Background: After critical illness, new or worsening impairments in physical, cognitive, and/or mental health function are common among patients who have survived. Who should be screened for long-term impairments, what tools to use, and when, remain unclear. Objectives: Provide pragmatic recommendations to clinicians caring for adult survivors of critical illness related to screening for post-discharge impairments. Participants: 31 international experts in risk-stratification and assessment of survivors of critical illness, including practitioners involved in the Society of Critical Care Medicine's (SCCM) Thrive Post-ICU Collaboratives, survivors of critical illness, and clinical researchers. Design: SCCM consensus conference on post-intensive care syndrome (PICS) prediction and assessment, held in Dallas, in May, 2019.Meeting Outcomes: We concluded that existing tools are insufficient to reliably predict PICS. We identified factors before (e.g., frailty, pre-existing functional impairments), during (e.g., duration of delirium, sepsis, acute respiratory distress syndrome), and after (e.g., early symptoms of anxiety, depression, or post-traumatic stress disorder (PTSD)) critical illness that can be used to identify patients at high-risk for cognitive, mental health, and physical impairments after critical illness in whom screening is recommended. We recommend serial assessments, beginning within 2-4 weeks of hospital discharge, using the following screening tools: Montreal Cognitive Assessment
The TraI protein of conjugative plasmid F factor binds and cleaves a single-stranded region of the plasmid prior to transfer to a recipient. TraI36, an N-terminal TraI fragment, binds ssDNA with a subnanomolar K(D) and remarkable sequence specificity. The structure of the TraI36 Y16F variant bound to ssDNA reveals specificity determinants, including a ssDNA intramolecular 3 base interaction and two pockets within the protein's binding cleft that accommodate bases in a knob-into-hole fashion. Mutagenesis results underscore the intricate design of the binding site, with the greatest effects resulting from substitutions for residues that both contact ssDNA and stabilize protein structure. The active site architecture suggests that the bound divalent cation, which is essential for catalysis, both positions the DNA by liganding two oxygens of the scissile phosphate and increases the partial positive charge on the phosphorus to enhance nucleophilic attack.
In a large health system in the United States, investigators examined whether mortality, receipt of mechanical ventilation, and patient acuity changed over time among adult patients with COVID-19–related critical illness admitted to intensive care units.
Human subjects. Human samples and accompanying clinical data were collected from ICU patients enrolled in the NIRFS study, a substudy of the MESSI cohort, which is a single-center, prospective cohort of patients admitted to the ICU at the Hospital of the University of Pennsylvania. This study was approved by the IRB of the University of Pennsylvania. Subjects or their available surrogates provided written informed consent.
PURPOSE:
A causal biomarker for acute respiratory distress syndrome (ARDS) could fuel precision therapy options. Plasma angiopoietin-2 (ANG2), a vascular permeability marker, is a strong candidate based on experimental and observational evidence. We used genetic causal inference methods – Mendelian Randomization and mediation – to infer potential effects of plasma ANG2.
METHODS:
We genotyped 703 septic subjects, measured ICU admission plasma ANG2, and performed a quantitative trait loci (QTL) analysis to determine variants in the ANGPT2 gene associated with plasma ANG2 (p < 0.005). We then used linear regression and post-estimation analysis to genetically predict plasma ANG2 and tested genetically-predicted ANG2 for ARDS association using logistic regression. We estimated the proportion of the genetic effect explained by plasma ANG2 using mediation analysis.
RESULTS:
Plasma ANG2 was strongly associated with ARDS (OR 1.59 (95% CI 1.35, 1.88) per log). Five ANGPT2 variants were associated with ANG2 in European ancestry subjects (n=404). Rs2442608C, the most extreme cis QTL (coefficient 0.22, 95% CI 0.09 – 0.36, p=0.001), was associated with higher ARDS risk: adjusted OR 1.38 (95% CI 1.01, 1.87), p=0.042. No significant QTL were identified in African ancestry subjects. Genetically-predicted plasma ANG2 was associated with ARDS risk: adjusted OR 2.25 (95% CI 1.06 – 4.78), p=0.035. Plasma ANG2 mediated 34% of the rs2442608C - ARDS risk.
CONCLUSIONS:
In septic European ancestry subjects, the strongest ANG2-determining ANGPT2 genetic variant associates with higher ARDS risk. Plasma ANG2 may be a causal factor in ARDS development. Strategies to reduce plasma ANG2 warrant testing to prevent or treat sepsis-associated ARDS.
Changes in fluorescence emission intensity and anisotropy can reflect changes in the environment and molecular motion of a fluorophore. Researchers can capitalize on these characteristics to assess the affinity and specificity of DNA-binding proteins using fluorophore-labeled oligonucleotides. While there are many advantages to measuring binding using fluorescent oligonucleotides, there are also some distinct disadvantages. Here we describe some of the relevant issues for the novice, illustrating key points using data collected with the F plasmid relaxase domain and a variety of labeled oligonucleotides. Topics include selection of a fluorophore, experimental design using a fluorometer equipped with an automatic titrating unit, and analysis of direct binding and competition assays.
BACKGROUND: Critically ill patients who develop ARDS have substantial associated morbidity and mortality. Circulating mitochondrial DNA (mtDNA) released during critical illness causes endothelial dysfunction and lung injury in experimental models. This study hypothesized that elevated plasma mtDNA is associated with ARDS in critically ill patients with trauma and sepsis.METHODS: Plasma mtDNA concentrations were measured at ED presentation and approximately 48 h later in separate prospective cohorts of critically ill patients with trauma and sepsis. ARDS was classified according to the Berlin definition. The association of mtDNA with ARDS was tested by using multivariable logistic regression, adjusted for covariates previously shown to contribute to ARDS risk in each population.RESULTS: ARDS developed in 41 of 224 (18%) trauma patients and in 45 of 120 (38%) patients with sepsis. Forty-eight-hour mtDNA levels were significantly associated with ARDS (trauma: OR, 1.58/log copies/mL; 95% CI, 1.14-2.19 [P ¼ .006]; sepsis: OR, 1.52/log copies/ mL; 95% CI, 1.12-2.06 [P ¼ .007]). Plasma mtDNA on presentation was not significantly associated with ARDS in either cohort. In patients with sepsis, 48-h mtDNA was more strongly associated with ARDS among those with a nonpulmonary infectious source (OR, 2.20/log copies/mL; 95% CI, 1.36-3.55 [P ¼ .001], n ¼ 69) than those with a pulmonary source (OR, 1.04/log copies/mL; 95% CI, 0.68-1.59 [P ¼ .84], n ¼ 51; P ¼ .014 for interaction).CONCLUSIONS: Plasma mtDNA levels were associated with incident ARDS in two critical illness populations. Given supportive preclinical data, our findings suggest a potential link between circulating mtDNA and lung injury and merit further investigation as a potentially targetable mediator of ARDS. CHEST 2020; 157(1):67-76
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