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Article ; Online: Surveillance for Spotted Fever Group Rickettsial Infections: Problems, Pitfalls, and Potential Solutions.

McClain, Micah T / Sexton, Daniel J

2019 Volume 221, Issue 8, Page(s) 1238–1240

MeSH term(s)	Blood Donors ; Humans ; Immunologic Tests ; Rickettsia Infections/diagnosis ; Rickettsia Infections/epidemiology ; Rickettsia rickettsii ; Spotted Fever Group Rickettsiosis/diagnosis ; Spotted Fever Group Rickettsiosis/epidemiology ; United States
Language	English
Publishing date	2019-07-02
Publishing country	United States
Document type	Editorial ; Comment
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiz317
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Article: Implementation of a Prospective Index-Cluster Sampling Strategy for the Detection of Presymptomatic Viral Respiratory Infection in Undergraduate Students.

Uthappa, Diya M / McClain, Micah T / Nicholson, Bradly P / Park, Lawrence P / Zhbannikov, Ilya / Suchindran, Sunil / Jimenez, Monica / Constantine, Florica J / Nichols, Marshall / Jones, Daphne C / Hudson, Lori L / Jaggers, L Brett / Veldman, Timothy / Burke, Thomas W / Tsalik, Ephraim L / Ginsburg, Geoffrey S / Woods, Christopher W

Open forum infectious diseases

2024 Volume 11, Issue 3, Page(s) ofae081

Abstract: Background: Index-cluster studies may help characterize the spread of communicable infections in the presymptomatic state. We describe a prospective index-cluster sampling strategy (ICSS) to detect presymptomatic respiratory viral illness and its ... ...

Abstract	Background: Index-cluster studies may help characterize the spread of communicable infections in the presymptomatic state. We describe a prospective index-cluster sampling strategy (ICSS) to detect presymptomatic respiratory viral illness and its implementation in a college population. Methods: We enrolled an annual cohort of first-year undergraduates who completed daily electronic symptom diaries to identify index cases (ICs) with respiratory illness. Investigators then selected 5-10 potentially exposed, asymptomatic close contacts (CCs) who were geographically co-located to follow for infections. Symptoms and nasopharyngeal samples were collected for 5 days. Logistic regression model-based predictions for proportions of self-reported illness were compared graphically for the whole cohort sampling group and the CC group. Results: We enrolled 1379 participants between 2009 and 2015, including 288 ICs and 882 CCs. The median number of CCs per IC was 6 (interquartile range, 3-8). Among the 882 CCs, 111 (13%) developed acute respiratory illnesses. Viral etiology testing in 246 ICs (85%) and 719 CCs (82%) identified a pathogen in 57% of ICs and 15% of CCs. Among those with detectable virus, rhinovirus was the most common (IC: 18%; CC: 6%) followed by coxsackievirus/echovirus (IC: 11%; CC: 4%). Among 106 CCs with a detected virus, only 18% had the same virus as their associated IC. Graphically, CCs did not have a higher frequency of self-reported illness relative to the whole cohort sampling group. Conclusions: Establishing clusters by geographic proximity did not enrich for cases of viral transmission, suggesting that ICSS may be a less effective strategy to detect spread of respiratory infection.
Language	English
Publishing date	2024-02-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2757767-3
ISSN	2328-8957
ISSN	2328-8957
DOI	10.1093/ofid/ofae081
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Article ; Online: Epigenetic and transcriptional responses in circulating leukocytes are associated with future decompensation during SARS-CoV-2 infection.

McClain, Micah T / Zhbannikov, Ilya / Satterwhite, Lisa L / Henao, Ricardo / Giroux, Nicholas S / Ding, Shengli / Burke, Thomas W / Tsalik, Ephraim L / Nix, Christina / Balcazar, Jorge Prado / Petzold, Elizabeth A / Shen, Xiling / Woods, Christopher W

iScience

2023 Volume 27, Issue 1, Page(s) 108288

Abstract: To elucidate host response elements that define impending decompensation during SARS-CoV-2 infection, we enrolled subjects hospitalized with COVID-19 who were matched for disease severity and comorbidities at the time of admission. We performed combined ... ...

