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.
The hematopoietic system produces a large number of highly specialized cell types that are derived through a hierarchical differentiation process from a common stem cell population. miRNAs are ...critical players in orchestrating this differentiation. Here, we report the development and application of a high-throughput microfluidic real-time quantitative PCR (RT-qPCR) approach for generating global miRNA profiles for 27 phenotypically distinct cell populations isolated from normal adult mouse hematopoietic tissues. A total of 80,000 RT-qPCR assays were used to map the landscape of miRNA expression across the hematopoietic hierarchy, including rare progenitor and stem cell populations. We show that miRNA profiles allow for the direct inference of cell lineage relations and functional similarity. Our analysis reveals a close relatedness of the miRNA expression patterns in multipotent progenitors and stem cells, followed by a major reprogramming upon restriction of differentiation potential to a single lineage. The analysis of miRNA expression in single hematopoietic cells further demonstrates that miRNA expression is very tightly regulated within highly purified populations, underscoring the potential of single-cell miRNA profiling for assessing compartment heterogeneity.
Large-scale copy number variants (CNVs) have recently been recognized to play a role in human genome variation and disease. Approaches for analysis of CNVs in small samples such as microdissected ...tissues can be confounded by limited amounts of material. To facilitate analyses of such samples, whole genome amplification (WGA) techniques were developed. In this study, we explored the impact of Phi29 multiple-strand displacement amplification on detection of CNVs using oligonucleotide arrays. We extracted DNA from fresh frozen lymph node samples and used this for amplification and analysis on the Affymetrix Mapping 500k SNP array platform. We demonstrated that the WGA procedure introduces hundreds of potentially confounding CNV artifacts that can obscure detection of bona fide variants. Our analysis indicates that many artifacts are reproducible, and may correlate with proximity to chromosome ends and GC content. Pair-wise comparison of amplified products considerably reduced the number of apparent artifacts and partially restored the ability to detect real CNVs. Our results suggest WGA material may be appropriate for copy number analysis when amplified samples are compared to similarly amplified samples and that only the CNVs with the greatest significance values detected by such comparisons are likely to be representative of the unamplified samples.
The 2014–2015 Bárðarbunga‐Veiðivötn fissure eruption at Holuhraun produced about 1.5 km3 of lava, making it the largest eruption in Iceland in more than 200 years. Over the course of the eruption, ...daily volcanic sulfur dioxide (SO2) emissions exceeded daily SO2 emissions from all anthropogenic sources in Europe in 2010 by at least a factor of 3. We present surface air quality observations from across Northern Europe together with satellite remote sensing data and model simulations of volcanic SO2 for September 2014. We show that volcanic SO2 was transported in the lowermost troposphere over long distances and detected by air quality monitoring stations up to 2750 km away from the source. Using retrievals from the Ozone Monitoring Instrument (OMI) and the Infrared Atmospheric Sounding Interferometer (IASI), we calculate an average daily SO2 mass burden of 99 ± 49 kilotons (kt) of SO2 from OMI and 61 ± 18 kt of SO2 from IASI for September 2014. This volcanic burden is at least a factor of 2 greater than the average SO2 mass burden between 2007 and 2009 due to anthropogenic emissions from the whole of Europe. Combining the observational data with model simulations using the United Kingdom Met Office's Numerical Atmospheric‐dispersion Modelling Environment model, we are able to constrain SO2 emission rates to up to 120 kilotons per day (kt/d) during early September 2014, followed by a decrease to 20–60 kt/d between 6 and 22 September 2014, followed by a renewed increase to 60–120 kt/d until the end of September 2014. Based on these fluxes, we estimate that the eruption emitted a total of 2.0 ± 0.6 Tg of SO2 during September 2014, in good agreement with ground‐based remote sensing and petrological estimates. Although satellite‐derived and model‐simulated vertical column densities of SO2 agree well, the model simulations are biased low by up to a factor of 8 when compared to surface observations of volcanic SO2 on 6–7 September 2014 in Ireland. These biases are mainly due to relatively small horizontal and vertical positional errors in the simulations of the volcanic plume occurring over transport distances of thousands of kilometers. Although the volcanic air pollution episodes were transient and lava‐dominated volcanic eruptions are sporadic events, the observations suggest that (i) during an eruption, volcanic SO2 measurements should be assimilated for near real‐time air quality forecasting and (ii) existing air quality monitoring networks should be retained or extended to monitor SO2 and other volcanic pollutants.
Key Points
The 2014–2015 Icelandic fissure eruption at Bárðarbunga affected air quality in far field
Satellite‐derived average daily SO2 burden of 99 ± 49 kt (OMI) and 61 ± 18 kt (IASI) in September 2014
We calculate a total release of 2.0 ± 0.6 Tg of SO2 for September 2014 and fluxes up to 120 kt/d
Airborne particulate matter (PM) consists of particles from diverse sources, including vehicle exhausts. Associations between short-term PM changes and stroke incidence have been shown. Cumulative ...exposures over several months, or years, are less well studied; few studies examined ischaemic subtypes or PM source.
