Cumulative Prognostic Score Predicting Mortality in Patients Older Than 80 Years Admitted to the ICU.

OBJECTIVES: To develop a scoring system model that predicts mortality within 30 days of admission of patients older than 80 years admitted to intensive care units (ICUs). DESIGN: Prospective cohort study. SETTING: A total of 306 ICUs from 24 European countries. PARTICIPANTS: Older adults admitted to European ICUs (N = 3730; median age = 84 years [interquartile range = 81-87 y]; 51.8% male). MEASUREMENTS: Overall, 24 variables available during ICU admission were included as potential predictive variables. Multivariable logistic regression was used to identify independent predictors of 30-day mortality. Model sensitivity, specificity, and accuracy were evaluated with receiver operating characteristic curves. RESULTS: The 30-day-mortality was 1562 (41.9%). In multivariable analysis, these variables were selected as independent predictors of mortality: age, sex, ICU admission diagnosis, Clinical Frailty Scale, Sequential Organ Failure Score, invasive mechanical ventilation, and renal replacement therapy. The discrimination, accuracy, and calibration of the model were good: the area under the curve for a score of 10 or higher was .80, and the Brier score was .18. At a cut point of 10 or higher (75% of all patients), the model predicts 30-day mortality in 91.1% of all patients who die. CONCLUSION: A predictive model of cumulative events predicts 30-day mortality in patients older than 80 years admitted to ICUs. Future studies should include other potential predictor variables including functional status, presence of advance care plans, and assessment of each patient's decision-making capacity

The implementation of a translational study involving a primary care based behavioral program to improve blood pressure control: The HTN-IMPROVE study protocol (01295)

<p>Abstract</p> <p>Background</p> <p>Despite the impact of hypertension and widely accepted target values for blood pressure (BP), interventions to improve BP control have had limited success.</p> <p>Objectives</p> <p>We describe the design of a 'translational' study that examines the implementation, impact, sustainability, and cost of an evidence-based nurse-delivered tailored behavioral self-management intervention to improve BP control as it moves from a research context to healthcare delivery. The study addresses four specific aims: assess the implementation of an evidence-based behavioral self-management intervention to improve BP levels; evaluate the clinical impact of the intervention as it is implemented; assess organizational factors associated with the sustainability of the intervention; and assess the cost of implementing and sustaining the intervention.</p> <p>Methods</p> <p>The project involves three geographically diverse VA intervention facilities and nine control sites. We first conduct an evaluation of barriers and facilitators for implementing the intervention at intervention sites. We examine the impact of the intervention by comparing 12-month pre/post changes in BP control between patients in intervention sites versus patients in the matched control sites. Next, we examine the sustainability of the intervention and organizational factors facilitating or hindering the sustained implementation. Finally, we examine the costs of intervention implementation. Key outcomes are acceptability and costs of the program, as well as changes in BP. Outcomes will be assessed using mixed methods (<it>e.g</it>., qualitative analyses--pattern matching; quantitative methods--linear mixed models).</p> <p>Discussion</p> <p>The study results will provide information about the challenges and costs to implement and sustain the intervention, and what clinical impact can be expected.</p

Relationship between the Clinical Frailty Scale and short-term mortality in patients ≥ 80 years old acutely admitted to the ICU: a prospective cohort study.

BACKGROUND: The Clinical Frailty Scale (CFS) is frequently used to measure frailty in critically ill adults. There is wide variation in the approach to analysing the relationship between the CFS score and mortality after admission to the ICU. This study aimed to evaluate the influence of modelling approach on the association between the CFS score and short-term mortality and quantify the prognostic value of frailty in this context. METHODS: We analysed data from two multicentre prospective cohort studies which enrolled intensive care unit patients ≥ 80 years old in 26 countries. The primary outcome was mortality within 30-days from admission to the ICU. Logistic regression models for both ICU and 30-day mortality included the CFS score as either a categorical, continuous or dichotomous variable and were adjusted for patient's age, sex, reason for admission to the ICU, and admission Sequential Organ Failure Assessment score. RESULTS: The median age in the sample of 7487 consecutive patients was 84 years (IQR 81-87). The highest fraction of new prognostic information from frailty in the context of 30-day mortality was observed when the CFS score was treated as either a categorical variable using all original levels of frailty or a nonlinear continuous variable and was equal to 9% using these modelling approaches (p < 0.001). The relationship between the CFS score and mortality was nonlinear (p < 0.01). CONCLUSION: Knowledge about a patient's frailty status adds a substantial amount of new prognostic information at the moment of admission to the ICU. Arbitrary simplification of the CFS score into fewer groups than originally intended leads to a loss of information and should be avoided. Trial registration NCT03134807 (VIP1), NCT03370692 (VIP2)

