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Following acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) a significant proportion of individuals develop prolonged symptoms, a serious condition termed post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS) or long COVID. Predictors of PACS are needed. In a prospective multicentric cohort study of 215 individuals, we study COVID-19 patients during primary infection and up to one year later, compared to healthy subjects. We discover an immunoglobulin (Ig) signature, based on total IgM and IgG3 levels, which – combined with age, history of asthma bronchiale, and five symptoms during primary infection – is able to predict the risk of PACS independently of timepoint of blood sampling. We validate the score in an independent cohort of 395 individuals with COVID-19. Our results highlight the benefit of measuring Igs for the early identification of patients at high risk for PACS, which facilitates the study of targeted treatment and pathomechanisms of PACS. Studying a prospective cohort, the authors develop and validate a predictive score for post-acute COVID-19 syndrome, also known as long-COVID. This score relies on an immunoglobulin signature and is independent of timepoint of blood sampling.

Background Delirium is a well-known complication in cardiac surgery and intensive care unit (ICU) patients. However, in many other settings its prevalence and clinical consequences are understudied. The aims of this study were: (1) To assess delirium prevalence in a large, diverse cohort of acute care patients classified as either at risk or not at risk for delirium; (2) To compare these two groups according to defined indicators; and (3) To compare delirious with non-delirious patients regarding hospital mortality, ICU and hospital length of stay, nursing hours and cost per case. Methods This cohort study was performed in a Swiss university hospital following implementation of a delirium management guideline. After excluding patients aged < 18 years or with a length of stay (LOS) < 1 day, 29′278 patients hospitalized in the study hospital in 2014 were included. Delirium period prevalence was calculated based on a Delirium Observation Scale (DOS) score ≥ 3 and / or Intensive Care Delirium Screening Checklist (ICDSC) scores ≥4. Results Of 10′906 patients admitted, DOS / ICDSC scores indicated delirium in 28.4%. Delirium was most prevalent (36.2–40.5%) in cardiac surgery, neurosurgery, trauma, radiotherapy and neurology patients. It was also common in geriatrics, internal medicine, visceral surgery, reconstructive plastic surgery and cranio-maxillo-facial surgery patients (prevalence 21.6–28.6%). In the unadjusted and adjusted models, delirious patients had a significantly higher risk of inpatient mortality, stayed significantly longer in the ICU and hospital, needed significantly more nursing hours and generated significantly higher costs per case. For the seven most common ICD-10 diagnoses, each diagnostic group’s delirious patients had worse outcomes compared to those with no delirium. Conclusions The results indicate a high number of patients at risk for delirium, with high delirium prevalence across all patient groups. Delirious patients showed significantly worse clinical outcomes and generated higher costs. Subgroup analyses highlighted striking variations in delirium period-prevalence across patient groups. Due to the high prevalence of delirium in patients treated in care centers for radiotherapy, visceral surgery, reconstructive plastic surgery, cranio-maxillofacial surgery and oral surgery, it is recommended to expand the current focus of delirium management to these patient groups.

Delirium in the general intensive care unit (ICU) population is common, associated with adverse outcomes and well studied. However, knowledge on delirium in the increasing number of ICU patients with malignancy is scarce. The aim was to assess the frequency of delirium and its impact on resource utilizations and outcomes in ICU patients with malignancy. This retrospective, single-center longitudinal cohort study included all patients with malignancy admitted to ICUs of a University Hospital during one year. Delirium was diagnosed by an Intensive Care Delirium Screening Checklist (ICDSC) score ≥ 4. Of 488 ICU patients with malignancy, 176/488 (36%) developed delirium. Delirious patients were older (66 [55–72] vs. 61 [51–69] years, p  = 0.001), had higher SAPS II (41 [27–68] vs. 24 [17–32], p  < 0.001) and more frequently sepsis (26/176 [15%] vs. 6/312 [1.9%], p  < 0.001) and/or shock (30/176 [6.1%] vs. 6/312 [1.9%], p  < 0.001). In multivariate analysis, delirium was independently associated with lower discharge home (OR [95% CI] 0.37 [0.24–0.57], p  < 0.001), longer ICU (HR [95% CI] 0.30 [0.23–0.37], p  < 0.001) and hospital length of stay (HR [95% CI] 0.62 [0.50–0.77], p  < 0.001), longer mechanical ventilation (HR [95% CI] 0.40 [0.28–0.57], p  < 0.001), higher ICU nursing workload (B [95% CI] 1.92 [1.67–2.21], p  < 0.001) and ICU (B [95% CI] 2.08 [1.81–2.38], p  < 0.001) and total costs (B [95% CI] 1.44 [1.30–1.60], p  < 0.001). However, delirium was not independently associated with in-hospital mortality (OR [95% CI] 2.26 [0.93–5.54], p  = 0.074). In conclusion, delirium was a frequent complication in ICU patients with malignancy independently associated with high resource utilizations, however, it was not independently associated with in-hospital mortality.

