The host innate immune response mediated by type I interferon (IFN) and the resulting up-regulation of hundreds of interferon-stimulated genes (ISGs) provide an immediate barrier to virus infection. ...Studies of the type I 'interferome' have mainly been carried out at a single species level, often lacking the power necessary to understand key evolutionary features of this pathway. Here, using a single experimental platform, we determined the properties of the interferomes of multiple vertebrate species and developed a webserver to mine the dataset. This approach revealed a conserved 'core' of 62 ISGs, including genes not previously associated with IFN, underscoring the ancestral functions associated with this antiviral host response. We show that gene expansion contributes to the evolution of the IFN system and that interferomes are shaped by lineage-specific pressures. Consequently, each mammal possesses a unique repertoire of ISGs, including genes common to all mammals and others unique to their specific species or phylogenetic lineages. An analysis of genes commonly down-regulated by IFN suggests that epigenetic regulation of transcription is a fundamental aspect of the IFN response. Our study provides a resource for the scientific community highlighting key paradigms of the type I IFN response.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Acute kidney injury (AKI) complicates recovery from cardiac surgery in up to 30 % of patients, injures and impairs the function of the brain, lungs, and gut, and places patients at a 5-fold increased ...risk of death during hospitalization. Renal ischemia, reperfusion, inflammation, hemolysis, oxidative stress, cholesterol emboli, and toxins contribute to the development and progression of AKI. Preventive strategies are limited, but current evidence supports maintenance of renal perfusion and intravascular volume while avoiding venous congestion, administration of balanced salt as opposed to high-chloride intravenous fluids, and the avoidance or limitation of cardiopulmonary bypass exposure. AKI that requires renal replacement therapy occurs in 2-5 % of patients following cardiac surgery and is associated with 50 % mortality. For those who recover from renal replacement therapy or even mild AKI, progression to chronic kidney disease in the ensuing months and years is more likely than for those who do not develop AKI. Cardiac surgery continues to be a popular clinical model to evaluate novel therapeutics, off-label use of existing medications, and nonpharmacologic treatments for AKI, since cardiac surgery is fairly common, typically elective, provides a relatively standardized insult, and patients remain hospitalized and monitored following surgery. More efficient and time-sensitive methods to diagnose AKI are imperative to reduce this negative outcome. The discovery and validation of renal damage biomarkers should in time supplant creatinine-based criteria for the clinical diagnosis of AKI.
Management of oliguria Ostermann, Marlies; Shaw, Andrew D.; Joannidis, Michael
Intensive care medicine,
2023/1, Letnik:
49, Številka:
1
Journal Article
One of the primary reasons for intensive care admission is shock. Identifying the underlying cause of shock (hypovolemic, distributive, cardiogenic, and obstructive) may lead to entirely different ...clinical pathways for management. Among patients with hypovolemic and distributive shock, fluid therapy is one of the leading management strategies. Although an appropriate amount of fluid administration might save a patient's life, inadequate (or excessive) fluid use could lead to more complications, including organ failure and mortality due to either hypovolemia or volume overload. Currently, intensivists have access to a wide variety of information sources and tools to monitor the underlying hemodynamic status, including medical history, physical examination, and specific hemodynamic monitoring devices. Although appropriate and timely assessment and interpretation of this information can promote adequate fluid resuscitation, misinterpretation of these data can also lead to additional mortality and morbidity. This article provides a narrative review of the most commonly used hemodynamic monitoring approaches to assessing fluid responsiveness and fluid tolerance. In addition, we describe the benefits and disadvantages of these tools.
