Browsing by Subject "Infections"

Now showing 1 - 5 of 5
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    An Atlas of Genetic Variation Linking Pathogen-Induced Cellular Traits to Human Disease.
    (Cell host & microbe, 2018-08) Wang, Liuyang; Pittman, Kelly J; Barker, Jeffrey R; Salinas, Raul E; Stanaway, Ian B; Williams, Graham D; Carroll, Robert J; Balmat, Tom; Ingham, Andy; Gopalakrishnan, Anusha M; Gibbs, Kyle D; Antonia, Alejandro L; eMERGE Network; Heitman, Joseph; Lee, Soo Chan; Jarvik, Gail P; Denny, Joshua C; Horner, Stacy M; DeLong, Mark R; Valdivia, Raphael H; Crosslin, David R; Ko, Dennis C
    Pathogens have been a strong driving force for natural selection. Therefore, understanding how human genetic differences impact infection-related cellular traits can mechanistically link genetic variation to disease susceptibility. Here we report the Hi-HOST Phenome Project (H2P2): a catalog of cellular genome-wide association studies (GWAS) comprising 79 infection-related phenotypes in response to 8 pathogens in 528 lymphoblastoid cell lines. Seventeen loci surpass genome-wide significance for infection-associated phenotypes ranging from pathogen replication to cytokine production. We combined H2P2 with clinical association data from patients to identify a SNP near CXCL10 as a risk factor for inflammatory bowel disease. A SNP in the transcriptional repressor ZBTB20 demonstrated pleiotropy, likely through suppression of multiple target genes, and was associated with viral hepatitis. These data are available on a web portal to facilitate interpreting human genome variation through the lens of cell biology and should serve as a rich resource for the research community.
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    PAMPs and DAMPs: signal 0s that spur autophagy and immunity.
    (Immunological reviews, 2012-09) Tang, Daolin; Kang, Rui; Coyne, Carolyn B; Zeh, Herbert J; Lotze, Michael T
    Pathogen-associated molecular pattern molecules (PAMPs) are derived from microorganisms and recognized by pattern recognition receptor (PRR)-bearing cells of the innate immune system as well as many epithelial cells. In contrast, damage-associated molecular pattern molecules (DAMPs) are cell-derived and initiate and perpetuate immunity in response to trauma, ischemia, and tissue damage, either in the absence or presence of pathogenic infection. Most PAMPs and DAMPs serve as so-called 'Signal 0s' that bind specific receptors [Toll-like receptors, NOD-like receptors, RIG-I-like receptors, AIM2-like receptors, and the receptor for advanced glycation end products (RAGE)] to promote autophagy. Autophagy, a conserved lysosomal degradation pathway, is a cell survival mechanism invoked in response to environmental and cellular stress. Autophagy is inferred to have been present in the last common eukaryotic ancestor and only to have been lost by some obligatory intracellular parasites. As such, autophagy represents a unifying biology, subserving survival and the earliest host defense strategies, predating apoptosis, within eukaryotes. Here, we review recent advances in our understanding of autophagic molecular mechanisms and functions in emergent immunity.
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    Probiotic and synbiotic therapy in critical illness: a systematic review and meta-analysis.
    (Crit Care, 2016-08-19) Manzanares, William; Lemieux, Margot; Langlois, Pascal L; Wischmeyer, Paul E
    BACKGROUND: Critical illness is characterized by a loss of commensal flora and an overgrowth of potentially pathogenic bacteria, leading to a high susceptibility to nosocomial infections. Probiotics are living non-pathogenic microorganisms, which may protect the gut barrier, attenuate pathogen overgrowth, decrease bacterial translocation and prevent infection. The purpose of this updated systematic review is to evaluate the overall efficacy of probiotics and synbiotic mixtures on clinical outcomes in critical illness. METHODS: Computerized databases from 1980 to 2016 were searched. Randomized controlled trials (RCT) evaluating clinical outcomes associated with probiotic therapy as a single strategy or in combination with prebiotic fiber (synbiotics). Overall number of new infections was the primary outcome; secondary outcomes included mortality, ICU and hospital length of stay (LOS), and diarrhea. Subgroup analyses were performed to elucidate the role of other key factors such as probiotic type and patient mortality risk on the effect of probiotics on outcomes. RESULTS: Thirty trials that enrolled 2972 patients were identified for analysis. Probiotics were associated with a significant reduction in infections (risk ratio 0.80, 95 % confidence interval (CI) 0.68, 0.95, P = 0.009; heterogeneity I (2) = 36 %, P = 0.09). Further, a significant reduction in the incidence of ventilator-associated pneumonia (VAP) was found (risk ratio 0.74, 95 % CI 0.61, 0. 90, P = 0.002; I (2) = 19 %). No effect on mortality, LOS or diarrhea was observed. Subgroup analysis indicated that the greatest improvement in the outcome of infections was in critically ill patients receiving probiotics alone versus synbiotic mixtures, although limited synbiotic trial data currently exists. CONCLUSION: Probiotics show promise in reducing infections, including VAP in critical illness. Currently, clinical heterogeneity and potential publication bias reduce strong clinical recommendations and indicate further high quality clinical trials are needed to conclusively prove these benefits.
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    Survival and Functional Outcomes in Boys with Cerebral Adrenoleukodystrophy with and without Hematopoietic Stem Cell Transplantation.
    (Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2019-03) Raymond, Gerald V; Aubourg, Patrick; Paker, Asif; Escolar, Maria; Fischer, Alain; Blanche, Stephane; Baruchel, André; Dalle, Jean-Hugues; Michel, Gérard; Prasad, Vinod; Miller, Weston; Paadre, Susan; Balser, John; Kurtzberg, Joanne; Nascene, David R; Orchard, Paul J; Lund, Troy
    Cerebral adrenoleukodystrophy (CALD) is a rapidly progressing, often fatal neurodegenerative disease caused by mutations in the ABCD1 gene, resulting in deficiency of ALD protein. Clinical benefit has been reported following allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a large multicenter retrospective chart review to characterize the natural history of CALD, to describe outcomes after HSCT, and to identify predictors of treatment outcomes. Major functional disabilities (MFDs) were identified as having the most significant impact on patients' abilities to function independently and were used to assess HSCT outcome. Neurologic function score (NFS) and Loes magnetic resonance imaging score were assessed. Data were collected on 72 patients with CALD who did not undergo HSCT (untreated cohort) and on 65 patients who underwent transplantation (HSCT cohort) at 5 clinical sites. Kaplan-Meier (KM) estimates of 5-year overall survival (OS) from the time of CALD diagnosis were 55% (95% confidence interval [CI], 42.2% to 65.7%) for the untreated cohort and 78% (95% CI, 64% to 86.6%) for the HSCT cohort overall (P = .01). KM estimates of 2-year MFD-free survival for patients with gadolinium-enhanced lesions (GdE+) were 29% (95% CI, 11.7% to 48.2%) for untreated patients (n = 21). For patients who underwent HSCT with GdE+ at baseline, with an NFS ≤1 and Loes score of 0.5 to ≤9 (n = 27), the 2-year MFD-free survival was 84% (95% CI, 62.3% to 93.6%). Mortality rates post-HSCT were 8% (5 of 65) at 100days and 18% (12 of 65) at 1 year, with disease progression (44%; 7 of 16) and infection (31%; 5 of 16) listed as the most common causes of death. Adverse events post-HSCT included infection (29%; 19 of 65), acute grade II-IV graft-versus-host disease (GVHD) (31%; 18 of 58), and chronic GVHD (7%; 4 of 58). Eighteen percent of the patients (12 of 65) experienced engraftment failure after their first HSCT. Positive predictors of OS in the HSCT cohort may include donor-recipient HLA matching and lack of GVHD, and early disease treatment was predictive of MFD-free survival. GdE+ status is a strong predictor of disease progression in untreated patients.‎ This study confirms HSCT as an effective treatment for CALD when performed early. We propose survival without MFDs as a relevant treatment goal, rather than solely assessing OS as an indicator of treatment success.
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    The risk of risk-adjustment measures for perioperative spine infection after spinal surgery.
    (Spine, 2011-04) Goode, Adam P; Cook, Chad; Gill, J Brian; Tackett, Sean; Brown, Christopher; Richardson, William

