Purpose
To determine whether early goal-directed therapy (EGDT) reduces mortality compared with other resuscitation strategies for patients presenting to the emergency department (ED) with septic ...shock.
Methods
Using a search strategy of PubMed, EmBase and CENTRAL, we selected all relevant randomised clinical trials published from January 2000 to January 2015. We translated non-English papers and contacted authors as necessary. Our primary analysis generated a pooled odds ratio (OR) from a fixed-effect model. Sensitivity analyses explored the effect of including non-ED studies, adjusting for study quality, and conducting a random-effects model. Secondary outcomes included organ support and hospital and ICU length of stay.
Results
From 2395 initially eligible abstracts, five randomised clinical trials (
n
= 4735 patients) met all criteria and generally scored high for quality except for lack of blinding. There was no effect on the primary mortality outcome (EGDT: 23.2 % 495/2134 versus control: 22.4 % 582/2601; pooled OR 1.01 95 % CI 0.88–1.16,
P
= 0.9, with heterogeneity
I
2
= 57 %;
P
= 0.055). The pooled estimate of 90-day mortality from the three recent multicentre studies (
n
= 4063) also showed no difference pooled OR 0.99 (95 % CI 0.86–1.15),
P
= 0.93 with no heterogeneity (
I
2
= 0.0 %;
P
= 0.97). EGDT increased vasopressor use (OR 1.25 95 % CI 1.10–1.41;
P
< 0.001) and ICU admission OR 2.19 (95 % CI 1.82–2.65);
P
< 0.001. Including six non-ED randomised trials increased heterogeneity (
I
2
= 71 %;
P
< 0.001) but did not change overall results pooled OR 0.94 (95 % CI 0.82 to 1.07);
P
= 0.33.
Conclusion
EGDT is not superior to usual care for ED patients with septic shock but is associated with increased utilisation of ICU resources.
Summary Background Unexplained differences between classes of antihypertensive drugs in their effectiveness in preventing stroke might be due to class effects on intraindividual variability in blood ...pressure. We did a systematic review to assess any such effects in randomised controlled trials. Methods Baseline and follow-up data for mean (SD) of systolic blood pressure (SBP) were extracted from trial reports. Effect of treatment on interindividual variance (SD2 ) in blood pressure (a surrogate for within-individual variability), expressed as the ratio of the variances (VR), was related to effects on clinical outcomes. Pooled estimates were derived by use of random-effects meta-analysis. Findings Mean (SD) SBP at follow-up was reported in 389 (28%) of 1372 eligible trials. There was substantial heterogeneity between trials in VR (p<1×10−40 ), 68% of which was attributable to allocated drug class. Compared with other drugs, interindividual variation in SBP was reduced by calcium-channel blockers (VR 0·81, 95% CI 0·76–0·86, p<0·0001) and non-loop diuretic drugs (0·87, 0·79–0·96, p=0·007), and increased by angiotensin-converting enzyme (ACE) inhibitors (1·08, 1·02–1·15, p=0·008), angiotensin-receptor blockers (1·16, 1·07–1·25, p=0·0002), and β blockers (1·17, 1·07–1·28, p=0·0007). Compared with placebo only, interindividual variation in SBP was reduced the most by calcium-channel blockers (0·76, 0·67–0·85, p<0·0001). Effects were consistent in parallel group and crossover design trials, and in analyses of dose-response. Across all trials, effects of treatment on VR of SBP ( r2 =0·372, p=0·0006) and on mean SBP ( r2 =0·328, p=0·0015) accounted for effects on stroke risk (eg, odds ratio 0·79, 0·71–0·87, p<0·0001, for VR≤0·80), and both remained significant in a combined model. Interpretation Drug-class effects on interindividual variation in blood pressure can account for differences in effects of antihypertensive drugs on risk of stroke independently of effects on mean SBP. Funding None.
