Clinical and molecular correlates of the Index of Severity for Eosinophilic Esophagitis.

BACKGROUND: The Index of Severity for Eosinophilic Esophagitis (I-SEE) is a new expert-defined clinical tool that classifies disease severity of eosinophilic esophagitis (EoE). OBJECTIVE: We aimed to determine whether I-SEE is associated with patient characteristics, molecular features of EoE, or both. METHODS: We analyzed a prospective cohort of patients with EoE from the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). Associations between I-SEE and clinical and molecular features (assessed by an EoE diagnostic panel [EDP]) were assessed. RESULTS: In 318 patients with chronic EoE (209 adults, 109 children), median total I-SEE score was 7.0, with a higher symptoms and complications score in children than adults (4.0 vs 1.0; P < .001) and higher inflammatory and fibrostenotic features scores in adults than children (3.0 vs 1.0 and 3.0 vs 0, respectively; both P < .001). Total I-SEE score had a bimodal distribution with the inactive to moderate categories and severe category. EDP score correlated with total I-SEE score (r = -0.352, P < .001) and both inflammatory and fibrostenotic features scores (r = -0.665, P < .001; r = -0.446, P < .001, respectively), but not with symptoms and complications scores (r = 0.047, P = .408). Molecular severity increased from inactive to mild and moderate, but not severe, categories. Longitudinal changes of modified I-SEE scores and inflammatory and fibrostenotic features scores reflected histologic and molecular activity. CONCLUSIONS: I-SEE score is associated with select clinical features across severity categories and with EoE molecular features for nonsevere categories, warranting further validation.

Hypermethylation Loci of ZNF671, IRF8, and OTX1 as Potential Urine-Based Predictive Biomarkers for Bladder Cancer.

Bladder cancer (BCa) is a significant health issue and poses a healthcare burden on patients, highlighting the importance of an effective detection method. Here, we developed a urine DNA methylation diagnostic panel for distinguishing between BCa and non-BCa. In the discovery stage, an analysis of the TCGA database was conducted to identify BCa-specific DNA hypermethylation markers. In the validation phase, DNA methylation levels of urine samples were measured with real-time quantitative methylation-specific PCR (qMSP). Comparative analysis of the methylation levels between BCa and non-BCa, along with the receiver operating characteristic (ROC) analyses with machine learning algorithms (logistic regression and decision tree methods) were conducted to develop practical diagnostic panels. The performance evaluation of the panel shows that the individual biomarkers of ZNF671, OTX1, and IRF8 achieved AUCs of 0.86, 0.82, and 0.81, respectively, while the combined yielded an AUC of 0.91. The diagnostic panel using the decision tree algorithm attained an accuracy, sensitivity, and specificity of 82.6%, 75.0%, and 90.9%, respectively. Our results show that the urine-based DNA methylation diagnostic panel provides a sensitive and specific method for detecting and stratifying BCa, showing promise as a standard test that could enhance the diagnosis and prognosis of BCa in clinical settings.

Persistent esophageal changes after histologic remission in eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is characterized by persistent or relapsing allergic inflammation, and both clinical and histologic features of esophageal inflammation persist over time in most individuals. Mechanisms contributing to EoE relapse are not understood, and chronic EoE-directed therapy is therefore required to prevent long-term sequelae. OBJECTIVE: We investigated whether EoE patients in histologic remission have persistent dysregulation of esophageal gene expression. METHODS: Esophageal biopsy samples from 51 pediatric and 52 adult subjects with EoE in histopathologic remission (<15 eosinophils per high-power field [eos/hpf]) and control (48 pediatric and 167 adult) subjects from multiple institutions were subjected to molecular profiling by the EoE diagnostic panel, which comprises a set of 94 esophageal transcripts differentially expressed in active EoE. RESULTS: Defining remission as <15 eos/hpf, we identified 51 and 32 differentially expressed genes in pediatric and adult EoE patients compared to control individuals, respectively (false discovery rate < 0.05). Using the stringent definition of remission (0 eos/hpf), the adult and pediatric cohorts continued to have 18 and 25 differentially expressed genes (false discovery rate < 0.05). Among 6 shared genes between adults and children, CDH26 was upregulated in both children and adults; immunohistochemistry demonstrated increased cadherin 26 staining in the epithelium of EoE patients in remission compared to non-EoE controls. In the adult cohort, POSTN expression correlated with the endoscopic reference system score (Spearman r = 0.35, P = .011), specifically correlating with the rings' endoscopic reference system subscore (r = 0.53, P = .004). CONCLUSION: We have identified persistent EoE-associated esophageal gene expression in patients with disease in deep remission. These data suggest potential inflammation-induced epigenetic mechanisms may influence gene expression during remission in EoE and provide insight into possible mechanisms that underlie relapse in EoE.