Abstract	To elucidate host response elements that define impending decompensation during SARS-CoV-2 infection, we enrolled subjects hospitalized with COVID-19 who were matched for disease severity and comorbidities at the time of admission. We performed combined single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) on peripheral blood mononuclear cells (PBMCs) at admission and compared subjects who improved from their moderate disease with those who later clinically decompensated and required invasive mechanical ventilation or died. Chromatin accessibility and transcriptomic immune profiles were markedly altered between the two groups, with strong signals in CD4
Language	English
Publishing date	2023-11-29
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.108288
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Article ; Online: Epigenetic and transcriptional responses in circulating leukocytes are associated with future decompensation during SARS-CoV-2 infection

Micah T. McClain / Ilya Zhbannikov / Lisa L. Satterwhite / Ricardo Henao / Nicholas S. Giroux / Shengli Ding / Thomas W. Burke / Ephraim L. Tsalik / Christina Nix / Jorge Prado Balcazar / Elizabeth A. Petzold / Xiling Shen / Christopher W. Woods

iScience, Vol 27, Iss 1, Pp 108288- (2024)

1481

Abstract: ... signals in CD4+ T cells, inflammatory T cells, dendritic cells, and NK cells. Multiomic signature scores ...

Abstract	Summary: To elucidate host response elements that define impending decompensation during SARS-CoV-2 infection, we enrolled subjects hospitalized with COVID-19 who were matched for disease severity and comorbidities at the time of admission. We performed combined single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) on peripheral blood mononuclear cells (PBMCs) at admission and compared subjects who improved from their moderate disease with those who later clinically decompensated and required invasive mechanical ventilation or died. Chromatin accessibility and transcriptomic immune profiles were markedly altered between the two groups, with strong signals in CD4+ T cells, inflammatory T cells, dendritic cells, and NK cells. Multiomic signature scores at admission were tightly associated with future clinical deterioration (auROC 1.0). Epigenetic and transcriptional changes in PBMCs reveal early, broad immune dysregulation before typical clinical signs of decompensation are apparent and thus may act as biomarkers to predict future severity in COVID-19.
Keywords	Health sciences ; Molecular mechanism of gene regulation ; Epigenetics ; Immune response ; Components of the immune system ; Virology ; Science ; Q
Subject code	610
Language	English
Publishing date	2024-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Systematic comparison of published host gene expression signatures for bacterial/viral discrimination.

Bodkin, Nicholas / Ross, Melissa / McClain, Micah T / Ko, Emily R / Woods, Christopher W / Ginsburg, Geoffrey S / Henao, Ricardo / Tsalik, Ephraim L

Genome medicine

2022 Volume 14, Issue 1, Page(s) 18

Abstract: Background: Measuring host gene expression is a promising diagnostic strategy to discriminate bacterial and viral infections. Multiple signatures of varying size, complexity, and target populations have been described. However, there is little ... ...

