Epistemic_Statements  

CORD-19:12f9d385be20fc59e52070d0ce51daa580ec0f0c JSONTXT 8 Projects

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Id Subject Object Predicate Lexical cue
T1 0-160 Epistemic_statement denotes Polymorphisms in the mannose binding lectin-2 gene and acute respiratory distress syndrome * NIH Public Access NIH-PA Author Manuscript NIH-PA Author Manuscript
T2 171-326 Epistemic_statement denotes Objective-The variant alleles in the mannose binding lectin-2 (MBL-2) gene have been associated with MBL deficiency and increased susceptibility to sepsis.
T3 327-481 Epistemic_statement denotes We postulate that the variant MBL-2 genotypes are associated with increased susceptibility to and mortality in acute respiratory distress syndrome (ARDS).
T4 680-1032 Epistemic_statement denotes Measurements and Main Results-Patients homozygous for the variant codon 54B allele (54BB) had worse severity of illness on admission (p = .007), greater likelihood of septic shock (p = .04), and increased odds of ARDS (adjusted odds ratio, 6.7; 95% confidence interval, 1.5-31) when compared with heterozygotes and homozygotes for the wild-type allele.
T5 1033-1184 Epistemic_statement denotes This association with ARDS was especially strong among the 311 patients with septic shock (adjusted odds ratio, 12.0; 95% confidence interval, 1.9-74).
T6 1185-1374 Epistemic_statement denotes Among the patients with ARDS, the 54BB genotype was associated with more daily organ dysfunction (p = .01) and higher mortality (adjusted hazard rate, 4.0; 95% confidence interval, 1.6-10).
T7 1375-1577 Epistemic_statement denotes Development of ARDS and outcomes in ARDS did not vary significantly with variant alleles of codon -221, 52, and 57, but the power to detect an effect was limited secondary to the low allele frequencies.
T8 1578-1672 Epistemic_statement denotes Conclusions-The MBL-2 codon 54BB genotype may be important in ARDS susceptibility and outcome.
T9 1673-1750 Epistemic_statement denotes Additional studies are needed to confirm these findings in other populations.
T10 1752-1926 Epistemic_statement denotes Although clinical predictors for the development to acute respiratory distress syndrome (ARDS) are well recognized, a minority of patients with these risks develop ARDS (1) .
T11 1927-2061 Epistemic_statement denotes Genetic susceptibility to acute lung injury may explain the observed interindividual differences in risk and in outcomes (2) (3) (4) .
T12 2753-2954 Epistemic_statement denotes The variant alleles in exon 1 and the X allele in the MBLXY polymorphism have been found to be associated with serum MBL deficiency especially in individuals homozygous for the variant alleles (8, 9) .
T13 2955-3222 Epistemic_statement denotes In clinical studies, variant MBL-2 alleles have been associated with increased susceptibility to meningococcemia (10) , invasive pneumococcal infection (11) , hepatitis B (12, 13) , severe acute respiratory syndrome (14) , and other infections (8, 9, (15) (16) (17) .
T14 3223-3506 Epistemic_statement denotes In critical illnesses, two small studies have found an association between the variant MBL-2 alleles and increased incidence of systemic inflammatory syndrome from both infectious and noninfectious causes, increased severity of sepsis, and/or increased mortality in sepsis (18, 19) .
T15 3507-3680 Epistemic_statement denotes In both studies, the variant alleles were associated with serum MBL deficiency with the lowest levels found among those patients who were homozygous for the variant alleles.
T16 3681-3807 Epistemic_statement denotes Genes that are important in sepsis are likely to be relevant in ARDS because of the many common links between sepsis and ARDS.
T17 4038-4260 Epistemic_statement denotes We hypothesized that the X allele of the MBLXY polymorphism and the variant D, B, and C alleles of the codon 52, 54, and 57 in the MBL-2 gene are associated with increased susceptibility to and increased mortality in ARDS.
T18 4599-4836 Epistemic_statement denotes Exclusion criteria included age <18, diffuse alveolar hemorrhage, chronic lung diseases, directive to withhold intubation, immunosuppression except if secondary to corticosteroid, and treatment with granulocyte colony-stimulating factor.
T19 4947-5485 Epistemic_statement denotes Enrolled patients were screened daily for the primary outcome of ARDS as defined by respiratory failure requiring intubation and fulfillment of American-European Consensus Conference criteria for ARDS as follows (23, 24) : a) presence of hypoxemia as evidenced by PaO 2 /FIO 2 ≤200 mm Hg; b) presence of bilateral infiltrates on chest radiographs; and c) absence of left atrial hypertension as evidenced by pulmonary arterial occlusion pressure ≤18 mm Hg or lack of notation for congestive heart failure as a problem in the progress note.
