scholarly journals Discovery and Validation of a Three-Cytokine Plasma Signature as a Biomarker for Diagnosis of Pediatric Tuberculosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Nathella Pavan Kumar ◽  
Syed Hissar ◽  
Kannan Thiruvengadam ◽  
Velayuthum V. Banurekha ◽  
N. Suresh ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Validation Cohort ◽  
Diagnostic Study ◽  
Operating Characteristics ◽  
Discovery Cohort ◽  
Roc Curve Analysis ◽  
Immune Biomarkers ◽  
Cytokine Plasma ◽  
Pediatric Tb ◽  
Pediatric Tuberculosis

Pediatric TB poses challenge in diagnosis due to the paucibacillary nature of the disease. We conducted a prospective diagnostic study to identify immune biomarkers of pediatric TB and controls (discovery cohort) and obtained a separate “validation” cohort of confirmed cases of pediatric TB and controls. Multiplex ELISA was performed to examine the plasma levels of cytokines. Discovery and validation cohorts revealed that baseline plasma levels of IFNγ, TNFα, IL-2, and IL-17A were significantly higher in active TB (confirmed TB and unconfirmed TB) in comparison to unlikely TB children. Receiver operating characteristics (ROC) curve analysis revealed that IFNγ, IL-2, TNFα, and IL-17A (in the discovery cohort) and TNFα and IL-17A (in the validation cohort) could act as biomarkers distinguishing confirmed or unconfirmed TB from unlikely TB with the sensitivity and specificity of more than 90%. In the discovery cohort, cytokines levels were significantly diminished following anti-tuberculosis treatment. In both the cohorts, combiROC models offered 100% sensitivity and 98% to 100% specificity for a three-cytokine signature of TNFα, IL-2, and IL-17A, which can distinguish confirmed or unconfirmed TB children from unlikely TB. Thus, a baseline cytokine signature of TNFα, IL-2, and IL-17A could serve as an accurate biomarker for the diagnosis of pediatric tuberculosis.

scholarly journals Identification of gut microbiome markers for schizophrenia delineates a potential role of Streptococcus

2019 ◽  
Author(s):  
Feng Zhu ◽  
Yanmei Ju ◽  
Wei Wang ◽  
Qi Wang ◽  
Ruijin Guo ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Validation Cohort ◽  
Bacterial Species ◽  
Metagenomic Sequencing ◽  
Operating Characteristics ◽  
Discovery Cohort ◽  
Peripheral Tissues ◽  
Functional Changes ◽  
Microbial Biomarkers

AbstractEmerging evidence has linked the gut microbiota to schizophrenia. However, the functional changes in the gut microbiota and the biological role of individual bacterial species in schizophrenia have not been explored systematically. Here, we characterized the gut microbiota in schizophrenia using shotgun metagenomic sequencing of feces from a discovery cohort of 90 drug-free patients and 81 controls, as well as a validation cohort of 45 patients taking antipsychotics and 45 controls. We screened 83 schizophrenia-associated bacterial species and constructed a classifier comprising 26 microbial biomarkers that distinguished patients from controls with a 0.896 area under the receiver operating characteristics curve (AUC) in the discovery cohort and 0.765 AUC in the validation cohort. Our analysis of fecal metagenomes revealed that schizophrenia-associated gut–brain modules included short-chain fatty acids synthesis, tryptophan metabolism, and synthesis/degradation of neurotransmitters including glutamate, γ-aminobutyric acid, and nitric oxide. The schizophrenia-enriched gut bacterial species include several oral cavity-resident microbes, such as Streptococcus vestibularis. We transplanted Streptococcus vestibularis into the gut of the mice with antibiotic-induced microbiota depletion to explore its functional role. We observed that this microbe transiently inhabited the mouse gut and this was followed by hyperactivity and deficit in social behaviors, accompanied with altered neurotransmitter levels in peripheral tissues. In conclusion, our study identified 26 schizophrenia-associated bacterial species representing potential microbial targets for future treatment, as well as gut–brain modules, some of which may give rise to new microbial metabolites involved in the development of schizophrenia.