Abstract	Background: Measuring host gene expression is a promising diagnostic strategy to discriminate bacterial and viral infections. Multiple signatures of varying size, complexity, and target populations have been described. However, there is little information to indicate how the performance of various published signatures compare to one another. Methods: This systematic comparison of host gene expression signatures evaluated the performance of 28 signatures, validating them in 4589 subjects from 51 publicly available datasets. Thirteen COVID-specific datasets with 1416 subjects were included in a separate analysis. Individual signature performance was evaluated using the area under the receiving operating characteristic curve (AUC) value. Overall signature performance was evaluated using median AUCs and accuracies. Results: Signature performance varied widely, with median AUCs ranging from 0.55 to 0.96 for bacterial classification and 0.69-0.97 for viral classification. Signature size varied (1-398 genes), with smaller signatures generally performing more poorly (P < 0.04). Viral infection was easier to diagnose than bacterial infection (84% vs. 79% overall accuracy, respectively; P < .001). Host gene expression classifiers performed more poorly in some pediatric populations (3 months-1 year and 2-11 years) compared to the adult population for both bacterial infection (73% and 70% vs. 82%, respectively; P < .001) and viral infection (80% and 79% vs. 88%, respectively; P < .001). We did not observe classification differences based on illness severity as defined by ICU admission for bacterial or viral infections. The median AUC across all signatures for COVID-19 classification was 0.80 compared to 0.83 for viral classification in the same datasets. Conclusions: In this systematic comparison of 28 host gene expression signatures, we observed differences based on a signature's size and characteristics of the validation population, including age and infection type. However, populations used for signature discovery did not impact performance, underscoring the redundancy among many of these signatures. Furthermore, differential performance in specific populations may only be observable through this type of large-scale validation.
MeSH term(s)	Adult ; Bacterial Infections/diagnosis ; Bacterial Infections/epidemiology ; Bacterial Infections/genetics ; Biomarkers/analysis ; COVID-19/diagnosis ; COVID-19/genetics ; Child ; Cohort Studies ; Datasets as Topic/statistics & numerical data ; Diagnosis, Differential ; Gene Expression Profiling/statistics & numerical data ; Genetic Association Studies/statistics & numerical data ; Host-Pathogen Interactions/genetics ; Humans ; Publications/statistics & numerical data ; SARS-CoV-2/pathogenicity ; Transcriptome ; Validation Studies as Topic ; Virus Diseases/diagnosis ; Virus Diseases/epidemiology ; Virus Diseases/genetics
Chemical Substances	Biomarkers
Language	English
Publishing date	2022-02-21
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2484394-5
ISSN	1756-994X ; 1756-994X
ISSN (online)	1756-994X
ISSN	1756-994X
DOI	10.1186/s13073-022-01025-x
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Article ; Online: Transcriptional Profiles Elucidate Differential Host Responses to Infection with

Holcomb, Zachary E / Steinbrink, Julie M / Zaas, Aimee K / Betancourt, Marisol / Tenor, Jennifer L / Toffaletti, Dena L / Alspaugh, J Andrew / Perfect, John R / McClain, Micah T

Journal of fungi (Basel, Switzerland)

2022 Volume 8, Issue 5

Abstract: Many aspects of the host response to invasive cryptococcal infections remain poorly understood. In order to explore the pathobiology of infection with common clinical strains, we infected BALB/cJ mice ... ...

Abstract	Many aspects of the host response to invasive cryptococcal infections remain poorly understood. In order to explore the pathobiology of infection with common clinical strains, we infected BALB/cJ mice with
Language	English
Publishing date	2022-04-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2784229-0
ISSN	2309-608X ; 2309-608X
ISSN (online)	2309-608X
ISSN	2309-608X
DOI	10.3390/jof8050430
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Article ; Online: Transcriptional responses define dysregulated immune activation in Hepatitis C (HCV)-naïve recipients of HCV-infected donor kidneys.

Steinbrink, Julie M / Miller, Cameron / Myers, Rachel A / Sanoff, Scott / Mazur, Anna / Burke, Thomas W / Byrns, Jennifer / Jackson, Annette M / Luo, Xunrong / McClain, Micah T

PloS one

2023 Volume 18, Issue 1, Page(s) e0280602

Abstract: Renal transplantation from hepatitis C (HCV) nucleic acid amplification test-positive (NAAT-positive) donors to uninfected recipients has greatly increased the organ donation pool. However, there is concern for adverse outcomes in these recipients due to ...

