Predictors for outcome among cardiac arrest patients:the importance of initial cardiac arrest rhythm versus time to return of spontaneous circulation, a retrospective cohort study

BACKGROUND: In the past decade, early treatment of cardiac arrest (CA) victims has been improved in several ways, leading to more optimistic over all prognoses. However, the global survival rate after out-of-hospital CA (OHCA) is still not more than 5-10%. With a better knowledge of the predictors for outcome among CA patients, we can improve the management of CA, in order to strengthen the leads in the chain of survival. METHODS: A retrospective cohort study including 172 CA patients admitted to the intensive care unit (ICU) in Odense University Hospital (OUH) in a three-year period was conducted. We determined the 90-day mortality and neurological outcome at discharge for CA patients treated with therapeutic hypothermia (TH), in regard to determine the importance of the predictors for mortality and neurological outcome, with emphasize on combining initial rhythm and time to return of spontaneous circulation (ROSC). RESULTS: The overall mortality was 44% and a favorable neurological outcome was seen among 52%. Strong predictors for survival and favorable neurological outcome were ventricular tachycardia/ventricular fibrillation (VT/VF) as initial rhythm, cardiac etiology and time to ROSC < 20 minutes. Age < 60 years was a predictor for survival only. Patients with the combination of VT/VF and ROSC < 20 minutes had undeniably the best chance of both survival and a favorable neurological outcome. CONCLUSIONS: We found significant predictors for both survival and neurological outcome, in which an initial rhythm of VT/VF and a cardiac etiology were the strongest

Cutaneous Expression of Familial Cancer Syndromes

Genodermatoses are inherited syndromes with cutaneous manifestations. Some genodermatoses are associated with malignancy of internal organs and tissues. Early detection of the typical signs of these syndromes is important, because those lesions are a sign of underlying predisposition to extracutaneous neoplasms. The dermatologist has an important role in the early detection of these signs and syndromes, as early detection may affect the clinical course of the disease. We report here the characteristic cutaneous findings that dermatologists should be aware of in order to identify a genodermatosis with a possible associated malignancy. An updated overview of the pathogenesis and clinical findings of these syndromes is provided. Furthermore, surveillance protocols and treatment recommendations are explored.</p

Identification of Pharmacological Modulators of HMGB1-Induced Inflammatory Response by Cell-Based Screening

High mobility group box 1 (HMGB1), a highly conserved, ubiquitous protein, is released into the circulation during sterile inflammation (e.g. arthritis, trauma) and circulatory shock. It participates in the pathogenesis of delayed inflammatory responses and organ dysfunction. While several molecules have been identified that modulate the release of HMGB1, less attention has been paid to identify pharmacological inhibitors of the downstream inflammatory processes elicited by HMGB1 (C23-C45 disulfide C106 thiol form). In the current study, a cell-based medium-throughput screening of a 5000+ compound focused library of clinical drugs and drug-like compounds was performed in murine RAW264.7 macrophages, in order to identify modulators of HMGB1-induced tumor-necrosis factor alpha (TNFα) production. Clinically used drugs that suppressed HMGB1-induced TNFα production included glucocorticoids, beta agonists, and the anti-HIV compound indinavir. A re-screen of the NIH clinical compound library identified beta-agonists and various intracellular cAMP enhancers as compounds that potentiate the inhibitory effect of glucocorticoids on HMGB1-induced TNFα production. The molecular pathways involved in this synergistic anti-inflammatory effect are related, at least in part, to inhibition of TNFα mRNA synthesis via a synergistic suppression of ERK/IκB activation. Inhibition of TNFα production by prednisolone+salbutamol pretreatment was also confirmed in vivo in mice subjected to HMGB1 injection; this effect was more pronounced than the effect of either of the agents administered separately. The current study unveils several drug-like modulators of HMGB1-mediated inflammatory responses and offers pharmacological directions for the therapeutic suppression of inflammatory responses in HMGB1-dependent diseases. © 2013 Gerö et al

Surgical complications after immediate breast reconstruction<i> vs.</i> mastectomy alone: impact on the time to delivery of adjuvant therapy

