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      Expression of HO1 and PER2 can predict the incidence of delirium in trauma patients with concomitant brain injury

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          Abstract

          Intensive care unit (ICU)-acquired delirium is associated with adverse outcome in trauma patients with concomitant traumatic brain injury (TBI), but diagnosis remains challenging. Quantifying circadian disruption by analyzing expression of the circadian gene period circadian regulator 2 ( PER2) and heme oxygenase 1 ( HO1), which determines heme turnover, may prove to be potential diagnostic tools. Expression of PER2 and HO1 was quantified using qPCR from blood samples 1 day and 7 days after trauma. Association analysis was performed comparing mRNA expression levels with parameters of trauma (ISS—injury severity score), delirium, acute kidney injury (AKI) and length of ICU stay. 48 polytraumatized patients were included (equal distribution of TBI versus non-TBI) corrected for ISS, age and gender using a matched pairs approach. Expression levels of PER2 and HO1 were independent of age ( PER2: P = 0.935; HO1: P = 0.988), while expression levels were significantly correlated with trauma severity ( PER2: P = 0.009; HO1: P < 0.001) and longer ICU length of stay ( PER2: P = 0.018; HO1: P < 0.001). High expression levels increased the odds of delirium occurrence ( PER2: OR = 4.32 [1.14–13.87]; HO1: OR = 4.50 [1.23–14.42]). Patients with TBI showed a trend towards elevated PER2 ( OR = 3.00 [0.84–9.33], P = 0.125) , but not towards delirium occurrence ( P = 0.556). TBI patients were less likely to develop AKI compared to non-TBI ( P = 0.022). Expression levels of PER2 and HO1 correlate with the incidence of delirium in an age-independent manner and may potentially improve diagnostic algorithms when used as delirium biomarkers.

          Trial registration: German Clinical Trials Register (Trial-ID DRKS00008981; Universal Trial Number U1111-1172-6077; Jan. 18, 2018).

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          Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit.

          In the intensive care unit (ICU), delirium is a common yet underdiagnosed form of organ dysfunction, and its contribution to patient outcomes is unclear. To determine if delirium is an independent predictor of clinical outcomes, including 6-month mortality and length of stay among ICU patients receiving mechanical ventilation. Prospective cohort study enrolling 275 consecutive mechanically ventilated patients admitted to adult medical and coronary ICUs of a US university-based medical center between February 2000 and May 2001. Patients were followed up for development of delirium over 2158 ICU days using the Confusion Assessment Method for the ICU and the Richmond Agitation-Sedation Scale. Primary outcomes included 6-month mortality, overall hospital length of stay, and length of stay in the post-ICU period. Secondary outcomes were ventilator-free days and cognitive impairment at hospital discharge. Of 275 patients, 51 (18.5%) had persistent coma and died in the hospital. Among the remaining 224 patients, 183 (81.7%) developed delirium at some point during the ICU stay. Baseline demographics including age, comorbidity scores, dementia scores, activities of daily living, severity of illness, and admission diagnoses were similar between those with and without delirium (P>.05 for all). Patients who developed delirium had higher 6-month mortality rates (34% vs 15%, P =.03) and spent 10 days longer in the hospital than those who never developed delirium (P<.001). After adjusting for covariates (including age, severity of illness, comorbid conditions, coma, and use of sedatives or analgesic medications), delirium was independently associated with higher 6-month mortality (adjusted hazard ratio [HR], 3.2; 95% confidence interval [CI], 1.4-7.7; P =.008), and longer hospital stay (adjusted HR, 2.0; 95% CI, 1.4-3.0; P<.001). Delirium in the ICU was also independently associated with a longer post-ICU stay (adjusted HR, 1.6; 95% CI, 1.2-2.3; P =.009), fewer median days alive and without mechanical ventilation (19 [interquartile range, 4-23] vs 24 [19-26]; adjusted P =.03), and a higher incidence of cognitive impairment at hospital discharge (adjusted HR, 9.1; 95% CI, 2.3-35.3; P =.002). Delirium was an independent predictor of higher 6-month mortality and longer hospital stay even after adjusting for relevant covariates including coma, sedatives, and analgesics in patients receiving mechanical ventilation.
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            Linking neural activity and molecular oscillations in the SCN.

            Neurons in the suprachiasmatic nucleus (SCN) function as part of a central timing circuit that drives daily changes in our behaviour and underlying physiology. A hallmark feature of SCN neuronal populations is that they are mostly electrically silent during the night, start to fire action potentials near dawn and then continue to generate action potentials with a slow and steady pace all day long. Sets of currents are responsible for this daily rhythm, with the strongest evidence for persistent Na(+) currents, L-type Ca(2+) currents, hyperpolarization-activated currents (I(H)), large-conductance Ca(2+) activated K(+) (BK) currents and fast delayed rectifier (FDR) K(+) currents. These rhythms in electrical activity are crucial for the function of the circadian timing system, including the expression of clock genes, and decline with ageing and disease. This article reviews our current understanding of the ionic and molecular mechanisms that drive the rhythmic firing patterns in the SCN.
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              AKI in the ICU: definition, epidemiology, risk stratification, and outcomes.

              Acute kidney injury (AKI) has emerged as a major public health problem that affects millions of patients worldwide and leads to decreased survival and increased progression of underlying chronic kidney disease (CKD). Recent consensus criteria for definition and classification of AKI have provided more consistent estimates of AKI epidemiology. Patients, in particular those in the ICU, are dying of AKI and not just simply with AKI. Even small changes in serum creatinine concentrations are associated with a substantial increase in the risk of death. AKI is not a single disease but rather a syndrome comprising multiple clinical conditions. Outcomes from AKI depend on the underlying disease, the severity and duration of renal impairment, and the patient's renal baseline condition. The development of AKI is the consequence of complex interactions between the actual insult and subsequent activation of inflammation and coagulation. Contrary to the conventional view, recent experimental and clinical data argue against renal ischemia-reperfusion as a sine qua non condition for the development of AKI. Loss of renal function can occur without histological signs of tubular damage or even necrosis. The detrimental effects of AKI are not limited to classical well-known symptoms such as fluid overload and electrolyte abnormalities. AKI can also lead to problems that are not readily appreciated at the bedside and can extend well beyond the ICU stay, including progression of CKD and impaired innate immunity. Experimental and small observational studies provide evidence that AKI impairs (innate) immunity and is associated with higher infection rates.
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                Author and article information

                Contributors
                nils.schallner@uniklinik-freiburg.de
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                28 July 2021
                28 July 2021
                2021
                : 11
                : 15388
                Affiliations
                [1 ]GRID grid.5963.9, Department of Anesthesiology & Critical Care Medicine, Medical Center - Faculty of Medicine, , University of Freiburg, ; Hugstetter Str. 55, 79106 Freiburg, Germany
                [2 ]GRID grid.5963.9, Faculty of Medicine, , University of Freiburg, ; Freiburg, Germany
                Author information
                http://orcid.org/0000-0003-2120-788X
                Article
                94773
                10.1038/s41598-021-94773-6
                8319290
                34321570
                85002a66-e800-4534-afa0-105ac14a7fff
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 4 December 2020
                : 16 July 2021
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: SCHA 1838/4-1
                Funded by: Faculty of Medicine, University of Freiburg
                Award ID: Berta-Ottenstein-Programme for Advanced Clinician Scientists
                Award Recipient :
                Funded by: Universitätsklinikum Freiburg (8975)
                Categories
                Article
                Custom metadata
                © The Author(s) 2021

                Uncategorized
                biomarkers,circadian rhythms and sleep,translational research,neurological manifestations

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