Supporting Clinical Decisions with Rapid Molecular Diagnostic Pneumonia Panel in Pediatric Intensive Care Unit: Single Center Experience in Turkiye.

INTRODUCTION: Lower respiratory tract infections are the leading cause of morbidity and mortality in children worldwide. It is crucial to promptly conduct diagnostic investigations in order to determine the microbiological cause of pneumonia, since this is necessary to ensure the appropriate delivery of antibiotic therapy to each individual patient. We evaluated the results of a rapid molecular diagnostic pneumonia panel in children with LRTI in a pediatric intensive care unit (PICU). PATIENTS AND METHODS: Rapid molecular diagnostic pneumonia panel (BioFire®, FilmArray Pneumonia Panel plus; FA-PP) findings (71 results from 46 children) in a tertiary care PICU between 2019 and 2023 were retrospectively reviewed. RESULTS: At least one bacterial pathogen was detected in 57 cases. A total of 77% of children had underlying conditions. A total of 70.4% of children needed invasive mechanical ventilation and 54.4% had ventilator-associated pneumonia. Pseudomonas aeruginosa (50.8%), Acinetobacter calcoaceticus baumannii complex (42%), and Klebsiella pneumoniae (38.6%) were the most common pathogens detected with the FA-PP. Of the 33 cases diagnosed with VAP, more than one pathogen was identified in 65.9% of cases, with the most commonly identified bacteria being K. pneumoniae (43.1%), P. aeruginosa (38.6%), and Acinetobacter calcoaceticus baumannii complex (31.8%). According to the FA-PP results, the same antibiotic therapy was continued in 39.4% of cases, escalated in 54.5%, and de-escalated in 6.1%. CONCLUSIONS: The utilization of the FA-PP has some beneficial effects, including more prompt delivery of findings compared to conventional approaches. Additionally, this approach enables the identification of resistance profiles in children diagnosed with pneumonia in the PICU. Consequently, these test results facilitate the organization of antibiotic treatment strategies, including escalation and de-escalation approaches. The detection of resistance patterns was exclusively determined via the implementation of molecular testing, prompting a reevaluation of the isolation technique in accordance with the obtained data.

Metabolomic characterization benefits the identification of acute lung injury in patients with type A acute aortic dissection.