Hepatic dysfunction and jaundice are traditionally viewed as late features of sepsis and portend poor outcomes. We hypothesized that changes in liver function occur early in the onset of sepsis, yet pass undetected by standard laboratory tests. In a long-term rat model of faecal peritonitis, biotransformation and hepatobiliary transport were impaired, depending on subsequent disease severity, as early as 6 h after peritoneal contamination. Phosphatidylinositol-3-kinase (PI3K) signalling was simultaneously induced at this time point. At 15 h there was hepatocellular accumulation of bilirubin, bile acids, and xenobiotics, with disturbed bile acid conjugation and drug metabolism. Cholestasis was preceded by disruption of the bile acid and organic anion transport machinery at the canalicular pole. Inhibitors of PI3K partially prevented cytokine-induced loss of villi in cultured HepG2 cells. Notably, mice lacking the PI3Kγ gene were protected against cholestasis and impaired bile acid conjugation. This was partially confirmed by an increase in plasma bile acids (e.g., chenodeoxycholic acid [CDCA] and taurodeoxycholic acid [TDCA]) observed in 48 patients on the day severe sepsis was diagnosed; unlike bilirubin (area under the receiver-operating curve: 0.59), these bile acids predicted 28-d mortality with high sensitivity and specificity (area under the receiver-operating curve: CDCA: 0.77; TDCA: 0.72; CDCA+TDCA: 0.87). Liver dysfunction is an early and commonplace event in the rat model of sepsis studied here; PI3K signalling seems to play a crucial role. All aspects of hepatic biotransformation are affected, with severity relating to subsequent prognosis. Detected changes significantly precede conventional markers and are reflected by early alterations in plasma bile acids. These observations carry important implications for the diagnosis of liver dysfunction and pharmacotherapy in the critically ill. Further clinical work is necessary to extend these concepts into clinical practice. Please see later in the article for the Editors' Summary.

Asymmetric dimethylarginine (ADMA) and monomethyl arginine ( L -NMMA) are endogenously produced amino acids that inhibit all three isoforms of nitric oxide synthase (NOS) 1 . ADMA accumulates in various disease states, including renal failure, diabetes and pulmonary hypertension, and its concentration in plasma is strongly predictive of premature cardiovascular disease and death 2 , 3 , 4 . Both L -NMMA and ADMA are eliminated largely through active metabolism by dimethylarginine dimethylaminohydrolase (DDAH) 5 and thus DDAH dysfunction may be a crucial unifying feature of increased cardiovascular risk. However, despite considerable interest in this pathway and in the role of ADMA as a cardiovascular risk factor, there is little evidence to support a causal role of ADMA in pathophysiology. Here we reveal the structure of human DDAH-1 and probe the function of DDAH-1 both by deleting the DDAH1 gene in mice and by using DDAH-specific inhibitors which, as we demonstrate by crystallography, bind to the active site of human DDAH-1. We show that loss of DDAH-1 activity leads to accumulation of ADMA and reduction in NO signaling. This in turn causes vascular pathophysiology, including endothelial dysfunction, increased systemic vascular resistance and elevated systemic and pulmonary blood pressure. Our results also suggest that DDAH inhibition could be harnessed therapeutically to reduce the vascular collapse associated with sepsis.

