Sepsis is considered to induce immune suppression, leading to increased susceptibility to secondary infections with associated late mortality.
To determine the clinical and host genomic ...characteristics, incidence, and attributable mortality of intensive care unit (ICU)-acquired infections in patients admitted to the ICU with or without sepsis.
Prospective observational study comprising consecutive admissions of more than 48 hours in 2 ICUs in the Netherlands from January 2011 to July 2013 stratified according to admission diagnosis (sepsis or noninfectious).
The primary outcome was ICU-acquired infection (onset >48 hours). Attributable mortality risk (fraction of mortality that can be prevented by elimination of the risk factor, acquired infection) was determined using time-to-event models accounting for competing risk. In a subset of sepsis admissions (n = 461), blood gene expression (whole-genome transcriptome in leukocytes) was analyzed at baseline and at onset of ICU-acquired infectious (n = 19) and noninfectious (n = 9) events.
The primary cohort included 1719 sepsis admissions (1504 patients; median age, 62 years; interquartile range IQR, 51-71 years; 924 men 61.4%). A comparative cohort included 1921 admissions (1825 patients, median age, 62 years; IQR, 49-71 years; 1128 men 61.8% in whom infection was not present in the first 48 hours. Intensive care unit-acquired infections occurred in 13.5% of sepsis ICU admissions (n = 232) and 15.1% of nonsepsis ICU admissions (n = 291). Patients with sepsis who developed an ICU-acquired infection had higher disease severity scores on admission than patients with sepsis who did not develop an ICU-acquired infection (Acute Physiology and Chronic Health Evaluation IV APACHE IV median score, 90 IQR, 72-107 vs 79 IQR, 62-98; P < .001) and throughout their ICU stay but did not have differences in baseline gene expression. The population attributable mortality fraction of ICU-acquired infections in patients with sepsis was 10.9% (95% CI, 0.9%-20.6%) by day 60; the estimated difference between mortality in all patients with a sepsis admission diagnosis and mortality in those without ICU-acquired infection was 2.0% (95% CI, 0.2%-3.8%; P = .03) by day 60. Among nonsepsis ICU admissions, ICU-acquired infections had a population attributable mortality fraction of 21.1% (95% CI, 0.6%-41.7%) by day 60. Compared with baseline, blood gene expression at the onset of ICU-acquired infections showed reduced expression of genes involved in gluconeogenesis and glycolysis.
Intensive care unit-acquired infections occurred more commonly in patients with sepsis with higher disease severity, but such infections contributed only modestly to overall mortality. The genomic response of patients with sepsis was consistent with immune suppression at the onset of secondary infection.
Plastic pollution is ubiquitous throughout the marine environment, yet estimates of the global abundance and weight of floating plastics have lacked data, particularly from the Southern Hemisphere ...and remote regions. Here we report an estimate of the total number of plastic particles and their weight floating in the world's oceans from 24 expeditions (2007-2013) across all five sub-tropical gyres, costal Australia, Bay of Bengal and the Mediterranean Sea conducting surface net tows (N = 680) and visual survey transects of large plastic debris (N = 891). Using an oceanographic model of floating debris dispersal calibrated by our data, and correcting for wind-driven vertical mixing, we estimate a minimum of 5.25 trillion particles weighing 268,940 tons. When comparing between four size classes, two microplastic <4.75 mm and meso- and macroplastic >4.75 mm, a tremendous loss of microplastics is observed from the sea surface compared to expected rates of fragmentation, suggesting there are mechanisms at play that remove <4.75 mm plastic particles from the ocean surface.
Endothelial dysfunction is involved in the development of atherosclerosis, which precedes asymptomatic structural vascular alterations as well as clinical manifestations of cardiovascular disease ...(CVD). Endothelial function can be assessed non-invasively using the flow-mediated dilation (FMD) technique. Flow-mediated dilation represents an endothelium-dependent, largely nitric oxide (NO)-mediated dilatation of conduit arteries in response to an imposed increase in blood flow and shear stress. Flow-mediated dilation is affected by cardiovascular (CV) risk factors, relates to coronary artery endothelial function, and independently predicts CVD outcome. Accordingly, FMD is a tool for examining the pathophysiology of CVD and possibly identifying subjects at increased risk for future CV events. Moreover, it has merit in examining the acute and long-term impact of physiological and pharmacological interventions in humans. Despite concerns about its reproducibility, the available evidence shows that highly reliable FMD measurements can be achieved when specialized laboratories follow standardized protocols. For this purpose, updated expert consensus guidelines for the performance of FMD are presented, which are based on critical appraisal of novel technical approaches, development of analysis software, and studies exploring the physiological principles underlying the technique. Uniformity in FMD performance will (i) improve comparability between studies, (ii) contribute to construction of reference values, and (iii) offer an easy accessible and early marker of atherosclerosis that could complement clinical symptoms of structural arterial disease and facilitate early diagnosis and prediction of CVD outcomes.