T20 7487-7762 Epistemic_statement denotes Haplotypes were generated from the genotype results using the Partition Ligation-Expectation Maximization (PL-EM) version 1.0 (26), as in other association studies (27) that reconstruct individual probabilities for individual phasing accuracy based on unphased genotype data.
T21 8522-8596 Epistemic_statement denotes Backward selection algorithms were used to determine possible confounders.
T22 9614-9781 Epistemic_statement denotes To evaluate whether the MODS score varied significantly by genotype during the course of ARDS, an interaction term between genotype and time was included in the model.
T23 10233-10562 Epistemic_statement denotes Assuming an α-error of .05, 80% power, and genotype frequencies of 24% for the MBLXY X allele and 12%, 26%, and 3% for variant 52D, 54B, and 57C, respectively (9,31), a study with 212 cases and 442 controls would have a minimum detectable odds ratios of 1.6 for MBLXY and 1.9, 1.7, and 2.9 for codon 52, 54, and 57, respectively.
T24 11948-12053 Epistemic_statement denotes However, this was not statistically significant (p = .4), given the smaller number of patients with ARDS.
T25 12184-12280 Epistemic_statement denotes This is unlikely to be due to genotyping error as there was no discrepancy on repeat genotyping.
T26 12281-12522 Epistemic_statement denotes However, controls in this study were not healthy, and patients homozygous for the codon 54B genotype were more likely to have septic shock on ICU admission as a predisposing injury for ARDS (eight of ten [80%] vs. 303 of 643 [47%]; p = .04).
T27 12523-12675 Epistemic_statement denotes An association between the codon 54B genotype and the underlying condition among the controls may explain the deviation from Hardy Weinberg equilibrium.
T28 13260-13551 Epistemic_statement denotes On multivariate analyses after adjustment for age, gender, APACHE III, septic shock, trauma, direct pulmonary injury, hematologic and hepatic failure, and transfusion, the codon 54B genotype was still significantly associated with development of ARDS (OR adj , 6.7; 95% CI, 1.5-31; p = .01).
T29 13552-13756 Epistemic_statement denotes When the analysis was restricted to the 311 patients admitted to the ICU with septic shock, the association between the 54BB genotype and ARDS was even stronger (OR adj , 12.0; 95% CI, 1.9 -74; p = .008).
T30 14053-14262 Epistemic_statement denotes However, the frequency of the variant alleles of MBL XY, codon 52, or codon 57 on the MBL-2 gene did not vary significantly with ARDS ( The four polymorphisms are in complete linkage disequilibrium (D' = 1.0).
T31 14509-14588 Epistemic_statement denotes Only the ABAY haplotype was associated with the development of ARDS (Table 5) .
T32 14928-15075 Epistemic_statement denotes However, non-survivors had significantly fewer ventilator-free days than survivors (median 0 days [25-75% 0-0] vs. 7 days [25-75% 2-14]; p < .001).
T33 15436-15706 Epistemic_statement denotes Among controls, the codon 54BB genotype was not significantly associated with ICU mortality (HR adj , 7.4; 95% CI, 0.90-61.3), although the power to determine an association was limited given that there were only three patients with the BB genotype who did develop ARDS.
T34 15707-16000 Epistemic_statement denotes ARDS patients homozygous for the variant codon 54B allele had a nonsignificant trend to greater severity of illness on admission (p = .08) and significantly greater daily multiple organ dysfunction score after development of ARDS even after adjustment for potentially important variables (Fig.
T35 16006-16217 Epistemic_statement denotes On multivariate analysis, the codon 54BB genotype remained associated with increased mortality compared with ARDS patients who were homozygous for the wild-type A allele (HR adj , 4.0; 95% CI, 1.6-10; p = .003).
T36 16430-16780 Epistemic_statement denotes In a study of prospectively enrolled ICU patients with clearly defined ARDS risk factors, we found significant associations between the BB genotype of the MBL-2 codon 54 polymorphism and increased severity of illness on admission, increased development of ARDS, more multiple organ failures after development of ARDS, and increased mortality in ARDS.
T37 17032-17169 Epistemic_statement denotes Using critically ill controls who have the opportunity to develop the outcome is more clinically relevant than using healthy individuals.
T38 17170-17370 Epistemic_statement denotes Although this may bias the study toward the null, using at-risk controls also reduces the confounding from any possible association between the gene and the risk condition such as sepsis or pneumonia.
T39 17371-17688 Epistemic_statement denotes Several other studies have found the variant O allele (codon 52D, codon 54B, or codon 57C allele) to be associated with infections, systemic inflammatory responses, or other disease states in a codominant (AO and OO vs. AA genotype) (8, 15, 18, 34, 35) or recessive model (OO vs. AO and AA genotype) (11, 10, 9, 36) .