Introduction: Acute aortic dissection (AAD) often leads to the development of acute lung injury (ALI). However, the early detection and diagnosis of AAD in patients with ALI pose significant challenges. The objective of this study is to investigate distinct metabolic alterations in the plasma samples of AAD patients with ALI, AAD patients without ALI, and healthy individuals. Method: Between September 2019 and September 2022, we retrospectively collected data from 228 AAD patients who were diagnosed with ALI through post-surgery chest X-ray and PaO2/FiO2 assessments. Univariate analysis was employed to identify pre-surgery risk factors for ALI. Additionally, we conducted high-throughput target metabolic analysis on 90 plasma samples, comprising 30 samples from AAD patients with ALI, 30 from patients with AAD only, and 30 from healthy controls. After LC-MS spectral processing and metabolite quantification, the recursive feature elimination with cross-validation (RFECV) analysis based on the random forest was used to select the optimal metabolites as a diagnostic panel for the detection of AAD patients with ALI. The support vector machines (SVM) machine learning model was further applied to validate the diagnostic accuracy of the established biomarker panel. Results: In the univariate analysis, preoperative ß-HB and TNF-α exhibited a significant association with lung injury (OR = 0.906, 95% CI 0.852-0.965, p = 0.002; OR = 1.007, 95% CI 1.003-1.011, p < 0.0001). The multiple-reaction monitoring analysis of 417 common metabolites identified significant changes in 145 metabolites (fold change >1.2 or <0.833, p < 0.05) across the three groups. Multivariate statistical analysis revealed notable differences between AAD patients and healthy controls. When compared with the non-ALI group, AAD patients with ALI displayed remarkable upregulation in 19 metabolites and downregulation in 4 metabolites. Particularly, combining citric acid and glucuronic acid as a biomarker panel improved the classification performance for distinguishing between the ALI and non-ALI groups. Discussion: Differentially expressed metabolites in the ALI group were primarily involved in amino acids biosynthesis, carbohydrate metabolism (TCA cycle), arginine and proline metabolism, and glucagon signaling pathway. These findings demonstrate a great potential of the targeted metabolomic approach for screening, routine surveillance, and diagnosis of pulmonary injury in patients with AAD.

Plasma biomarker panel for major depressive disorder by quantitative proteomics using ensemble learning algorithm: A preliminary study.

Major depressive disorder (MDD) is a major international public health issue; thus, investigating its underlying mechanisms and identifying suitable biomarkers to enable its early detection are imperative. Using data-independent acquisition-mass spectrometry-based proteomics, the plasma of 44 patients with MDD and 25 healthy controls was studied to detect differentially expressed proteins. Bioinformatics analyses, such as Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis, Protein-Protein Interaction network, and weighted gene co-expression network analysis were employed. Moreover, an ensemble learning technique was used to build a prediction model. A panel of two biomarkers, L-selectin and an isoform of the Ras oncogene family was identified. With an area under the receiver operating characteristic curve of 0.925 and 0.901 for the training and test sets, respectively, the panel was able to distinguish MDD from the controls. Our investigation revealed numerous potential biomarkers and a diagnostic panel based on several algorithms, which may contribute to the future development of a plasma-based diagnostic approach and better understanding of the molecular mechanisms of MDD.

Genetic and Molecular Contributors in Eosinophilic Esophagitis.

PURPOSE OF REVIEW: Eosinophilic esophagitis (EoE) is an allergic inflammatory esophageal disorder with a complex underlying genetic and molecular etiology. The interest of the scientific community in EoE has grown considerably over the past three decades, and the understanding of the genetic and molecular mechanisms involved in this disease has greatly increased. RECENT FINDINGS: In this article, we aim to provide both historic aspects and updates on the recent genetic and molecular advances in the understanding of EoE. Although EoE is a relatively newly described disorder, much progress has been made toward identifying the genetic and molecular factors contributing to the disease pathogenesis by a variety of approaches with next-generation sequencing technologies, including genome-wide association study, whole exome sequencing, and bulk and single-cell RNA sequencing. This review highlights the multifaceted impacts of various findings that have shaped the current molecular and genetic landscape of EoE, providing insights that facilitate further understanding of the disease process.

Securing access to a comprehensive diagnostic panel for children with suspected acute lymphoblastic leukemia: Results from the Mexico in Alliance with St. Jude "Bridge Project".