    Study design

    Cross-sectional data analysis of the Nationwide Inpatient Sample (NIS).

    Objective

    To develop a risk-adjustment index specific for perioperative spine infection and compare this specific index to the Deyo Comorbidity Index. Assess specific mortality and morbidity adjustments between teaching and nonteaching facilities.

    Summary of background data

    Risk-adjustment measures have been developed specifically for mortality and may not be sensitive enough to adjust for morbidity across all diagnosis.

    Methods

    This condition-specific index was developed by using the NIS in a two-step process to determine confounders and weighting. Crude and adjusted point estimates for the Deyo and condition-specific index were compared for routine discharge, death, length of stay, and total hospital charges and then stratified by teaching hospital status.

    Results

    A total of 23,846 perioperative spinal infection events occurred in the NIS database between 1988 and 2007 of 1,212,241 procedures. Twenty-three diagnoses made up this condition-specific index. Significant differences between the Deyo and the condition-specific index were seen among total charges and length of stay at nonteaching hospitals (P < 0.001) and death, length of stay, and total charges (P < 0.001) for teaching hospitals.

    Conclusion

    This study demonstrates several key points. One, condition-specific measures may be useful when morbidity is of question. Two, a condition-specific perioperative spine infection adjustment index appears to be more sensitive at adjusting for comorbidities. Finally, there are inherent differences in hospital disposition characteristics for perioperative spine infection across teaching and nonteaching hospitals even after adjustment.