Epigenetic dynamics of monocyte-to-macrophage differentiation.

BACKGROUND: Monocyte-to-macrophage differentiation involves major biochemical and structural changes. In order to elucidate the role of gene regulatory changes during this process, we used high-throughput sequencing to analyze the complete transcriptome and epigenome of human monocytes that were differentiated in vitro by addition of colony-stimulating factor 1 in serum-free medium. RESULTS: Numerous mRNAs and miRNAs were significantly up- or down-regulated. More than 100 discrete DNA regions, most often far away from transcription start sites, were rapidly demethylated by the ten eleven translocation enzymes, became nucleosome-free and gained histone marks indicative of active enhancers. These regions were unique for macrophages and associated with genes involved in the regulation of the actin cytoskeleton, phagocytosis and innate immune response. CONCLUSIONS: In summary, we have discovered a phagocytic gene network that is repressed by DNA methylation in monocytes and rapidly de-repressed after the onset of macrophage differentiation.

BariSurg trial: Sleeve gastrectomy versus Roux-en-Y gastric bypass in obese patients with BMI 35-60 kg/m(2) - a multi-centre randomized patient and observer blind non-inferiority trial.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) rank among the most frequently applied bariatric procedures worldwide due to their positive risk/benefit correlation. A systematic review revealed a similar excess weight loss (EWL) 2 years postoperatively between SG and RYGB. However, there is a lack of randomized controlled multi-centre trials comparing SG and RYGB, not only concerning EWL, but also in terms of remission of obesity-related co-morbidities, gastroesophageal reflux disease (GERD) and quality of life (QoL) in the mid- and long-term. METHODS: The BariSurg trial was designed as a multi-centre, randomized controlled patient and observer blind trial. The trial protocol was approved by the corresponding ethics committees of the centres. To demonstrate EWL non-inferiority of SG compared to RYGB, power calculation was performed according to a non-inferiority study design. Morbidity, mortality, remission of obesity-related co-morbidities, GERD course and QoL are major secondary endpoints. 248 patients between 18 and 70 years, with a body mass index (BMI) between 35-60 kg/m(2) and indication for bariatric surgery according to the most recent German S3-guidelines will be randomized. The primary and secondary endpoints will be assessed prior to surgery and afterwards at discharge and at the time points 3-6, 12, 24, 36, 48 and 60 months postoperatively. DISCUSSION: With its five year follow-up, the BariSurg-trial will provide further evidence based data concerning the impact of SG and RYGB on EWL, remission of obesity-related co-morbidities, the course of GERD and QoL. TRIAL REGISTRATION: The trial protocol has been registered in the German Clinical Trials Register DRKS00004766 .

Clinical evaluation of the Trauma Outcome Profile (TOP) in the longer-term follow-up of polytrauma patients.

BACKGROUND: No sufficiently validated disease-specific instrument is available to assess patient outcome after polytrauma. The aim of this investigation was to test the recently published Trauma Outcome Profile (TOP) in the longer-term outcome of multiply injured patients. METHODS: Single centre validation study on the TOP in comparison with objective and subjective measures of patient, injury or treatment characteristics and longer-term outcome (e.g. medical outcomes study Short Form-36, SF-36; Nottingham Health Profile, NHP; working capacity), at least 2 years following trauma in 117 survivors of polytrauma (injury severity score, ISS>16), using comparative analysis and correlation testing of prospectively collected data. RESULTS: Patients' mean weighted self-rating with regard to the 10 single TOP dimensions of Health Related Quality of Life (HRQoL, 0-100) ranged from lowest values for mental functioning (52.6+33.5) to highest values for daily activities (79.0+27.5). The rate of persons who indicated an abnormal level of function or pain increased significantly from pre-injury status (2% and 5%, resp.) to 46% for both values at longer-term follow-up (p<0.001). Observed associations between single dimensions or TOP component summary scores with the corresponding values from general HRQol instruments, such as the SF-36, resulted in R (Pearson) up to 0.85. Survivors of polytrauma who presented with a reduced working capacity (RWC) at longer-term follow-up in all TOP dimensions included a significantly higher rate of patients conspicuous for a relevantly reduced outcome compared with those with a non reduced working capacity (NRWC) (posttraumatic stress disease, PTSD: p<0.05; all other dimensions: p<0.001). Patients with a RWC were characterised by an almost fivefold probability of reduced outcome with regard to the TOP dimensions 'social interaction' or 'satisfaction' (odds ratio, OR 12.4 (95% CI 5.1-30.1) and 12.5 (4.0-39.0), resp.). CONCLUSIONS: This first clinical and methodological evaluation in a well defined cohort of polytrauma patients found the TOP to be a reliable and well discriminating score covering both relevant general and trauma-specific aspects of longer-term outcome. Despite these promising primary results, until further validation, the TOP should be used together with already accepted HRQoL measures to allow adequate international comparison of data in the future.