Sepsis at ICU admission does not decrease 30-day survival in very old patients: a post-hoc analysis of the VIP1 multinational cohort study.

BACKGROUND: The number of intensive care patients aged ≥ 80 years (Very old Intensive Care Patients; VIPs) is growing. VIPs have high mortality and morbidity and the benefits of ICU admission are frequently questioned. Sepsis incidence has risen in recent years and identification of outcomes is of considerable public importance. We aimed to determine whether VIPs admitted for sepsis had different outcomes than those admitted for other acute reasons and identify potential prognostic factors for 30-day survival. RESULTS: This prospective study included VIPs with Sequential Organ Failure Assessment (SOFA) scores ≥ 2 acutely admitted to 307 ICUs in 21 European countries. Of 3869 acutely admitted VIPs, 493 (12.7%) [53.8% male, median age 83 (81-86) years] were admitted for sepsis. Sepsis was defined according to clinical criteria; suspected or demonstrated focus of infection and SOFA score ≥ 2 points. Compared to VIPs admitted for other acute reasons, VIPs admitted for sepsis were younger, had a higher SOFA score (9 vs. 7, p < 0.0001), required more vasoactive drugs [82.2% vs. 55.1%, p < 0.0001] and renal replacement therapies [17.4% vs. 9.9%; p < 0.0001], and had more life-sustaining treatment limitations [37.3% vs. 32.1%; p = 0.02]. Frailty was similar in both groups. Unadjusted 30-day survival was not significantly different between the two groups. After adjustment for age, gender, frailty, and SOFA score, sepsis had no impact on 30-day survival [HR 0.99 (95% CI 0.86-1.15), p = 0.917]. Inverse-probability weight (IPW)-adjusted survival curves for the first 30 days after ICU admission were similar for acute septic and non-septic patients [HR: 1.00 (95% CI 0.87-1.17), p = 0.95]. A matched-pair analysis in which patients with sepsis were matched with two control patients of the same gender with the same age, SOFA score, and level of frailty was also performed. A Cox proportional hazard regression model stratified on the matched pairs showed that 30-day survival was similar in both groups [57.2% (95% CI 52.7-60.7) vs. 57.1% (95% CI 53.7-60.1), p = 0.85]. CONCLUSIONS: After adjusting for organ dysfunction, sepsis at admission was not independently associated with decreased 30-day survival in this multinational study of 3869 VIPs. Age, frailty, and SOFA score were independently associated with survival