Background: When mastectomy is planned in women with breast cancer who wish to have a breast reconstruction, there is a choice between immediate and delayed breast reconstruction. Mastectomy combined with immediate breast reconstruction (IBR) is, however, a more complex procedure than mastectomy alone. It is therefore of concern if adding IBR may result in a higher complication rate and thus a risk of delaying adjuvant therapy. The aim of this study was to compare the time from surgery to initiation of adjuvant therapy between women having a mastectomy and IBR with women having a simple mastectomy, and to evaluate if the postoperative complications may postpone the adjuvant therapy for women diagnosed with stage I-III breast cancer. Methods: This retrospective cohort study included all women who underwent a mastectomy from November 2015 to March 2017 at Odense University Hospital (n=314 mastectomies). The medical records were reviewed regarding patient demographics, health characteristics, post -operative complications and time from surgery to initiation of adjuvant therapy. Women were stratified according to surgery, simple mastectomy or mastectomy with IBR. Results: The group of women receiving IBR were younger (age 46 vs. 59 years,

High mobility group box protein 1 in complex with lipopolysaccharide or IL-1 promotes an increased inflammatory phenotype in synovial fibroblasts

Inflammation can be infectious and/or sterile depending on the initiating event. The proinflammatory mediator High mobility group box protein 1 (HMGB1) is a nuclear protein released from cells during both sterile and infectious inflammation and once extracellular, initates and potentiates inflammation by inducing cytokine production and by recruiting inflammatory cells. Autoimmune diseases are characterised by chronic sterile inflammation leading to tissue destruction. HMGB1 has been implicated in the pathogenesis of several autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosis, multiple sclerosis and myositis. The involvement of HMGB1 in arthritis has been shown by overexpression of HMGB1 in RA synovial tissue and synovial fluid, by beneficial outcome of therapeutic HMGB1-blockade in several experimental arthritis models and by the induction of arthritis by intra-articular injection of recombinant HMGB1 into mice. In this thesis work I set out to investigate the potential role of HMGB1 in juvenile idiopathic arthritis (JIA), to further delineate mechanisms by which HMGB1 can contribute to arthritis pathogenesis and to study the means by which HMGB1 activity can be suppressed. I could report for the first time that HMGB1 levels were increased in synovial fluid as compared to plasma during JIA. HMGB1 levels in synovial fluid did not correlate to disease duration. In contrast, the recorded levels of IL-8 and S100 proteins were higher in synovial fluid during early phases of disease. This indicates a change in the inflammatory phenotype during the progression of JIA. High HMGB1 levels in synovial fluid correlated with early JIA onset, suggesting differences in immunopathogenesis between patient groups. I have also demonstrated that HMGB1 may form complexes with the exogenous TLR ligand LPS or the endogenous inflammatory mediators IL-1α and IL-1β, respectively. Compared to each mediator alone such complexes stimulated synovial fibroblasts from arthritis patients to enhanced production of cytokines and tissue degrading enzymes. This enhancement is mediated via the reciprocal receptor for each HMGB1-partner molecule. Since all the studied mediators are present in arthritic joint during inflammation, this is a potential mechanism through which HMGB1 enhances ongoing inflammation and destruction during rheumatic diseases. Finally, I have demonstrated that the proinflammatory activity of HMGB1 can be therapeutically targeted, either by inhibiting its active release by clinically approved anti-rheumatic drugs or by neutralization with a HMGB1-specific monoclonal antibody. Extracellular secretion of HMGB1 from LPS+IFN-γ stimulated human primary monocytes was inhibited by dexamethasone, chloroquine and gold sodium thiomalate in vitro as recorded using an ELISPOT assay. Therapeutic administration of an HMGB1-specific HMGB1 monoclonal antibody ameliorated arthritis in two separate experimental models. In conclusion, my thesis work has added to the growing evidence that HMGB1 is involved in the pathogenesis of arthritis, has revealed a potential mechanism for its proinflammatory function and has demonstrated a means by which HMGB1-mediated activities can be counteracted

Diagnostic Performance of T2Candida Among ICU Patients With Risk Factors for Invasive Candidiasis