scholarly journals Uncovering reasons for treatment initiation delays among children with TB in Lima, Peru

2020 ◽  
Vol 24 (12) ◽  
pp. 1254-1260
Author(s):  
J. Coit ◽  
M. Wong ◽  
J. T. Galea ◽  
M. Mendoza ◽  
H. Marin ◽  
...  
Keyword(s):  
Treatment Initiation ◽  
Complex Interventions ◽  
Diagnostic Tools ◽  
Diagnostic Study ◽  
Burden Of Care ◽  
Structured Interviews ◽  
Tb Treatment ◽  
Pediatric Tb ◽  
Field Workers ◽  
Pediatric Tuberculosis

BACKGROUND: Timely diagnosis and treatment of pediatric tuberculosis (TB) is critical to reducing mortality but remains challenging in the absence of adequate diagnostic tools. Even once a TB diagnosis is made, delays in treatment initiation are common, but for reasons that are not well understood.METHODS: To examine reasons for delay post-diagnosis, we conducted semi-structured interviews with Ministry of Health (MoH) physicians and field workers affiliated with a pediatric TB diagnostic study, and caregivers of children aged 0–14 years who were diagnosed with pulmonary TB in Lima, Peru. Interviews were analyzed using systematic comparative and descriptive content analysis.RESULTS: We interviewed five physicians, five field workers and 26 caregivers with children who initiated TB treatment < 7 days after diagnosis (n = 15) or who experienced a delay of ≥7 days (n = 11). Median time in delay from diagnosis to treatment initiation was 26 days (range 7–117). Reasons for delay included: health systems challenges (administrative hurdles, medication stock, clinic hours), burden of care on families and caregiver perceptions of disease severity.CONCLUSION: Reasons for delay in treatment initiation are complex. Interventions to streamline administrative processes and tools to identify and support families at risk for delays in treatment initiation are urgently needed.

A digital pathology demonstration of an "immune hot" ICOS+/CD45RO+ immunephenotype and the impact on survival in patients with esophageal adenocarcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4062-4062
Author(s):  
Matthew Philip Humphries ◽  
Natalie Fisher ◽  
Rafal Kacprzyk ◽  
Stephanie G Craig ◽  
Victoria Bingham ◽  
...  
Keyword(s):  
Overall Survival ◽  
Esophageal Adenocarcinoma ◽  
Immune Checkpoint ◽  
Validation Cohort ◽  
Survival Advantage ◽  
Immune Checkpoints ◽  
Discovery Cohort ◽  
Therapeutic Implications ◽  
Immune Biomarkers ◽  
The Impact

4062 Background: Therapies targeting immune checkpoints are changing our understanding of the biology and treatment of cancer. Analysing the immune landscape in esophageal adenocarcinoma (EA) may help future prognostication and therapeutic decision-making. Methods: We assembled 310 EA cases in a tissue microarray format with associated clinicopathological information, including a discovery cohort of 156 EA from Northern Ireland and a 154 EA validation cohort from Aberdeen. We carried out validated immunohistochemistry (IHC), stained for range of adaptive immune (CD3, CD4, CD8 and CD45RO) and immune checkpoint biomarkers (ICOS and IDO-1). Slides were digitised and assessed using QuPath image analysis software program to quantify their expression and correlate them with outcome. Results: In the discovery cohort we identified a group of patients highly expressing several immune biomarkers, conferring a significant positive survival advantage (p = 0.022). CD3, CD4, CD8, CD45RO, and ICOS were individually prognostic for better overall survival (Log rank p = 0.0003; p = 0.0292; p = 0.0015; p = 0.0008; p = 0.0051 and p = 0.0264 respectively). Multivariate and correlation analysis identified a subgroup of CD45RO+/ICOS+ patients with significantly improved overall survival (p = 0.0002). The co-expression of CD45RO+/ICOS+ immunophenotype was investigated in the validation cohort and a confirmed survival advantage was seen (p = 0.042). Additionally, the Opal Multiplex IHC technology revealed the much higher frequency of single-cell, dual labelling of CD45RO+/ICOS+ in immune hot cases. Conclusions: These data demonstrate the advantage of immune markers other than the traditional CD3/CD4/CD8 in EA prognostication. The fact that one of these biomarkers is an immune checkpoint inhibitor may have therapeutic implications.