Severity of AKI is determined by the magnitude of increase in serum creatinine level or decrease in urine output. However, patients manifesting both oliguria and azotemia and those in which these ...impairments are persistent are more likely to have worse disease. Thus, we investigated the relationship of AKI severity and duration across creatinine and urine output domains with the risk for RRT and likelihood of renal recovery and survival using a large, academic medical center database of critically ill patients. We analyzed electronic records from 32,045 patients treated between 2000 and 2008, of which 23,866 (74.5%) developed AKI. We classified patients by levels of serum creatinine and/or urine output according to Kidney Disease Improving Global Outcomes staging criteria for AKI. In-hospital mortality and RRT rates increased from 4.3% and 0%, respectively, for no AKI to 51.1% and 55.3%, respectively, when serum creatinine level and urine output both indicated stage 3 AKI. Both short- and long-term outcomes were worse when patients had any stage of AKI defined by both criteria. Duration of AKI was also a significant predictor of long-term outcomes irrespective of severity. We conclude that short- and long-term risk of death or RRT is greatest when patients meet both the serum creatinine level and urine output criteria for AKI and when these abnormalities persist.
BACKGROUND:Intraoperative hypotension (IOH) occurs frequently during surgery and may be associated with organ ischemia; however, few multicenter studies report data regarding its associations with ...adverse postoperative outcomes across varying hemodynamic thresholds. Additionally, no study has evaluated the association between IOH exposure and adverse outcomes among patients by various age groups.
METHODS:A multicenter retrospective cohort study was conducted between 2008 and 2017 using intraoperative blood pressure data from the US electronic health records database to examine postoperative outcomes. IOH was assessed in 368,222 noncardiac surgical procedures using 5 methods(a) absolute maximum decrease in mean arterial pressure (MAP) during surgery, (b) time under each absolute threshold, (c) total area under each threshold, (d) time-weighted average MAP under each threshold, and (e) cumulative time under the prespecified relative MAP thresholds. MAP thresholds were defined by absolute limits (≤75, ≤65, ≤55 mm Hg) and by relative limits (20% and 40% lower than baseline). The primary outcome was major adverse cardiac or cerebrovascular events; secondary outcomes were all-cause 30- and 90-day mortality, 30-day acute myocardial injury, and 30-day acute ischemic stroke. Residual confounding was minimized by controlling for observable patient and surgical factors. In addition, we stratified patients into age subgroups (18–40, 41–50, 51–60, 61–70, 71–80, >80) to investigate how the association between hypotension and the likelihood of major adverse cardiac or cerebrovascular events and acute kidney injury differs in these age subgroups.
RESULTS:IOH was common with at least 1 reading of MAP ≤75 mm Hg occurring in 39.5% (145,743) of cases; ≤65 mm Hg in 19.3% (70,938) of cases, and ≤55 mm Hg in 7.5% (27,473) of cases. IOH was significantly associated with the primary outcome for all age groups. For an absolute maximum decrease, the estimated odds of a major adverse cardiac or cerebrovascular events in the 30-day postsurgery was increased by 12% (95% confidence interval CI, 11-14) for ≤75 mm Hg; 17.0% (95% CI, 15-19) for ≤65 mm Hg; and by 26.0% (95% CI, 22-29) for ≤55 mm Hg.
CONCLUSIONS:IOH during noncardiac surgery is common and associated with increased 30-day major adverse cardiac or cerebrovascular events. This observation is magnified with increasing hypotension severity. The potentially avoidable nature of the hazard, and the extent of the exposed population, makes hypotension in the operating room a serious public health issue that should not be ignored for any age group.
In the setting of early acute kidney injury (AKI), no test has been shown to definitively predict the progression to more severe stages.
We investigated the ability of a furosemide stress test (FST) ...(one-time dose of 1.0 or 1.5 mg/kg depending on prior furosemide-exposure) to predict the development of AKIN Stage-III in 2 cohorts of critically ill subjects with early AKI. Cohort 1 was a retrospective cohort who received a FST in the setting of AKI in critically ill patients as part of Southern AKI Network. Cohort 2 was a prospective multicenter group of critically ill patients who received their FST in the setting of early AKI.