BACH2 Directly Regulates Expression of Foxp3 in UCB CD4+ T-Cells

Abstract Introduction: We have previously reported low constitutive nuclear factor of activated T cells (NFAT1) protein expression in unstimulated umbilical cord blood (UCB) CD4+ T-cells, and delayed up-regulation of NFAT1 expression during primary stimulation compared to adult primary CD4+ T-cells. Recent data has shown NFAT1 regulating Foxp3, an observed inverse expression of BACH2 and NFAT1 in UCB CD4+ T-cells, and our work demonstrating BACH2 directly regulates IL2 expression in the absence of NFAT1 protein. We sought to determine if BACH2 plays a role in regulating Foxp3 expression in UCB CD4+ T-cells. BACH2, a member of the b-Zip family, has been shown to act as a heterodimer with the bZip protein mafK, as a transcriptional inhibitor via recruitment of a histone deacetylase class II complex (HDAC II) in differentiating B-cells, and neurons. We hypothesized that BACH2 may directly regulate Foxp3 transcription by binding to putative NFAT1/AP1 binding sites within the Foxp3 proximal promoter. These sites may be vacant due to an absence of NFAT1 protein in resting UCB CD4+ T-cells. This hypothesis was tested by siRNA knockdown of BACH2 in primary UCB-derived CD4+ T-cells and then examining the level of Foxp3 expression at both the mRNA and protein level. In addition chromatin immunoprecipitation (ChIP) was performed in order to identify if BACH2 was binding to regions proximal to the Foxp3 gene. Finally Foxp3 driven luciferase plasmids were constructed and transiently transfected into primary UCB CD4+ T-cells with and without BACH2 siRNA and the relative expression determined. Methods: UCB T-cells were purified using autoMACs system. After overnight culture, T-cells were transfected with BACH2 siRNA using Amaxa nucleofector system. Both siRNA treated and control cells were incubated in media for 24 hours, and then stimulated using anti-CD3 and anti-CD28 antibodies. Aliquots of cells were collected at 24 hours and 30 hours post-stimulation for protein and total RNA isolation. The relative changes in mRNA levels for BACH2, FoxP3, were determined by Applied Biosystems Taqman real time RT-PCR system. Western blots were run to confirm results seen in the qRT-PCR. ChIP using BACH2 antibody, and PCR was used to determine putative BACH2 binding in DNA region surround exon 1 of Foxp3. Results: Loss of BACH2 expression correlates with reduced expression of (40-fold) FoxP3, mRNA in CD4+ UCB T-cells. Western blot performed on BACH2 siRNA treated, and anti-CD3/CD28 antibody stimulated UCB CD4+ T-cells; confirmed the observed loss of Foxp3 in unstimulated UCB CD4+ T-cells. Analysis of ChIP data from unstimulated UCB CD4+ T-cells showed that BACH2 and smafK bound to 2 regions flanking exon 1 of the Foxp3 gene, while results from unstimulated adult PB CD4+ T-cells showed BACH2 and smafK co-precipitated with only one region flanking exon 1 of Foxp3. Conclusions: NFAT1 protein has recently been shown to be required for the activation of Foxp3 in CD4+ T-cells, yet in UCB CD4+ T-cells NFAT1 protein expression is significantly attenuated. However, Foxp3 expression is unchanged in UCB CD4+ T-cells compared to adult PB CD4+ T-cells. UCB CD4+ T-cells BACH2 binds to two site surrounding exon 1 of Foxp3 gene, promoting the expression of Foxp3 mRNA in the absence of NFAT1 protein expression. These results suggest that expression of BACH2 in UCB CD4+ T-cells may underlie UCB immune tolerance in the unrelated allogeneic setting via regulation of FoxP3 impacting Treg development.</jats:p

Regulation of IL-2 expression by transcription factor BACH2 in umbilical cord blood CD4+ T cells

On activation, umbilical cord blood (UCB) CD4+ T cells demonstrate reduced expression of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), where as maintaining equivalent interleukin-2 (IL-2) levels, as compared with adult peripheral blood (PB) CD4þ T cells. Nuclear factor of activated T cells (NFAT1) protein, a transcription factor known to regulate the expression of IL-2, TNF-α and IFN-γ, is reduced in resting and activated UCB CD4+ T cells. In contrast, expression of Broad-complex-Tramtrack-Bric-a-Brac and Cap n collar homology 1 bZip transcription factor 2 (BACH2) was shown by gene array analyses to be increased in UCB CD4+ T cells and was validated by qRT-PCR. Using chromatin immunoprecipitation, BACH2 was shown binding to the human IL-2 proximal promoter. Knockdown experiments of BACH2 by transient transfection of UCB CD4+ T cells with BACH2 siRNA resulted in significant reductions in stimulated IL-2 production. Decreased IL-2 gene transcription in UCB CD4+ T cells transfected with BACH2 siRNA was confirmed by a human IL-2 luciferase assay. In summary, BACH2 maintains IL-2 expression in UCB CD4þ T cells at levels equivalent to adult PB CD4+ T cells despite reduced NFAT1 protein expression. Thus, BACH2 expression is necessary to maintain IL-2 production when NFAT1 protein is reduced, potentially impacting UCB graft CD4+ T-cell allogeneic responses