scholarly journals Plasma chemokines as immune biomarkers for diagnosis of pediatric tuberculosis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Nathella Pavan Kumar ◽  
Syed Hissar ◽  
Kannan Thiruvengadam ◽  
Velayuthum V. Banurekha ◽  
Sarath Balaji ◽  
...  
Keyword(s):  
Sensitivity And Specificity ◽  
Regression Tree ◽  
Classification And Regression Tree ◽  
Operating Characteristics ◽  
Tb Treatment ◽  
Immune Biomarkers ◽  
Receiver Operating Characteristics Curve ◽  
Tree Models ◽  
Pediatric Tuberculosis ◽  
Control Study

Abstract Background Diagnosing tuberculosis (TB) in children is challenging due to paucibacillary disease, and lack of ability for microbiologic confirmation. Hence, we measured the plasma chemokines as biomarkers for diagnosis of pediatric tuberculosis. Methods We conducted a prospective case control study using children with confirmed, unconfirmed and unlikely TB. Multiplex assay was performed to examine the plasma CC and CXC levels of chemokines. Results Baseline levels of CCL1, CCL3, CXCL1, CXCL2 and CXCL10 were significantly higher in active TB (confirmed TB and unconfirmed TB) in comparison to unlikely TB children. Receiver operating characteristics curve analysis revealed that CCL1, CXCL1 and CXCL10 could act as biomarkers distinguishing confirmed or unconfirmed TB from unlikely TB with the sensitivity and specificity of more than 80%. In addition, combiROC exhibited more than 90% sensitivity and specificity in distinguishing confirmed and unconfirmed TB from unlikely TB. Finally, classification and regression tree models also offered more than 90% sensitivity and specificity for CCL1 with a cutoff value of 28 pg/ml, which clearly classify active TB from unlikely TB. The levels of CCL1, CXCL1, CXCL2 and CXCL10 exhibited a significant reduction following anti-TB treatment. Conclusion Thus, a baseline chemokine signature of CCL1/CXCL1/CXCL10 could serve as an accurate biomarker for the diagnosis of pediatric tuberculosis.

scholarly journals Developmental malformations in Huntington disease: neuropathologic evidence of focal neuronal migration defects in a subset of adult brains

2021 ◽  
Vol 141 (3) ◽  
pp. 399-413 ◽  
Author(s):  
R. A. Hickman ◽  
P. L. Faust ◽  
M. K. Rosenblum ◽  
K. Marder ◽  
M. F. Mehler ◽  
...  
Keyword(s):  
New York ◽  
Huntington Disease ◽  
Trinucleotide Repeat ◽  
Validation Cohort ◽  
Hypothalamic Hamartoma ◽  
Discovery Cohort ◽  
Brain Bank ◽  
Neuronal Precursors ◽  
Neurodevelopmental Abnormalities ◽  
Developmental Malformations