We studied 77 subjects; 23 from cohort 1 and 54 from cohort 2; 25 (32.4%) met the primary endpoint of progression to AKIN-III. Subjects with progressive AKI had significantly lower urine output following FST in each of the first 6 hours (p<0.001). The area under the receiver operator characteristic curves for the total urine output over the first 2 hours following FST to predict progression to AKIN-III was 0.87 (p = 0.001). The ideal-cutoff for predicting AKI progression during the first 2 hours following FST was a urine volume of less than 200mls(100ml/hr) with a sensitivity of 87.1% and specificity 84.1%.
The FST in subjects with early AKI serves as a novel assessment of tubular function with robust predictive capacity to identify those patients with severe and progressive AKI. Future studies to validate these findings are warranted.
Sea level extremes in southern Europe Marcos, Marta; Tsimplis, Michael N.; Shaw, Andrew G. P.
Journal of Geophysical Research - Oceans,
January 2009, Letnik:
114, Številka:
C1
Journal Article
Recenzirano
Odprti dostop
Knowledge of sea level extremes is important for coastal planning purposes. Temporal changes in the extremes may indicate changes in the forcing parameters, most probably the storm surges. Sea level ...extremes and their spatial and temporal variability in southern Europe are explored on the basis of 73 tide gauge records from 1940. This study uses all data available to infer risks at the coast caused by extreme sea levels. Extreme values of 250 cm are observed at the Atlantic coasts with smaller values in the Mediterranean where, with the exception of the Strait of Gibraltar and the Adriatic Sea, the extreme values are less than 60 cm. At the Adriatic Sea values of up to 200 cm are found. When the tidal contribution is removed the differences between the various areas reduce. The spatial distribution of the extremes of the tidal residuals is well represented by the hindcast of a two‐dimensional hydrodynamic model forced by the atmospheric pressure and the wind, although the model underestimates the extremes. Higher return levels (200–300 cm for the 50‐year return level) are observed in the Atlantic stations due to the larger tides. In the Mediterranean, higher values are found in the northern Adriatic (between 150 and 200 cm) while in the rest of the domain they vary between 20 and 60 cm. The nonlinear interaction between tides and surges is negligible in the Mediterranean, thus the joint tides‐surges distribution can be applied. The interannual and decadal variability in time of extremes is caused by mean sea level changes.
Cyclic GMP-AMP synthase (cGAS) plays a key role in the innate immune responses to both DNA and RNA virus infection. Here, we found that enterovirus 71 (EV-A71), Seneca Valley virus (SVV), and ...foot-and-mouth disease virus (FMDV) infection triggered mitochondria damage and mitochondrial DNA (mtDNA) release in vitro and vivo. These responses were mediated by picornavirus 2B proteins which induced mtDNA release during viral replication. SVV infection caused the opening of mitochondrial permeability transition pore (mPTP) and led to voltage-dependent anion channel 1 (VDAC1)- and BCL2 antagonist/killer 1 (Bak) and Bak/BCL2-associated X (Bax)-dependent mtDNA leakage into the cytoplasm, while EV-A71 and FMDV infection induced mPTP opening and resulted in VDAC1-dependent mtDNA release. The released mtDNA bound to cGAS and activated cGAS-mediated antiviral immune response. cGAS was essential for inhibiting EV-A71, SVV, and FMDV replication by regulation of IFN-β production. cGAS deficiency contributed to higher mortality of EV-A71- or FMDV-infected mice. In addition, we found that SVV 2C protein was responsible for decreasing cGAS expression through the autophagy pathway. The 9th and 153rd amino acid sites in 2C were critical for induction of cGAS degradation. Furthermore, we also show that EV-A71, CA16, and EMCV 2C antagonize the cGAS-stimulator of interferon genes (STING) pathway through interaction with STING, and highly conserved amino acids Y155 and S156 were critical for this inhibitory effect. In conclusion, these data reveal novel mechanisms of picornaviruses to block the antiviral effect mediated by the cGAS-STING signaling pathway, which will provide insights for developing antiviral strategies against picornaviruses.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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