Background: The "Bridge Project" is a Mexico in Alliance with St. Jude (MAS) initiative developed in 2019 to improve access, accuracy, and timeliness of specialized diagnostic studies for patients with suspected acute lymphoblastic leukemia (ALL). The project strategy relies on service centralization to improve service delivery, biological characterization, risk-group classification, and support proper treatment allocation. Methods: This is an ongoing prospective multisite intersectoral quality improvement (QI) project available to all patients 0-18 years of age presenting with suspected ALL to the 14 actively participating institutions in 12 Mexican states. Institutions send specimens to one centralized laboratory. From a clinical standpoint, the project secures access to a consensus-derived comprehensive diagnostic panel. From a service delivery standpoint, we assess equity, timeliness, effectiveness, and patient-centeredness. From an implementation science standpoint, we document feasibility, utility, and appropriateness of the diagnostic panel and centralized approach. This analysis spans from July 2019 to June 2023. Results: 612 patients have accessed the project. The median age was 6 years (IQR 3-11), and 53% were males. 94% of the specimens arrived within 48 hours, which documents the feasibility of the centralized model, and 100% of the patients received precise and timely diagnostic results, which documents the effectiveness of the approach. Of 505 (82.5%) patients with confirmed ALL, 463/505 (91.6%) had B-cell ALL, and 42/505 (8.3%) had T-cell ALL. High-hyperdiploidy was detected by DNA index in 36.6% and hypodiploidy in 1.6%. 76.6% of the patients had conclusive karyotype results. FISH studies showed t(12;21) in 15%, iAMP21 in 8.5%, t(1;19) in 7.5%, t(4;11) in 4.2%, t(9;22) in 3.2%, del(9)(p21) in 1.8%, and TRA/D (14)(q11.2) rearrangement in 2.4%. Among B-cell ALL patients, 344/403 (85.1%) had Day 15 MRD<1% and 261/305 (85.6%) Day 84 MRD<0.01. For T-cell ALL patients 20/28 (71.4%) had Day 29 MRD<0.01% and 19/22 (86.4%) Day 84 MRD<0.01%. Conclusions: By securing access to a standardized consensus-derived diagnostic panel, the Bridge Project has allowed better characterization of childhood ALL in Mexico while producing unprecedented service improvements and documenting key implementation outcomes. We are using these results to inform iterative changes to the diagnostic panel and an associated treatment guideline (MAS-ALL18).

Shotgun lipidomics combined targeted MRM reveals sphingolipid signatures of coronary artery disease.

Sphingolipids (SPLs) are bioactive lipids that manifest structural diversity and complexity in eukaryotes. However, the distributions and functions of these molecules in mammalian tissues/cells have not been systematically investigated. Herein, we integrated shotgun lipidomics with targeted LC-MRM/MS approach to comprehensively analyze SPL species in various biological samples with high accuracy. Preliminarily, 1311 SPL molecules were identified in 18 kinds of mammalian samples, including 3 groups of human sera, 10 mouse tissues and 5 cell lines via 26 sphingoid long-chain bases scanning. The sphingolipidome compositions and distributions were systematically characterized and distinct qualitative and quantitative profiles were clearly exhibited in various samples, indicating unique biological functions of the sphingolipidomes. Next, targeted SPLs analysis by LC-MRM/MS with critical criteria monitoring two characteristic fragments of one precursor was applied to human serum samples from 24 coronary artery disease (CAD) patients and 12 healthy controls, which successfully quantified 170 SPL molecules. Ten novel SPL molecules were discovered as a potential diagnostic panel for CAD patients via multivariate exploratory receiver operating characteristic curve-based biomarker analysis. The diagnostic panel with the 10 SPL molecules achieved 97.2% accuracy, with a favorable auxiliary diagnostic value (AUC = 1.000), for the detection of CAD. These results clearly support the sphingolipidomic approach in application to discovering disease biomarker panel as well as deep investigation of biological functions of complex SPLs in mammalian samples.

Expression Profile of miRs in Mesial Temporal Lobe Epilepsy: Systematic Review.