Abstract	Renal transplantation from hepatitis C (HCV) nucleic acid amplification test-positive (NAAT-positive) donors to uninfected recipients has greatly increased the organ donation pool. However, there is concern for adverse outcomes in these recipients due to dysregulated immunologic activation secondary to active inflammation from acute viremia at the time of transplantation. This includes increased rates of cytomegalovirus (CMV) DNAemia and allograft rejection. In this study, we evaluate transcriptional responses in circulating leukocytes to define the character, timing, and resolution of this immune dysregulation and assess for biomarkers of adverse outcomes in transplant patients. We enrolled 67 renal transplant recipients (30 controls, 37 HCV recipients) and performed RNA sequencing on serial samples from one, 3-, and 6-months post-transplant. CMV DNAemia and allograft rejection outcomes were measured. Least absolute shrinkage and selection operator was utilized to develop gene expression classifiers predictive of clinical outcomes. Acute HCV incited a marked transcriptomic response in circulating leukocytes of renal transplant recipients in the acute post-transplant setting, despite the presence of immunosuppression, with 109 genes significantly differentially expressed compared to controls. These HCV infection-associated genes were reflective of antiviral immune pathways and generally resolved by the 3-month timepoint after sustained viral response (SVR) for HCV. Differential gene expression was also noted from patients who developed CMV DNAemia or allograft rejection compared to those who did not, although transcriptomic classifiers could not accurately predict these outcomes, likely due to sample size and variable time-to-event. Acute HCV infection incites evidence of immune activation and canonical antiviral responses in the human host even in the presence of systemic immunosuppression. After treatment of HCV with antiviral therapy and subsequent aviremia, this immune activation resolves. Changes in gene expression patterns in circulating leukocytes are associated with some clinical outcomes, although larger studies are needed to develop accurate predictive classifiers of these events.
MeSH term(s)	Humans ; Hepatitis C ; Hepacivirus/genetics ; Tissue Donors ; Antiviral Agents/therapeutic use ; Kidney ; Cytomegalovirus Infections/drug therapy ; Transplant Recipients
Chemical Substances	Antiviral Agents
Language	English
Publishing date	2023-01-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0280602
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Article ; Online: Utility of predictive tools for risk stratification of elderly individuals with all-cause acute respiratory infection.

Bloom, Allison S / Suchindran, Sunil / Steinbrink, Julie / McClain, Micah T

Infection

2019 Volume 47, Issue 4, Page(s) 617–627

Abstract: Purpose: A number of scoring tools have been developed to predict illness severity and patient outcome for proven pneumonia, however, less is known about the utility of clinical prediction scores for all-cause acute respiratory infection (ARI), ... ...

Abstract	Purpose: A number of scoring tools have been developed to predict illness severity and patient outcome for proven pneumonia, however, less is known about the utility of clinical prediction scores for all-cause acute respiratory infection (ARI), especially in elderly subjects who are at increased risk of poor outcomes. Methods: We retrospectively analyzed risk factors and outcomes of individuals ≥ 60 years of age presenting to the emergency department with a clinical diagnosis of ARI. Results: Of 276 individuals in the study, 40 had proven viral infection and 52 proven bacterial infection, but 184 patients with clinically adjudicated ARI (67%) remained without a proven microbial etiology despite extensive clinical (and expanded research) workup. Patients who were older, had multiple comorbidities, or who had proven bacterial infection were more likely to require hospital and ICU admission. We identified a novel model based on 11 demographic and clinical variables that were significant risk factors for ICU admission or mortality in elderly subjects with all-cause ARI. As comparators, a modified PORT score was found to correlate more closely with all-cause ARI severity than a modified CURB-65 score (r, 0.54, 0.39). Interestingly, modified Jackson symptom scores were found to inversely correlate with severity (r, - 0.34) but show potential for differentiating viral and bacterial etiologies. Conclusions: Modified PORT, CURB-65, Jackson symptom scores, and a novel ARI scoring tool presented herein all offer predictive ability for all-cause ARI in elderly subjects. Such broadly applicable scoring metrics have the potential to assist in treatment and triage decisions at the point of care.
MeSH term(s)	Acute Disease/epidemiology ; Age Factors ; Aged ; Aged, 80 and over ; Comorbidity ; Female ; Hospitalization/statistics & numerical data ; Humans ; Intensive Care Units/statistics & numerical data ; Male ; Michigan ; Middle Aged ; Models, Theoretical ; North Carolina/epidemiology ; Respiratory Tract Infections/classification ; Respiratory Tract Infections/epidemiology ; Respiratory Tract Infections/microbiology ; Respiratory Tract Infections/virology ; Retrospective Studies ; Risk Assessment/methods
Language	English
Publishing date	2019-03-30
Publishing country	Germany
Document type	Journal Article
ZDB-ID	185104-4
ISSN	1439-0973 ; 0300-8126 ; 0173-2129
ISSN (online)	1439-0973
ISSN	0300-8126 ; 0173-2129
DOI	10.1007/s15010-019-01299-1
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Article ; Online: Transcriptional responses define dysregulated immune activation in Hepatitis C (HCV)-naïve recipients of HCV-infected donor kidneys