AbstractNeuropathologic hallmarks of Huntington Disease (HD) include the progressive neurodegeneration of the striatum and the presence of Huntingtin (HTT) aggregates that result from abnormal polyQ expansion of the HTT gene. Whether the pathogenic trinucleotide repeat expansion of the HTT gene causes neurodevelopmental abnormalities has garnered attention in both murine and human studies; however, documentation of discrete malformations in autopsy brains of HD individuals has yet to be described. We retrospectively searched the New York Brain Bank (discovery cohort) and an independent cohort (validation cohort) to determine whether developmental malformations are more frequently detected in HD versus non-HD brains and to document their neuropathologic features. One-hundred and thirty HD and 1600 non-HD whole brains were included in the discovery cohort and 720 HD and 1989 non-HD half brains were assessed in the validation cohort. Cases with developmental malformations were found at 6.4–8.2 times greater frequency in HD than in non-HD brains (discovery cohort: OR 8.68, 95% CI 3.48–21.63, P=4.8 × 10-5; validation cohort: OR 6.50, 95% CI 1.83–23.17, P=0.0050). Periventricular nodular heterotopias (PNH) were the most frequent malformations and contained HTT and p62 aggregates analogous to the cortex, whereas cortical malformations with immature neuronal populations did not harbor such inclusions. HD individuals with malformations had heterozygous HTT CAG expansions between 40 and 52 repeats, were more frequently women, and all were asymmetric and focal, aside from one midline hypothalamic hamartoma. Using two independent brain bank cohorts, this large neuropathologic series demonstrates an increased occurrence of developmental malformations in HD brains. Since pathogenic HTT gene expansion is associated with genomic instability, one possible explanation is that neuronal precursors are more susceptible to somatic mutation of genes involved in cortical migration. Our findings further support emerging evidence that pathogenic trinucleotide repeat expansions of the HTT gene may impact neurodevelopment.

scholarly journals Altered urinary tetrahydroisoquinoline derivatives in patients with Tourette syndrome: reflection of dopaminergic hyperactivity?

2020 ◽  
Author(s):  
Philipp Capetian ◽  
Veit Roessner ◽  
Caroline Korte ◽  
Susanne Walitza ◽  
Franz Riederer ◽  
...  
Keyword(s):  
Tourette Syndrome ◽  
Diagnostic Value ◽  
Tic Disorders ◽  
Operating Characteristics ◽  
Roc Curve Analysis ◽  
Two Phase ◽  
Dopaminergic Neurotransmission ◽  
Hyperactivity Disorder ◽  
The Central Nervous System ◽  
Chronic Tic Disorders

AbstractTetrahydroisoquinolines (TIQs) such as salsolinol (SAL), norsalsolinol (NSAL) and their methylated derivatives N-methyl-norsalsolinol (NMNSAL) and N-methyl-salsolinol (NMSAL), modulate dopaminergic neurotransmission and metabolism in the central nervous system. Dopaminergic neurotransmission is thought to play an important role in the pathophysiology of chronic tic disorders, such as Tourette syndrome (TS). Therefore, the urinary concentrations of these TIQ derivatives were measured in patients with TS and patients with comorbid attention-deficit/hyperactivity disorder (TS + ADHD) compared with controls. Seventeen patients with TS, 12 with TS and ADHD, and 19 age-matched healthy controls with no medication took part in this study. Free levels of NSAL, NMNSAL, SAL, and NMSAL in urine were measured by a two-phase chromatographic approach. Furthermore, individual TIQ concentrations in TS patients were used in receiver-operating characteristics (ROC) curve analysis to examine the diagnostic value. NSAL concentrations were elevated significantly in TS [434.67 ± 55.4 nmol/l (standard error of mean = S.E.M.), two-way ANOVA, p < 0.0001] and TS + ADHD patients [605.18 ± 170.21 nmol/l (S.E.M.), two-way ANOVA, p < 0.0001] compared with controls [107.02 ± 33.18 nmol/l (S.E.M.), two-way ANOVA, p < 0.0001] and NSAL levels in TS + ADHD patients were elevated significantly in comparison with TS patients (two-way ANOVA, p = 0.017). NSAL demonstrated an AUC of 0.93 ± 0.046 (S.E.M) the highest diagnostic value of all metabolites for the diagnosis of TS. Our results suggest a dopaminergic hyperactivity underlying the pathophysiology of TS and ADHD. In addition, NSAL concentrations in urine may be a potential diagnostic biomarker of TS.

