particularly when additional data could help improve the antigenic match between vaccine and circulating viruses.