Elevated circulating lipid levels are known risk factors for cardiovascular diseases (CVD). In order to examine the effects of quercetin on lipid metabolism, mice received a mild-high-fat diet ...without (control) or with supplementation of 0.33% (w/w) quercetin for 12 weeks. Gas chromatography and (1)H nuclear magnetic resonance were used to quantitatively measure serum lipid profiles. Whole genome microarray analysis of liver tissue was used to identify possible mechanisms underlying altered circulating lipid levels. Body weight, energy intake and hepatic lipid accumulation did not differ significantly between the quercetin and the control group. In serum of quercetin-fed mice, triglycerides (TG) were decreased with 14% (p<0.001) and total poly unsaturated fatty acids (PUFA) were increased with 13% (p<0.01). Palmitic acid, oleic acid, and linoleic acid were all decreased by 9-15% (p<0.05) in quercetin-fed mice. Both palmitic acid and oleic acid can be oxidized by omega (ω)-oxidation. Gene expression profiling showed that quercetin increased hepatic lipid metabolism, especially ω-oxidation. At the gene level, this was reflected by the up-regulation of cytochrome P450 (Cyp) 4a10, Cyp4a14, Cyp4a31 and Acyl-CoA thioesterase 3 (Acot3). Two relevant regulators, cytochrome P450 oxidoreductase (Por, rate limiting for cytochrome P450s) and the transcription factor constitutive androstane receptor (Car; official symbol Nr1i3) were also up-regulated in the quercetin-fed mice. We conclude that quercetin intake increased hepatic lipid ω-oxidation and lowered corresponding circulating lipid levels, which may contribute to potential beneficial effects on CVD.
Schizophrenia is a highly heritable disorder with a polygenic pattern of inheritance and a population prevalence of ~1%. Previous studies have implicated synaptic dysfunction in schizophrenia. We ...tested the accumulated association of genetic variants in expert-curated synaptic gene groups with schizophrenia in 4673 cases and 4965 healthy controls, using functional gene group analysis. Identifying groups of genes with similar cellular function rather than genes in isolation may have clinical implications for finding additional drug targets. We found that a group of 1026 synaptic genes was significantly associated with the risk of schizophrenia (P=7.6 × 10(-11)) and more strongly associated than 100 randomly drawn, matched control groups of genetic variants (P<0.01). Subsequent analysis of synaptic subgroups suggested that the strongest association signals are derived from three synaptic gene groups: intracellular signal transduction (P=2.0 × 10(-4)), excitability (P=9.0 × 10(-4)) and cell adhesion and trans-synaptic signaling (P=2.4 × 10(-3)). These results are consistent with a role of synaptic dysfunction in schizophrenia and imply that impaired intracellular signal transduction in synapses, synaptic excitability and cell adhesion and trans-synaptic signaling play a role in the pathology of schizophrenia.
Accurate surveillance of ventilator-associated pneumonia (VAP) is hampered by subjective diagnostic criteria. A novel surveillance paradigm for ventilator-associated events (VAEs) was introduced.
To ...determine the validity of surveillance using the new VAE algorithm.
Prospective cohort study in two Dutch academic medical centers (2011-2012). VAE surveillance was electronically implemented and included assessment of (infection-related) ventilator-associated conditions (VAC, IVAC) and VAP. Concordance with ongoing prospective VAP surveillance was assessed, along with clinical diagnoses underlying VAEs and associated mortality of all conditions. Consequences of minor differences in electronic VAE implementation were evaluated.
The study included 2,080 patients with 2,296 admissions. Incidences of VAC, IVAC, VAE-VAP, and VAP according to prospective surveillance were 10.0, 4.2, 3.2, and 8.0 per 1000 ventilation days, respectively. The VAE algorithm detected at most 32% of the patients with VAP identified by prospective surveillance. VAC signals were most often caused by volume overload and infections, but not necessarily VAP. Subdistribution hazards for mortality were 3.9 (95% confidence interval, 2.9-5.3) for VAC, 2.5 (1.5-4.1) for IVAC, 2.0 (1.1-3.6) for VAE-VAP, and 7.2 (5.1-10.3) for VAP identified by prospective surveillance. In sensitivity analyses, mortality estimates varied considerably after minor differences in electronic algorithm implementation.
Concordance between the novel VAE algorithm and VAP was poor. Incidence and associated mortality of VAE were susceptible to small differences in electronic implementation. More studies are needed to characterize the clinical entities underlying VAE and to ensure comparability of rates from different institutions.
Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory infections that can be life-threatening. To establish an infection and spread, MERS-CoV, like most other viruses, ...must navigate through an intricate network of antiviral host responses. Besides the well-known type I interferon (IFN-α/β) response, the protein kinase R (PKR)-mediated stress response is being recognized as an important innate response pathway. Upon detecting viral dsRNA, PKR phosphorylates eIF2α, leading to the inhibition of cellular and viral translation and the formation of stress granules (SGs), which are increasingly recognized as platforms for antiviral signaling pathways. It is unknown whether cellular infection by MERS-CoV activates the stress response pathway or whether the virus has evolved strategies to suppress this infection-limiting pathway. Here, we show that cellular infection with MERS-CoV does not lead to the formation of SGs. By transiently expressing the MERS-CoV accessory proteins individually, we identified a role of protein 4a (p4a) in preventing activation of the stress response pathway. Expression of MERS-CoV p4a impeded dsRNA-mediated PKR activation, thereby rescuing translation inhibition and preventing SG formation. In contrast, p4a failed to suppress stress response pathway activation that is independent of PKR and dsRNA. MERS-CoV p4a is a dsRNA binding protein. Mutation of the dsRNA binding motif in p4a disrupted its PKR antagonistic activity. By inserting p4a in a picornavirus lacking its natural PKR antagonist, we showed that p4a exerts PKR antagonistic activity also under infection conditions. However, a recombinant MERS-CoV deficient in p4a expression still suppressed SG formation, indicating the expression of at least one other stress response antagonist. This virus also suppressed the dsRNA-independent stress response pathway. Thus, MERS-CoV interferes with antiviral stress responses using at least two different mechanisms, with p4a suppressing the PKR-dependent stress response pathway, probably by sequestering dsRNA. MERS-CoV p4a represents the first coronavirus stress response antagonist described.
Psoriasis is a common chronic inflammatory skin disease that results from interplay between the immune system and the epithelium. In the light of very successful anticytokine therapies for psoriasis, ...the focus has been directed towards the adaptive immune system. Expression studies, genetic studies and treatments specifically targeting players of the IL‐23/IL‐17 pathway, point at an important role for IL‐17 in the pathogenesis of psoriasis. IL‐17 stimulates the keratinocytes to produce psoriasis‐associated molecules, eventually leading to chronic skin inflammation. The current opinion is that IL‐17 is mainly produced by T cells, so‐called T‐helper 17 (Th17) cells, in psoriasis. However, evidence is accumulating that cells of the innate immune system, like neutrophils, mast cells, γδ T cells and innate lymphoid cells are the main source of IL‐17 in psoriasis, rather than T cells. The paradigm in this field of research is shifting. With this viewpoint article, we will address this novel concept by critically summarizing the current literature on this subject. In psoriatic arthritis and atherosclerosis, important conditions related to psoriasis, it was also found that the majority of IL‐17 is associated with cells of the innate immune system. This new concept changes our view of IL‐17. Blocking IL‐17 with targeted treatments might be more far‐reaching than previously thought; not only IL‐17 production by T cells but also by innate immune cells is blocked. Furthermore, therapies specifically targeting IL‐17 may not only improve psoriasis, but also comorbidity that is associated with the IL‐17 pathway, hereby preventing serious complications on the long term.
Several studies have associated physical activity with the risk of dementia, but mostly did so during short follow-up. It remains unclear whether physical activity also affects dementia during longer ...follow-up. We examined the association between physical activity and risk of dementia during a follow-up period up to 14 years. From 1997 to 1999, physical activity was assessed using a validated questionnaire in 4,406 elderly persons (age range 61–97) from the prospective, population-based Rotterdam Study. Follow-up for dementia was complete until January 1, 2011. We used Cox proportional hazards models to assess the association between physical activity and incident dementia. Next, we stratified follow-up time using a cut-off of 4 years. We separately investigated dementia due to Alzheimer disease. During 38,631 person-years, 583 participants developed dementia. When adjusting for age and sex, we found a borderline significant association between higher physical activity and lower risk of dementia (HR 0.95; 95 % CI 0.87–1.04). This association was confined to follow-up up to 4 years (HR 0.82; 95 % CI 0.71–0.95), and not to follow-up of at least 4 years (HR 1.04; 95 % CI 0.93–1.16). Additional adjustments only slightly attenuated the associations. A similar pattern was present for Alzheimer disease. We found a higher level of physical activity to be associated with a lower risk of dementia. This association was confined to follow-up for up to 4 years and not to longer follow-up, suggesting either a role for reverse causality or only a short term effect of late-life physical activity in an elderly population.
PDF