Background: Invasive candidiasis (IC) comprises candidemia and deep-seated candidiasis. Blood culture (BC) is the gold standard test, but sensitivity is low. T2Candida is a new diagnostic test. We investigated the performance of T2Candida, BC, and Candida mannan antigen (MAg) for detection of IC in a high-risk intensive care unit (ICU) population.Methods: One-hundred twenty-six ICU patients at high risk of IC with sepsis despite 3 days of broad-spectrum antibiotics were included. Paired BC, T2Candida, and MAg were obtained twice weekly (334 sets). Patients were classified into proven, likely, possible, or unlikely IC based on patient record review.Results: At enrollment, 92 (77%) patients were receiving antifungal therapy (mainly fluconazole 66%). Fifteen (11.9%) patients were positive by BC (n = 4), T2Candida (n = 11), or MAg (n = 10). The T2Candida species distribution at inclusion (Candidaalbicans/Candida tropicalis: 8/11 [72.3%] and Candida glabrata/Candida krusei: 3/11 [27.3%]) was supported by the identification of BC or colonizing isolates in 10/11 cases. Patients were classified with proven (11), likely (6), possible (11), and unlikely (98) IC. Defining IC as proven/proven&amp;likely/proven&amp;likely&amp;possible, respectively, the sensitivity was as follows: T2Candida (55%/59%/39%), BC (45%/29%/ 8%), and MAg (36%/41%/32%). The negative predictive value was similar across the tests for proven vs others and proven/likely vs others (94%-96% and 90%-95%, respectively). For test combinations including T2Candida, the sensitivity increased to 64%-65%, without hampering the positive predictive value.Conclusions: In conclusion, although the diagnostic performance was modest for all the tests, the combination of T2Candida and BC seemed to have the best diagnostic performance, and thus implementation of T2Candida may improve the diagnosis of IC.</p

Patterns of cerebral tissue oxygen tension and cytoplasmic redox state in bacterial meningitis

Background: Compromised cerebral energy metabolism is common in patients with bacterial meningitis. In this study, simultaneous measurements of cerebral oxygen tension and lactate/pyruvate ratio were compared to explore whether disturbed energy metabolism was usually caused by insufficient tissue oxygenation or compromised oxidative metabolism of pyruvate indicating mitochondrial dysfunction. Subject and Methods: Ten consecutive patients with severe streptococcus meningitis were included in this prospective cohort study. Intracranial pressure, brain tissue oxygen tension (PbtO 2 ), and energy metabolism (intracerebral microdialysis) were continuously monitored in nine patients. A cerebral lactate/pyruvate (LP) ratio &lt;30 was considered indicating normal oxidative metabolism, LP ratio &gt;30 simultaneously with pyruvate below lower normal level (70 µmol/L) was interpreted as biochemical indication of ischemia, and LP ratio &gt;30 simultaneously with a normal or increased level of pyruvate was interpreted as mitochondrial dysfunction. The biochemical variables were compared with PbtO 2 simultaneously monitored within the same cerebral region. Results: In two cases, the LP ratio was normal during the whole study period and the simultaneously monitored PbtO 2 was 18 ± 6 mm Hg. In six cases, interpreted as mitochondrial dysfunction, the simultaneously monitored PbtO 2 was 20 ± 6 mm Hg and without correlation with the LP ratio. In one patient, exhibiting a pattern interpreted as ischemia, PbtO 2 decreased below 10 mm Hg and a correlation between LP and PbtO 2 was observed. Conclusion: This study demonstrated that compromised cerebral energy metabolism, evidenced by increased LP ratio, was common in patients with severe bacterial meningitis while not related to insufficient tissue oxygenation. </p

Discrete-time survival analysis in the critically ill:a deep learning approach using heterogeneous data

Prediction of survival for patients in intensive care units (ICUs) has been subject to intense research. However, no models exist that embrace the multiverse of data in ICUs. It is an open question whether deep learning methods using automated data integration with minimal pre-processing of mixed data domains such as free text, medical history and high-frequency data can provide discrete-time survival estimates for individual ICU patients. We trained a deep learning model on data from patients admitted to ten ICUs in the Capital Region of Denmark and the Region of Southern Denmark between 2011 and 2018. Inspired by natural language processing we mapped the electronic patient record data to an embedded representation and fed the data to a recurrent neural network with a multi-label output layer representing the chance of survival at different follow-up times. We evaluated the performance using the time-dependent concordance index. In addition, we quantified and visualized the drivers of survival predictions using the SHAP methodology. We included 37,355 admissions of 29,417 patients in our study. Our deep learning models outperformed traditional Cox proportional-hazard models with concordance index in the ranges 0.72–0.73, 0.71–0.72, 0.71, and 0.69–0.70, for models applied at baseline 0, 24, 48, and 72 h, respectively. Deep learning models based on a combination of entity embeddings and survival modelling is a feasible approach to obtain individualized survival estimates in data-rich settings such as the ICU. The interpretable nature of the models enables us to understand the impact of the different data domains.</p