Developing National Genotype-Independent Indicators for Recent Mycobacterium Tuberculosis Transmission Using Pediatric Cases—United States, 2011-2017

2021 ◽  
pp. 003335492098521
Author(s):  
Alexia V. Harrist ◽  
Clinton J. McDaniel ◽  
Jonathan M. Wortham ◽  
Sandy P. Althomsons
Keyword(s):  
United States ◽  
Mycobacterium Tuberculosis ◽  
Statistical Model ◽  
Moving Average ◽  
The United States ◽  
Tuberculosis Transmission ◽  
Average Proportion ◽  
Pediatric Tb ◽  
Case Rate ◽  
Pediatric Tuberculosis

Introduction Pediatric tuberculosis (TB) cases are sentinel events for Mycobacterium tuberculosis transmission in communities because children, by definition, must have been infected relatively recently. However, these events are not consistently identified by genotype-dependent surveillance alerting methods because many pediatric TB cases are not culture-positive, a prerequisite for genotyping. Methods We developed 3 potential indicators of ongoing TB transmission based on identifying counties in the United States with relatively high pediatric (aged <15 years) TB incidence: (1) a case proportion indicator: an above-average proportion of pediatric TB cases among all TB cases; (2) a case rate indicator: an above-average pediatric TB case rate; and (3) a statistical model indicator: a statistical model based on a significant increase in pediatric TB cases from the previous 8-quarter moving average. Results Of the 249 US counties reporting ≥2 pediatric TB cases during 2009-2017, 240 and 249 counties were identified by the case proportion and case rate indicators, respectively. The statistical model indicator identified 40 counties with a significant increase in the number of pediatric TB cases. We compared results from the 3 indicators with an independently generated list of 91 likely transmission events involving ≥2 pediatric cases (ie, known TB outbreaks or case clusters with reported epidemiologic links). All counties with likely transmission events involving multiple pediatric cases were identified by ≥1 indicator; 23 were identified by all 3 indicators. Practice Implications This retrospective analysis demonstrates the feasibility of using routine TB surveillance data to identify counties where ongoing TB transmission might be occurring, even in the absence of available genotyping data.

scholarly journals Association of plasma level of high-mobility group box-1 with necroptosis and sepsis outcomes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hongseok Yoo ◽  
Yunjoo Im ◽  
Ryoung-Eun Ko ◽  
Jin Young Lee ◽  
Junseon Park ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Validation Cohort ◽  
High Mobility ◽  
Kinase Domain ◽  
High Mobility Group ◽  
Rank Test ◽  
Enzyme Linked Immunosorbent Assay ◽  
Derivation Cohort ◽  
The Difference

AbstractThe role of high-mobility group box-1 (HMGB1) in outcome prediction in sepsis is controversial. Furthermore, its association with necroptosis, a programmed cell necrosis mechanism, is still unclear. The purpose of this study is to identify the association between the plasma levels of HMGB1 and the severity and clinical outcomes of sepsis, and to examine the correlation between HMGB1 and key executors of necroptosis including receptor-interacting kinase 3 (RIPK3) and mixed lineage kinase domain-like- (MLKL) proteins. Plasma HMGB1, RIPK3, and MLKL levels were measured with the enzyme-linked immunosorbent assay from the derivation cohort of 188 prospectively enrolled, critically-ill patients between April 2014 and December 2016, and from the validation cohort of 77 patients with sepsis between January 2017 and January 2019. In the derivation cohort, the plasma HMGB1 levels of the control (n = 46, 24.5%), sepsis (n = 58, 30.9%), and septic shock (n = 84, 44.7%) groups were significantly increased (P < 0.001). A difference in mortality between high (≥ 5.9 ng/mL) and low (< 5.9 ng/mL) HMGB1 levels was observed up to 90 days (Log-rank test, P = 0.009). There were positive linear correlations of plasma HMGB1 with RIPK3 (R2 = 0.61, P < 0.001) and MLKL (R2 = 0.7890, P < 0.001). The difference in mortality and correlation of HMGB1 levels with RIPK3 and MLKL were confirmed in the validation cohort. Plasma levels of HMGB1 were associated with the severity and mortality attributed to sepsis. They were correlated with RIPK3 and MLKL, thus suggesting an association of HMGB1 with necroptosis.