Climate change is driving an expansion of marine oxygen-deficient zones, which may alter the global cycles of carbon, sulfur, nitrogen, and trace metals. Currently, however, we lack a full ...mechanistic understanding of how oxygen deficiency affects organic carbon cycling and burial. Here, we show that cryptic microbial sulfate reduction occurs in sinking particles from the eastern tropical North Pacific oxygen-deficient zone and that some microbially produced sulfide reacts rapidly to form organic sulfur that is resistant to acid hydrolysis. Particle-hosted sulfurization could enhance carbon preservation in sediments underlying oxygen-deficient water columns and serve as a stabilizing feedback between expanding anoxic zones and atmospheric carbon dioxide. A similar mechanism may help explain more-extreme instances of organic carbon preservation associated with marine anoxia in Earth history.
Microplastics are increasingly being recognised as a potential threat to New Zealand's coastal waters, however there is limited data on abundance of microplastics in marine organisms for New Zealand. ...Microplastic ingestion by the iconic green-lipped mussel Perna canaliculus was assessed. Microplastics were found in Perna canaliculus from 6 out of 9 locations sampled at abundances ranging from 0 to 1.5 particles per mussel and tissue microplastic concentrations ranged from 0 to 0.48 particles g tissue -1 (wet wt). The microplastics ranged in size from 50 to 700 μm with a median diameter of 100 μm. Polyethylene was the most frequently detected polymer with fragments the most common morphotype. These results indicate that microplastics are widespread in New Zealand's coastal waters and further assessment of microplastic contamination of New Zealand coastal environments and biota is warranted.
•Microplastic ingestion by the iconic green-lipped mussel Perna canaliculus from around New Zealand was assessed.•Microplastics were found in Perna canaliculus at abundances ranging from 0 to 1.5 particles per mussel.•Polyethylene was the most frequently detected polymer with fragments the most common morphotype.
Intensity-modulated radiation therapy (IMRT) can sculpt the high-dose volume around the site of disease with hitherto unachievable precision. Conformal avoidance of normal tissues goes hand in hand ...with this. Inhomogeneous dose painting is possible. The technique has become a clinical reality and is likely to be the dominant approach this decade for improving the clinical practice of photon therapy. This Series will explore all aspects of the "IMRT chain". Only 15 years ago just a handful of physicists were working on this subject. IMRT has developed so rapidly that its recent past is also its ancient history. This article will review the history of IMRT with just a glance at precursors. The physical basis of IMRT is then described including an attempt to introduce the concepts of convex and concave dose distributions, ill-conditioning, inverse-problem degeneracy, cost functions and complex solutions all with a minimum of technical jargon or mathematics. The many techniques for inverse planning are described and the review concludes with a look forward to the future of image-guided IMRT (IG-IMRT).
Whether hydrocortisone reduces mortality among patients with septic shock is unclear.
We randomly assigned patients with septic shock who were undergoing mechanical ventilation to receive ...hydrocortisone (at a dose of 200 mg per day) or placebo for 7 days or until death or discharge from the intensive care unit (ICU), whichever came first. The primary outcome was death from any cause at 90 days.
From March 2013 through April 2017, a total of 3800 patients underwent randomization. Status with respect to the primary outcome was ascertained in 3658 patients (1832 of whom had been assigned to the hydrocortisone group and 1826 to the placebo group). At 90 days, 511 patients (27.9%) in the hydrocortisone group and 526 (28.8%) in the placebo group had died (odds ratio, 0.95; 95% confidence interval CI, 0.82 to 1.10; P=0.50). The effect of the trial regimen was similar in six prespecified subgroups. Patients who had been assigned to receive hydrocortisone had faster resolution of shock than those assigned to the placebo group (median duration, 3 days interquartile range, 2 to 5 vs. 4 days interquartile range, 2 to 9; hazard ratio, 1.32; 95% CI, 1.23 to 1.41; P<0.001). Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation than those in the placebo group (median, 6 days interquartile range, 3 to 18 vs. 7 days interquartile range, 3 to 24; hazard ratio, 1.13; 95% CI, 1.05 to 1.22; P<0.001), but taking into account episodes of recurrence of ventilation, there were no significant differences in the number of days alive and free from mechanical ventilation. Fewer patients in the hydrocortisone group than in the placebo group received a blood transfusion (37.0% vs. 41.7%; odds ratio, 0.82; 95% CI, 0.72 to 0.94; P=0.004). There were no significant between-group differences with respect to mortality at 28 days, the rate of recurrence of shock, the number of days alive and out of the ICU, the number of days alive and out of the hospital, the recurrence of mechanical ventilation, the rate of renal-replacement therapy, and the incidence of new-onset bacteremia or fungemia.
Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo. (Funded by the National Health and Medical Research Council of Australia and others; ADRENAL ClinicalTrials.gov number, NCT01448109 .).
Plant plasma-membrane (PM) proteins are involved in several vital processes, such as detection of pathogens, solute transport, and cellular signaling. For these proteins to function effectively there ...needs to be structure within the PM allowing, for example, proteins in the same signaling cascade to be spatially organized. Here we demonstrate that several proteins with divergent functions are located in clusters of differing size in the membrane using subdiffraction-limited Airyscan confocal microscopy. Single particle tracking reveals that these proteins move at different rates within the membrane. Actin and microtubule cytoskeletons appear to significantly regulate the mobility of one of these proteins (the pathogen receptor FLS2) and we further demonstrate that the cell wall is critical for the regulation of cluster size by quantifying single particle dynamics of proteins with key roles in morphogenesis (PIN3) and pathogen perception (FLS2). We propose a model in which the cell wall and cytoskeleton are pivotal for regulation of protein cluster size and dynamics, thereby contributing to the formation and functionality of membrane nanodomains.
Deep brain stimulation (DBS) is increasingly applied for the treatment of brain disorders, but its mechanism of action remains unknown. Here we evaluate the effect of basal ganglia DBS on cortical ...function using invasive cortical recordings in Parkinson's disease (PD) patients undergoing DBS implantation surgery. In the primary motor cortex of PD patients, neuronal population spiking is excessively synchronized to the phase of network oscillations. This manifests in brain surface recordings as exaggerated coupling between the phase of the beta rhythm and the amplitude of broadband activity. We show that acute therapeutic DBS reversibly reduces phase-amplitude interactions over a similar time course as that of the reduction in parkinsonian motor signs. We propose that DBS of the basal ganglia improves cortical function by alleviating excessive beta phase locking of motor cortex neurons.
Dexmedetomidine produces sedation while maintaining a degree of arousability and may reduce the duration of mechanical ventilation and delirium among patients in the intensive care unit (ICU). The ...use of dexmedetomidine as the sole or primary sedative agent in patients undergoing mechanical ventilation has not been extensively studied.
In an open-label, randomized trial, we enrolled critically ill adults who had been undergoing ventilation for less than 12 hours in the ICU and were expected to continue to receive ventilatory support for longer than the next calendar day to receive dexmedetomidine as the sole or primary sedative or to receive usual care (propofol, midazolam, or other sedatives). The target range of sedation-scores on the Richmond Agitation and Sedation Scale (which is scored from -5 unresponsive to +4 combative) was -2 to +1 (lightly sedated to restless). The primary outcome was the rate of death from any cause at 90 days.
We enrolled 4000 patients at a median interval of 4.6 hours between eligibility and randomization. In a modified intention-to-treat analysis involving 3904 patients, the primary outcome event occurred in 566 of 1948 (29.1%) in the dexmedetomidine group and in 569 of 1956 (29.1%) in the usual-care group (adjusted risk difference, 0.0 percentage points; 95% confidence interval, -2.9 to 2.8). An ancillary finding was that to achieve the prescribed level of sedation, patients in the dexmedetomidine group received supplemental propofol (64% of patients), midazolam (3%), or both (7%) during the first 2 days after randomization; in the usual-care group, these drugs were administered as primary sedatives in 60%, 12%, and 20% of the patients, respectively. Bradycardia and hypotension were more common in the dexmedetomidine group.
Among patients undergoing mechanical ventilation in the ICU, those who received early dexmedetomidine for sedation had a rate of death at 90 days similar to that in the usual-care group and required supplemental sedatives to achieve the prescribed level of sedation. More adverse events were reported in the dexmedetomidine group than in the usual-care group. (Funded by the National Health and Medical Research Council of Australia and others; SPICE III ClinicalTrials.gov number, NCT01728558.).
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