Temporal lobe epilepsy (TLE) is one of the most common forms of focal epilepsy in children and adults. TLE is characterized by variable onset and seizures. Moreover, this form of epilepsy is often resistant to pharmacotherapy. The search for new mechanisms for the development of TLE may provide us with a key to the development of new diagnostic methods and a personalized approach to the treatment. In recent years, the role of non-coding ribonucleic acids (RNA) has been actively studied, among which microRNA (miR) is of the greatest interest. (1) Background: The purpose of the systematic review is to analyze the studies carried out on the role of miRs in the development of mesial TLE (mTLE) and update the existing knowledge about the biomarkers of this disease. (2) Methods: The search for publications was carried out in the databases PubMed, Springer, Web of Science, Clinicalkeys, Scopus, OxfordPress, Cochrane. The search was carried out using keywords and combinations. We analyzed publications for 2016-2021, including original studies in an animal model of TLE and with the participation of patients with TLE, thematic and systemic reviews, and Cochrane reviews. (3) Results: this thematic review showed that miR‒155, miR‒153, miR‒361‒5p, miR‒4668‒5p, miR‒8071, miR‒197‒5p, miR‒145, miR‒181, miR‒199a, miR‒1183, miR‒129‒2‒3p, miR‒143‒3p (upregulation), miR-134, miR‒0067835, and miR‒153 (downregulation) can be considered as biomarkers of mTLE. However, the roles of miR‒146a, miR‒142, miR‒106b, and miR‒223 are questionable and need further study. (4) Conclusion: In the future, it will be possible to consider previously studied miRs, which have high specificity and sensitivity in mTLE, as prognostic biomarkers (predictors) of the risk of developing this disease in patients with potentially epileptogenic structural damage to the mesial regions of the temporal lobe of the brain (congenital disorders of the neuronal migration and neurogenesis, brain injury, neuro-inflammation, tumor, impaired blood supply, neurodegeneration, etc.).

Diagnostic merits of the Eosinophilic Esophagitis Diagnostic Panel from a single esophageal biopsy.

BACKGROUND: Eosinophilic esophagitis (EoE) is a histologically "patchy" disease with uneven eosinophil distribution along the esophagus, posing a dilemma for histologically analyzing endoscopic biopsy samples, especially when biopsy samples are limited to only the distal esophagus. OBJECTIVE: We investigated whether molecular mRNA profiling of a distal esophageal biopsy sample predicts eosinophilia in the proximal esophagus. METHODS: Esophageal biopsy samples (n = 507) from subjects with EoE were collected from multiple institutions, spanning adults and pediatric patients. Subjects were grouped on the basis of distinct distal (D) and proximal (P) eosinophil counts (D+P+, D+P-, D-P+, and D-P-, with + and - defined as ≥15 or <15 eosinophils/hpf, respectively). Molecular profiles were assessed by using the EoE Diagnostic Panel (EDP), a set of 96 esophageal transcripts used to derive the EDP score. RESULTS: The distal EDP score was correlated with proximal eosinophil levels (r = -0.73; P < .0001). EDP analysis of a histologically negative distal biopsy sample predicted the presence of proximal esophagitis with high sensitivity (85%). In a 2-year follow-up focusing on the cases with discordant histologic and EDP results, histologically negative patients (D-P-) had higher rates of EoE relapse when the EDP was positive than when the EDP was negative (odds ratio = 11; P = .003), indicating predictive medicine capacity. CONCLUSION: EDP analysis of a single distal esophageal biopsy sample predicts remote inflammation in patients with spatially heterogeneous eosinophilia and disease relapse in patients with histologic remission, providing diagnostic merit and predictive medicine capacity for molecular diagnosis of EoE.

Predictors of Infarction in Tuberculous Meningitis in Indian Patients.

BACKGROUND: Stroke is a devastating complication of tuberculous meningitis (TBM) and is an important determinant of its outcome. We propose a model which would help to predict development of infarction or cerebrovascular events in patients of TBM. METHODS: A prospective study with n=129 patients of TBM were evaluated for predictors and outcomes of stroke. A diagnostic grid was formulated with clinical, laboratory and radiology as parameters to predict the vascular outcomes. All patients were followed up for mortality and disability on the basis of modified rankin score (mRS). MRI & CSF cytokines TNF-alpha, IFN- gamma & IL-6,8, 10 were measured at baseline and 3 months. The diagnosis of TBM included definite, probable & possible types and stage I & II with early and late onset of symptoms respectively. RESULTS: The mortality was 16.2% and 19.4% of all patients developed stroke. The mean GCS, barthel index and mRS at admission was 57.03± 9.5,10.2±2.3 & 3.3±0.03 respectively mild to moderate infection and functional limitation. Barthel index (BI) happened to be a strong predictor [F=32.6, p=0.001, t=15.5, ßeta coefficient =0.002] followed by biomarker TNF-α [F=18.9, p=0.02, t= -2.07, ßeta coefficient=-0.04]. N=25 patients developed stroke with TNF-α, IL-6, IFN -γ showing statistically significant increase in all the stroke affected TBM (95% CI; 4.5 to 1.2; p=0.003). At 3 months, it was observed that mRS was statistically significant between stage I & II (95% CI; 5.4 to 2.1; p=0.04). CONCLUSIONS: Our data revealed that 19.4% patients developed vascular events during the hospital stay or follow up. We recruited late onset TBM as compared to early onset. BI, TNF-α, IL6 are most potent predictors of stroke post TBM.