Electrical cardioversion (ECV) is the recommended treatment for atrial fibrillation (AFib) in critically ill patients, despite lacking data showing hemodynamic benefits of restoring sinus rhythm in this setting. The aim of this study was to assess the hemodynamic effect of successful ECV in a cohort of hemodynamically unstable critically ill patients. This study included 66 successful ECV performed in hemodynamically unstable critically ill patients with new-onset AFib. The primary outcome was the requirement of norepinephrine and inotropes 6 h after successful ECV in relation to baseline. Baseline norepinephrine dose was 0.19 ± 0.02 μg/kg/min, and 67% of patients were treated with positive inotropic drugs. Six hours after ECV, 33 patients (50%) were considered hemodynamic non-responders. Overall, the mean norepinephrine dose at 6 h was 0.17 ± 0.02 μg/kg/min (P = 0.051 compared to baseline) and 61% of patients were on inotropes (P = 0.13 compared to baseline). During the 6-hour period after ECV the mean norepinephrine dose temporary increased to 0.20 ± 0.02 μg/kg/min (P = 0.033 compared to baseline). ECV is associated with a large proportion of hemodynamic non-responders and a numerically modest, non-significant hemodynamic improvement in critically ill patients with new-onset AFib.

Rising demands for repetitive SARS-CoV-2 screens and mass testing necessitate additional test strategies. Saliva may serve as an alternative to nasopharyngeal swab (NPS) as its collection is simple, non-invasive and amenable for mass- and home testing, but its rigorous validation, particularly in children, is missing. We conducted a large-scale head-to-head comparison of SARS-CoV-2 detection by RT-PCR in saliva and NPS of 1270 adults and children reporting to outpatient test centers and an emergency unit. In total, 273 individuals were tested positive for SARS-CoV-2 in either NPS or saliva. SARS-CoV-2 RT-PCR results in the two specimens showed a high agreement (overall percent agreement = 97.8%). Despite lower viral loads in the saliva of both adults and children, detection of SARS-CoV-2 in saliva fared well compared to NPS (positive percent agreement = 92.5%). Importantly, in children, SARS-CoV-2 infections were more often detected in saliva than NPS (positive predictive value = 84.8%), underlining that NPS sampling in children can be challenging. The comprehensive parallel analysis reported here establishes saliva as a generally reliable specimen for the detection of SARS-CoV-2, with particular advantages for testing children, that is readily applicable to increase and facilitate repetitive and mass testing in adults and children.

In the intensive care setting, delirium is a common occurrence that comes with subsequent adversities. Therefore, several instruments have been developed to screen for and detect delirium. Their validity and psychometric properties, however, remain controversial. In this prospective cohort study, the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC) were evaluated versus the DSM-IV-TR in the diagnosis of delirium with respect to their validity and psychometric properties. Out of some 289 patients, 210 with matching CAM-ICU, ICDSC, and DSM-IV-TR diagnoses were included. Between the scales, the prevalence of delirium ranged from 23.3% with the CAM-ICU, to 30.5% with the ICDSC, to 43.8% with the DSM-IV-TR criteria. The CAM-ICU showed only moderate concurrent validity (Cohen's κ = 0.44) and sensitivity (50%), but high specificity (95%). The ICDSC also reached moderate agreement (Cohen's κ = 0.60) and sensitivity (63%) while being very specific (95%). Between the CAM-ICU and the ICDSC, the concurrent validity was again only moderate (Cohen's κ = 0.56); however, the ICDSC yielded higher sensitivity and specificity (78 and 83%, respectively). In the daily clinical routine, neither the CAM-ICU nor the ICDSC, common tools used in screening and detecting delirium in the intensive care setting, reached sufficient concurrent validity; nor did they outperform the DSM-IV-TR diagnostic criteria with respect to sensitivity or positive prediction, but they were very specific. Thus, the non-prediction by the CAM-ICU or ICDSC did not refute the presence of delirium. Between the CAM-ICU and ICDSC, the ICDSC proved to be the more accurate instrument.