Factors associated with reduced longer-term capacity to work in patients after polytrauma: a Swiss trauma center experience.

BACKGROUND: Knowledge of the factors associated with longer-term reduced capacity to work (RCW) is lacking in patients after polytrauma. STUDY DESIGN: We studied a prospectively collected cohort of polytrauma survivors (n = 115; age 39.5 +/- 20.6 years [mean +/- SD]; 98% blunt trauma; Injury Severity Score [ISS] 27.5 +/- 8.2) at a university trauma center. Uni- and multivariable analyses of patient, trauma, and treatment characteristics as well as parameters of self-reported functional outcomes were studied to determine their association with a reduced capacity to work (RCW) at least 2 years after injury. RESULTS: Postinjury quality of life was worse compared with preinjury status in univariate analysis (eg, Euro Quality of Life Group Visual Analogue Scale [EQ VAS] 66.2 +/- 24.4 vs 89.7 +/- 14.7; p = <0.001). In 53% of patients (n = 61), an RCW was found and functional outcomes were significantly lower than those in non-RCW patients (p < 0.001). Lower educational status (odds ratio [OR] 0.25; 95% CI 0.07 to 0.92; p = 0.036), higher ISS (OR 1.12; 95% CI 1.02 to 1.22; p = 0.017), less time in the emergency room (OR 0.92; 95% CI 0.86 to 0.97; p = 0.005), higher mean nurse labor per day and patient (OR 1.01; 95% CI 1.000 to 1.004; p = 0.033), and a reduced Nottingham Health Profile value (OR 1.10; 95% CI 1.06 to 1.15; p < 0.001) were associated with an RCW in the multiple logistic regression model (proportion of variance explained: 0.74). CONCLUSIONS: In this cohort of patients surviving polytrauma, approximately 50% of patients sustained longer-term RCW. Several characteristics, such as level of education or trauma severity, showed an independent association with patients' capacity to work, which was significantly associated with patients' self-rated scorings of well-being.

Prognostic value of Sequential Organ Failure Assessment and Simplified Acute Physiology II Score compared with trauma scores in the outcome of multiple-trauma patients.

BACKGROUND: Prospective data regarding the prognostic value of the Sequential Organ Failure Assessment (SOFA) score in comparison with the Simplified Acute Physiology Score (SAPS II) and trauma scores on the outcome of multiple-trauma patients are lacking. METHODS: Single-center evaluation (n = 237, Injury Severity Score [ISS] >16; mean ISS = 29). Uni- and multivariate analysis of SAPS II, SOFA, revised trauma, polytrauma, and trauma and ISS scores (TRISS) was performed. RESULTS: The 30-day mortality was 22.8% (n = 54). SOFA day 1 was significantly higher in nonsurvivors compared with survivors (P < .001) and correlated well with the length of intensive care unit stay (r = .50, P < .001). Logistic regression revealed SAPS II to have the best predictive value of 30-day mortality (area under the receiver operating characteristic = .86 +/- .03). The SOFA score significantly added prognostic information with regard to mortality to both SAPS II and TRISS. CONCLUSIONS: The combination of critically ill and trauma scores may increase the accuracy of mortality prediction in multiple-trauma patients.

In search of benchmarking for mortality following multiple trauma: a Swiss trauma center experience.

BACKGROUND: The manifestations associated with non-survival after multiple trauma may vary importantly between countries and institutions. The aim of the present study was to assess the quality of performance by comparing actual mortality rates to the literature. METHODS: The study involved evaluation of a prospective consecutive multiple trauma cohort (injury severity score, ISS > 16) primarily admitted to a university hospital. Univariate and multivariate testing of routine parameters and scores, such as the Trauma and Injury Severity Score (TRISS), was used to determine their predictive powers for mortality. RESULTS: The 30-day mortality of 22.8% (n = 54) exactly matched predicted TRISS versions of Champion or the Major Trauma Outcome Study for our 237 multiple trauma patients (42.8 +/- 20.9 years; ISS 29.5 +/- 11.5). Univariate analysis revealed significant differences between survivors and non-survivors when compared for age, ISS, Glasgow coma scale (GCS), pulse oximeter saturation (SapO2), hemoglobin, prothrombin time, and lactate. In multivariate analysis, age, ISS, and GCS (P < 0.001 each) functioned as major independent prognostic parameters of both 24 h and 30-day mortality. Various TRISS versions hardly differed in their precision (area under the curve [AUC] 0.83-0.84), but they did differ considerably in their level of requirement, with the TRISS using newer National Trauma Data Bank coefficients (NTDB-TRISS) offering the highest target benchmark (predicted mortality 13%, Z value -5.7) in the prediction of 30-day mortality. CONCLUSIONS: Because of the current lack of a single, internationally accepted scoring system for the prediction of mortality after multiple trauma, the comparison of outcomes between medical centers remains unreliable. To achieve effective quality control, a practical benchmarking model, such as the TRISS-NTDB, should be used worldwide.