scholarly journals Breath can discriminate tuberculosis from other lower respiratory illness in children

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Carly A. Bobak ◽  
Lili Kang ◽  
Lesley Workman ◽  
Lindy Bateman ◽  
Mohammad S. Khan ◽  
...  
Keyword(s):  
Machine Learning ◽  
Lower Respiratory Tract ◽  
Cross Validation ◽  
Pediatric Patients ◽  
Respiratory Illness ◽  
Health Crisis ◽  
Machine Learning Model ◽  
Childhood Tb ◽  
Pediatric Tb ◽  
Pediatric Tuberculosis

AbstractPediatric tuberculosis (TB) remains a global health crisis. Despite progress, pediatric patients remain difficult to diagnose, with approximately half of all childhood TB patients lacking bacterial confirmation. In this pilot study (n = 31), we identify a 4-compound breathprint and subsequent machine learning model that accurately classifies children with confirmed TB (n = 10) from children with another lower respiratory tract infection (LRTI) (n = 10) with a sensitivity of 80% and specificity of 100% observed across cross validation folds. Importantly, we demonstrate that the breathprint identified an additional nine of eleven patients who had unconfirmed clinical TB and whose symptoms improved while treated for TB. While more work is necessary to validate the utility of using patient breath to diagnose pediatric TB, it shows promise as a triage instrument or paired as part of an aggregate diagnostic scheme.

scholarly journals Right choice of a method for determination of cut-off values: A statistical tool for a diagnostic test

2014 ◽  
Vol 5 (3) ◽  
pp. 30-34 ◽  
Author(s):  
Balkishan Sharma ◽  
Ravikant Jain
Keyword(s):  
Logistic Regression ◽  
Discriminant Analysis ◽  
Diagnostic Test ◽  
Roc Curve ◽  
Traditional Method ◽  
Statistical Technique ◽  
Curve Analysis ◽  
Operating Characteristics ◽  
Roc Curve Analysis

Objective: The clinical diagnostic tests are generally used to identify the presence of a disease. The cutoff value of a diagnostic test should be chosen to maximize the advantage that accrues from testing a population of human and others. When a diagnostic test is to be used in a clinical condition, there may be an opportunity to improve the test by changing the cutoff value. To enhance the accuracy of diagnosis is to develop new tests by using a proper statistical technique with optimum sensitivity and specificity. Method: Mean±2SD method, Logistic Regression Analysis, Receivers Operating Characteristics (ROC) curve analysis and Discriminant Analysis (DA) have been discussed with their respective applications. Results: The study highlighted some important methods to determine the cutoff points for a diagnostic test. The traditional method is to identify the cut-off values is Mean±2SD method. Logistic Regression Analysis, Receivers Operating Characteristics (ROC) curve analysis and Discriminant Analysis (DA) have been proved to be beneficial statistical tools for determination of cut-off points.Conclusion: There may be an opportunity to improve the test by changing the cut-off value with the help of a correctly identified statistical technique in a clinical condition when a diagnostic test is to be used. The traditional method is to identify the cut-off values is Mean ± 2SD method. It was evidenced in certain conditions that logistic regression is found to be a good predictor and the validity of the same can be confirmed by identifying the area under the ROC curve. Abbreviations: ROC-Receiver operating characteristics and DA-Discriminant Analysis. Asian Journal of Medical Science, Volume-5(3) 2014: 30-34 http://dx.doi.org/10.3126/ajms.v5i3.9296      

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