Serum Metabolic Disturbances Associated with Acute-on-chronic Liver Failure in Patients with Underlying Alcoholic Liver Diseases: An Elaborative NMR-based Metabolomics Study.

OBJECTIVES: Acute-on-chronic liver failure (ACLF), which develops in patients with underlying alcoholic liver disease (ALD), is characterized by acute deterioration of liver function and organ failures are secondary to that. The clear understanding of metabolic pathways perturbed in ALD-ACLF patients can greatly decrease the mortality and morbidity of patients through predicting outcome, guiding treatment, and monitoring response to treatment. The purpose of this study was to investigate the metabolic disturbances associated with ACLF using nuclear magnetic resonance (NMR)-based serum metabolomics approach and further to assess if the serum metabolic alterations are affected by the severity of hepatic impairment. MATERIALS AND METHODS: The serum-metabolic profiles of 40 ALD-ACLF patients were compared to those of 49 age and sex-matched normal-control (NC) subjects making composite use of both multivariate and univariate statistical tests. RESULTS: Compared to NC, the sera of ACLF patients were characterized by significantly decreased serum levels of several amino acids (except methionine and tyrosine), lipid, and membrane metabolites suggesting a kind of nutritional deficiency and disturbed metabolic homeostasis in ACLF. Twelve serum metabolic entities (including BCAA, histidine, alanine, threonine, and glutamine) were found with AUROC (i.e., area under ROC curve) value >0.9 suggesting their potential in clinical diagnosis and surveillance. CONCLUSION: Overall, the study revealed important metabolic changes underlying the pathophysiology of ACLF and those related to disease progression would add value to standard clinical scores of severity to predict outcome and may serve as surrogate endpoints for evaluating treatment response.

Diagnostic pre-screening method based on N-gene dropout or delay to increase feasibility of SARS-CoV-2 VOC B.1.1.7 detection.

To compare the RT-PCR Allplex SARS-CoV-2/FluA/FluB/RSV Assay (Allplex assay) with other methods of detection of VOC B.1.1.7. Suspected and non-suspected cases of VOC B.1.1.7 were defined according to the VirSNiP assay, which detects N501Y and deletion H69-V70. For pre-screening, the Allplex™ and TaqPath assays were used. One hundred and sixteen suspected and 113 non-suspected cases were included. In the suspected cases, the Allplex assay showed N-gene dropout, or delayed Ct values of 6.27 ± 1.21 and 6.66 ± 1.41 compared with those of the RdRP and S-gene target, respectively. Agreement between the Allplex and TaqPath assays was 100% when the RdRP and S-gene targets had Ct values <35. Agreement between the Allplex and VirSNiP assays was 100% with Ct value <30. The Allplex assay showed excellent agreement with the current pre-screening method for VOC B.1.1.7. In addition, its automated processing enhances the feasibility of widespread use in laboratories.

Methylation as a critical epigenetic process during tumor progressions among Iranian population: an overview.