Julie M. Steinbrink / Cameron Miller / Rachel A. Myers / Scott Sanoff / Anna Mazur / Thomas W. Burke / Jennifer Byrns / Annette M. Jackson / Xunrong Luo / Micah T. McClain

PLoS ONE, Vol 18, Iss

2023 Volume 1

Abstract	Renal transplantation from hepatitis C (HCV) nucleic acid amplification test-positive (NAAT-positive) donors to uninfected recipients has greatly increased the organ donation pool. However, there is concern for adverse outcomes in these recipients due to dysregulated immunologic activation secondary to active inflammation from acute viremia at the time of transplantation. This includes increased rates of cytomegalovirus (CMV) DNAemia and allograft rejection. In this study, we evaluate transcriptional responses in circulating leukocytes to define the character, timing, and resolution of this immune dysregulation and assess for biomarkers of adverse outcomes in transplant patients. We enrolled 67 renal transplant recipients (30 controls, 37 HCV recipients) and performed RNA sequencing on serial samples from one, 3-, and 6-months post-transplant. CMV DNAemia and allograft rejection outcomes were measured. Least absolute shrinkage and selection operator was utilized to develop gene expression classifiers predictive of clinical outcomes. Acute HCV incited a marked transcriptomic response in circulating leukocytes of renal transplant recipients in the acute post-transplant setting, despite the presence of immunosuppression, with 109 genes significantly differentially expressed compared to controls. These HCV infection-associated genes were reflective of antiviral immune pathways and generally resolved by the 3-month timepoint after sustained viral response (SVR) for HCV. Differential gene expression was also noted from patients who developed CMV DNAemia or allograft rejection compared to those who did not, although transcriptomic classifiers could not accurately predict these outcomes, likely due to sample size and variable time-to-event. Acute HCV infection incites evidence of immune activation and canonical antiviral responses in the human host even in the presence of systemic immunosuppression. After treatment of HCV with antiviral therapy and subsequent aviremia, this immune activation resolves. Changes in gene ...
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Transcriptional responses define dysregulated immune activation in Hepatitis C (HCV)-naïve recipients of HCV-infected donor kidneys.

Julie M Steinbrink / Cameron Miller / Rachel A Myers / Scott Sanoff / Anna Mazur / Thomas W Burke / Jennifer Byrns / Annette M Jackson / Xunrong Luo / Micah T McClain

PLoS ONE, Vol 18, Iss 1, p e

2023 Volume 0280602

Abstract	Renal transplantation from hepatitis C (HCV) nucleic acid amplification test-positive (NAAT-positive) donors to uninfected recipients has greatly increased the organ donation pool. However, there is concern for adverse outcomes in these recipients due to dysregulated immunologic activation secondary to active inflammation from acute viremia at the time of transplantation. This includes increased rates of cytomegalovirus (CMV) DNAemia and allograft rejection. In this study, we evaluate transcriptional responses in circulating leukocytes to define the character, timing, and resolution of this immune dysregulation and assess for biomarkers of adverse outcomes in transplant patients. We enrolled 67 renal transplant recipients (30 controls, 37 HCV recipients) and performed RNA sequencing on serial samples from one, 3-, and 6-months post-transplant. CMV DNAemia and allograft rejection outcomes were measured. Least absolute shrinkage and selection operator was utilized to develop gene expression classifiers predictive of clinical outcomes. Acute HCV incited a marked transcriptomic response in circulating leukocytes of renal transplant recipients in the acute post-transplant setting, despite the presence of immunosuppression, with 109 genes significantly differentially expressed compared to controls. These HCV infection-associated genes were reflective of antiviral immune pathways and generally resolved by the 3-month timepoint after sustained viral response (SVR) for HCV. Differential gene expression was also noted from patients who developed CMV DNAemia or allograft rejection compared to those who did not, although transcriptomic classifiers could not accurately predict these outcomes, likely due to sample size and variable time-to-event. Acute HCV infection incites evidence of immune activation and canonical antiviral responses in the human host even in the presence of systemic immunosuppression. After treatment of HCV with antiviral therapy and subsequent aviremia, this immune activation resolves. Changes in gene ...
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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