T40 17689-17801 Epistemic_statement denotes We did not find any associations between ARDS and the MBLXY X allele or the variant alleles for codon 52 and 57.
T41 17802-17952 Epistemic_statement denotes However, it is important to note that, given the low variant allele frequency, our power to detect an association for the codon 52 and 57 was limited.
T42 17953-18018 Epistemic_statement denotes Nevertheless, codon 54 may be very significant in the MBL-2 gene.
T43 18365-18513 Epistemic_statement denotes Of the four polymorphisms, codon 54B has been independently found to be associated with increased susceptibility to infection (12, 14, 16, 17, 38) .
T44 18514-18644 Epistemic_statement denotes It is not clear why patients with the codon 54 BB genotype may be at increased risk of developing and dying of ARDS in this study.
T45 18645-18744 Epistemic_statement denotes Homozygotes for the variant MBL-2 alleles have been associated with a low circulating MBL (9, 18) .
T46 18745-18863 Epistemic_statement denotes It is possible that patients with low MBL may be more susceptible to multilobar pneumonia or more severe septic shock.
T47 18864-18992 Epistemic_statement denotes Alternatively, it is possible that MBL may influence the inflammatory response to the initial injury in critical illnesses (7) .
T48 18993-19196 Epistemic_statement denotes MBL has been shown to decrease tumor necrosis factor release (39) and stimulate the production of anti-inflammatory cytokines such as interleukin-10 (40), but MBL modulation of TNF may be dose dependent.
T49 19390-19636 Epistemic_statement denotes It is possible that in critically ill patients with the low or defective MBL-producing genotypes, circulating MBL may not be sufficiently high or effective enough to switch from enhancement to suppression of the proinflammatory cytokine response.
T50 19637-19791 Epistemic_statement denotes Unfortunately, the functional significance of the MBL-2 polymorphisms and the inflammatory response of these patients in this study could not be examined.
T51 19792-19932 Epistemic_statement denotes Additional studies are clearly needed to investigate the possible mechanisms by which MBL-2 genotypes may be important in acute lung injury.
T52 20079-20126 Epistemic_statement denotes This is unlikely to be due to genotyping error.
T53 20325-20523 Epistemic_statement denotes It is more likely that deviation from Hardy-Weinberg occurred because of a possible association between the codon 54 polymorphism and the underlying condition requiring ICU admission such as sepsis.
T54 20524-20670 Epistemic_statement denotes Indeed, patients in this study who were homozygous for the variant codon 54B allele were more likely to have septic shock on admission to the ICU.
T55 20671-20836 Epistemic_statement denotes The association found between the codon 54 MBL-2 polymorphism and ARDS cannot be attributed to this association between 54B and septic shock, a risk factor for ARDS.
T56 20837-20984 Epistemic_statement denotes The association between the 54BB genotype and ARDS was actually strengthened when the analyses were restricted to those patients with septic shock.
T57 21156-21232 Epistemic_statement denotes However, the findings in this report are unlikely to be due to type I error.
T58 21233-21375 Epistemic_statement denotes The polymorphism was chosen a priori as a candidate in ARDS based on previous studies supporting its role in infection and critical illnesses.
T59 21376-21473 Epistemic_statement denotes The results are consistent with our hypothesis and with previous reports on infection and sepsis.
T60 21637-21758 Epistemic_statement denotes Nevertheless, as is true of all genetic association studies, our findings will need to be confirmed in other populations.
T61 21759-21808 Epistemic_statement denotes We recognize some other limitations to our study.
T62 21897-22101 Epistemic_statement denotes Because of the study design, the results may not be generalizable to the community setting, to immunocompromised hosts or patients without risk factors for ARDS, or with different clinical risks for ARDS.
T63 22102-22296 Epistemic_statement denotes In addition, the analyses were restricted to Caucasians, which reduces the possibility of confounding from ethnicity (42) but does not permit extrapolation of the results to other ethnic groups.
T64 22297-22421 Epistemic_statement denotes We report an association between the MBL-2 codon 54 genotype and severity of illness, septic shock, and development of ARDS.
T65 22422-22527 Epistemic_statement denotes The MBL-2 codon 54 genotype may also be associated with multiple organ dysfunction and mortality in ARDS.
T66 22528-22629 Epistemic_statement denotes Additional studies are needed to confirm these findings in other populations with other risk factors.
T67 23360-23763 Epistemic_statement denotes Daily Brussels multiple organ dysfunction score for each day after development of acute respiratory distress syndrome (ARDS) for the 212 patients with ARDS after adjustment for potentially important variables such as age, trauma as a risk factor for ARDS, Acute Physiology and Chronic Health Evaluation III scores, history of treatment with corticosteroids, liver failure, transfusion, and septic shock.