Cancer is one of the main health challenges and leading causes of deaths in the world. Various environmental and genetic risk factors are associated with tumorigenesis. Epigenetic deregulations are also important risk factors during tumor progression which are reversible transcriptional alterations without any genomic changes. Various mechanisms are involved in epigenetic regulations such as DNA methylation, chromatin modifications, and noncoding RNAs. Cancer incidence and mortality have a growing trend during last decades among Iranian population which are significantly related to the late diagnosis. Therefore, it is required to prepare efficient molecular diagnostic panels for the early detection of cancer in this population. Promoter hyper methylation is frequently observed as an inhibitory molecular mechanism in various genes associated with DNA repair, cell cycle regulation, and apoptosis during tumor progression. Since aberrant promoter methylations have critical roles in early stages of neoplastic transformations, in present review we have summarized all of the aberrant methylations which have been reported during tumor progression among Iranian cancer patients. Aberrant promoter methylations are targetable and prepare novel therapeutic options for the personalized medicine in cancer patients. This review paves the way to introduce a non-invasive methylation specific panel of diagnostic markers for the early detection of cancer among Iranians.

Classification of patients with esophageal eosinophilia by patterns of sensitization revealed by a diagnostic assay for multiple allergen-specific IgEs.

BACKGROUND: Eosinophilic esophagitis (EoE) is considered to be an immunoglobulin E (IgE)-mediated allergic disorder. Our goal was to examine IgE-mediated allergic sensitization patterns in patients with esophageal eosinophilia (EE). METHODS: We enrolled subjects with EE who underwent evaluation with a diagnostic panel to document multiple allergen-specific IgEs. Statistically significant groups were identified by cluster analysis. We also defined allergens based on their characteristics including outdoor, indoor, plant, and animal allergens. RESULTS: We classified patients with EE into 3 distinct groups, including cluster 1 (n = 62) who were minimally sensitized to most allergens except pollen and house dust, cluster 2 (n = 30) who were hypersensitized to outdoor and plant allergens, and cluster 3 (n = 15) who were hypersensitized to most allergens, most notably to indoor and animal allergens. Dysphagia reported among those in clusters 1, 2, and 3 at 35.5%, 46.7%, and 73.3%, respectively, (p = 0.028) and EoE endoscopic reference scores (EREFS) at 3.0, 6.0, and 8.0, respectively, (p < 0.001) differed significantly between the 3 clusters. Those in cluster 3 had a significantly higher prevalence of dysphagia (35.5% vs. 73.3%, p = 0.030), and higher EREFS with respect to rings (0.3 vs. 0.9, p = 0.003) and strictures (0.0 vs. 0.13, p = 0.011) compared to those in cluster 1. CONCLUSIONS: IgE-mediated allergic sensitization patterns are associated with clinical features of patients with EE. Use of a diagnostic panel that detects multiple allergen-specific IgEs can help to explain the heterogeneous phenotype of this patient cohort.

Transcriptomic analysis identifies a tumor subtype mRNA classifier for invasive non-functioning pituitary neuroendocrine tumor diagnostics.

Rationale: The invasive behavior of non-functioning pituitary neuroendocrine tumors (NF-PitNEts) presents obstacles for complete surgical resection and is indicative of poor prognosis. Therefore, developing reliable diagnostic tools for identifying invasive PitNEts would be helpful in guiding surgical decisions and, in particular, the follow-up treatment. Methods: We analyzed differential gene expression profiles between 39 non-invasive and 22 invasive NF-PitNEts by high-throughput sequencing, gene co-expression, and functional annotation. Twenty-one transcripts were further validated by Taqman-qPCR in another 143 NF-PitNEt samples. The histological expression and serum-exosomal mRNA of three candidate genes were examined by tissue microarray and droplet digital PCR. Results: Non-invasive and invasive NF-PitNEts were clustered into distinct groups with a few outliers because of their gonadotroph, corticotroph, or null cell lineages. The gene signature with strong invasive potential was enriched in 'Pathways in cancers' and 'MAPK pathway', with significantly higher in situ INSM1 and HSPA2 protein expression in invasive NF-PitNEts. Further integration of the 20 qPCR-validated differentially expressed genes and pituitary cell lineages provided a gene-subtype panel that performed 80.00-90.24% diagnostic accuracy for the invasiveness of NF-PitNEts. Conclusion: Our approach defined new characteristics in the core molecular network for patients at risk for invasive NF-PitNEt, representing a significant clinical advance in invasive PitNEt diagnostics.

Systematic evaluation, verification and comparison of tuberculosis-related non-coding RNA diagnostic panels.

We systematically summarized tuberculosis (TB)-related non-coding RNA (ncRNA) diagnostic panels, validated and compared panel performance. We searched TB-related ncRNA panels in PubMed, OVID and Web of Science up to 28 February 2020, and available datasets in GEO, SRA and EBI ArrayExpress up to 1 March 2020. We rebuilt models and synthesized the results of each model in validation sets by bivariate mixed models. Specificity at 90% sensitivity, area under curve (AUC) and inconsistence index (I2 ) were calculated. NcRNA biofunctions were analysed. Nineteen models based on 18 ncRNA panels (miRNA, lncRNA, circRNA and snoRNA panels) and 18 datasets were included. Limited available datasets only allowed to evaluate miRNA panels further. Cui 2017 and Latorre 2015 exhibited specificity >70% at 90% sensitivity and AUC >80% in all validation sets. Cui 2017 showed higher specificity at 90% sensitivity (92%) and AUC (95%) and lower heterogeneity (I2  = 0%) in ethological-confirmation validation sets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis indicated that most ncRNAs in panels involved in immune cell activation, oxidative stress, and Wnt and MAPK signalling pathway. Cui 2017 outperformed other models in both all available and aetiological-confirmed validation sets, meeting the criteria of target product profile of WHO. This work provided a basis for clinical choice of TB-related ncRNA diagnostic panels to a certain extent.

Selection of an Optimal Combination Panel to Better Triage COVID-19 Hospitalized Patients.

PURPOSE: It is difficult to predict the prognosis of COVID-19 patients at the disease onset. This study was designed to add new biomarkers into conventional inflammatory panels to build an optimal combination panel, to better triage patients and predict their outcomes. PATIENTS AND METHODS: Biochemical parameters representing multi-organ functions, cytokines, acute-phase proteins, and other inflammatory markers were measured in COVID-19 patients on hospital admission. Receiver operating characteristic (ROC) curves, logistic regression, event-free survival (EFS), and Cox analyses were performed to screen and compare the predictive capabilities of the new panel in patients with different illness severity and outcome. RESULTS: This study included 120 patients with COVID-19, consisting of 32 critical, 28 severe, and 60 mild/moderate patients. Initial levels of the selected biomarkers showed a significant difference in the three groups, all of which influenced patient outcome and EFS to varying degrees. Cox proportional hazard model revealed that procalcitonin (PCT) and interleukin 10 (IL-10) were independent risk factors, while superoxide dismutase (SOD) was an independent protective factor influencing EFS. In discriminating the critical and mild patients, a panel combining PCT, IL-6, and neutrophil (NEUT) yielded the best diagnostic performance with an AUC of 0.99, the sensitivity of 90.60% and specificity of 100%. In distinguishing between severe and mild patients, SOD's AUC of 0.89 was higher than any other single biomarker. In differentiating the critical and severe patients, the combination of white blood cell count (WBC), PCT, IL-6, IL-10, and SOD achieved the highest AUC of 0.95 with a sensitivity of 75.00% and specificity of 100%. CONCLUSION: The optimal combination panel has a substantial potential to better triage COVID-19 patients on admission. Better triage of patients will benefit the rational use of medical resources.

Consideration of a Legislative Framework to Support the Diagnostic Odyssey Commonly Encountered in the Instance of Rare Disease.

The diagnostic odyssey refers to the struggle to achieve a diagnosis for a medical condition in the face of significant implications if a diagnosis is not made. It is a common experience for people living with a rare disease. Western Australia has led the way in Australia in being the first State to establish a rare disease policy framework and an Undiagnosed Diseases Program (UDP). The UDP includes an expert panel made up of various specialists brought together with the aim of arriving at a diagnosis through collaboration. This article looks at the possibility of enhancing initiatives such as the UDP through a legislative framework. Relieving the medical, financial and emotional implications of the diagnostic odyssey is particularly important when one considers that taken together, rare diseases affect millions of people globally.