This study combines a high resolution urban air quality model with a population-based stroke register to explore associations between long-term exposure to PM and stroke incidence.
Data from the South London Stroke Register from 2005–2012 were included. Poisson regression explored association between stroke incidence and long-term (averaged across the study period) exposure to PM2.5(PM<2.5μm diameter) and PM10(PM<10μm), nitric oxide, nitrogen dioxide, nitrogen oxides and ozone, at the output area level (average population=309). Estimates were standardised for age and sex and adjusted for socio-economic deprivation. Models were stratified for ischaemic and haemorrhagic strokes and further broken down by Oxford Community Stroke Project classification and Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification.
1800 strokes were recorded (incidence=42.6/100,000 person-years). No associations were observed between PM and overall ischaemic or haemorrhagic incidence. For an interquartile range increase in PM2.5, there was a 23% increase in incidence (Incidence rate ratio=1.23 (95%CI: 1.03–1.44)) of total anterior circulation infarcts (TACI) and 20% increase for PM2.5 from exhausts (1.20(1.01–1.41)). There were similar associations with PM10, overall (1.21(1.01–1.44)) and from exhausts (1.20(1.01–1.41)). TACI incidence was not associated with non-exhaust sources. There were no associations with other stroke subtypes or pollutants.
Outdoor air pollution, particularly that arising from vehicle exhausts, may increase risk of TACI but not other stroke subtypes.
Display omitted
•Urban air quality data were combined with a population-based stroke register.•Associations between pollution and risk of stroke subtypes explored.•Particulate matter associated with total anterior circulation infarcts only.
Medulloblastoma (MB), the most common malignant paediatric brain tumor, is currently treated using a combination of surgery, craniospinal radiotherapy and chemotherapy. Owing to MB stem cells ...(MBSCs), a subset of MB patients remains untreatable despite standard therapy. CD133 is used to identify MBSCs although its functional role in tumorigenesis has yet to be determined. In this work, we showed enrichment of CD133 in Group 3 MB is associated with increased rate of metastasis and poor clinical outcome. The signal transducers and activators of transcription-3 (STAT3) pathway are selectively activated in CD133
MBSCs and promote tumorigenesis through regulation of c-MYC, a key genetic driver of Group 3 MB. We screened compound libraries for STAT3 inhibitors and treatment with the selected STAT3 inhibitors resulted in tumor size reduction in vivo. We propose that inhibition of STAT3 signaling in MBSCs may represent a potential therapeutic strategy to treat patients with recurrent MB.
Internet-recruited gay, bisexual, and other men who have sex with men (MSM) were offered HIV self-tests (HIVSTs) after completing baseline, 3-, 6-, and 9-month follow-up surveys. The surveys asked ...about the use and distribution of these HIVSTs. Among 995 who reported on their distribution of HIVSTs, 667 (67.0%) distributed HIVSTs to their social network associates (SNAs), which resulted in 34 newly identified HIV infections among 2301 SNAs (1.5%). The main reasons participants reported not distributing HIVSTs included: wanting to use the HIVSTs themselves (74.9%); thinking that their SNAs would get angry or upset if offered HIVSTs (12.5%); or not knowing that they could give the HIVSTs away (11.3%). Self-testing programs can provide multiple HIVSTs and encourage the distribution of HIVST by MSM to their SNAs to increase awareness of HIV status among persons disproportionately affected by HIV.
Marked prolongation of the QT interval and polymorphic ventricular tachycardia following medication (drug-induced long QT syndrome, diLQTS) is a severe adverse drug reaction (ADR) that phenocopies ...congenital long QT syndrome (cLQTS) and is one of the leading causes for drug withdrawal and relabeling. We evaluated the frequency of rare non-synonymous variants in genes contributing to the maintenance of heart rhythm in cases of diLQTS using targeted capture coupled to next-generation sequencing. Eleven of 31 diLQTS subjects (36%) carried a novel missense mutation in genes with known congenital arrhythmia associations or with a known cLQTS mutation. In the 26 Caucasian subjects, 23% carried a highly conserved rare variant predicted to be deleterious to protein function in these genes compared with only 2-4% in public databases (P<0.003). We conclude that the rare variation in genes responsible for congenital arrhythmia syndromes is frequent in diLQTS. Our findings demonstrate that diLQTS is a pharmacogenomic syndrome predisposed by rare genetic variants.
Genetic diversity levels within and between the two commercial breeding areas in the United States were analyzed using the DraI restriction fragment length polymorphism of the COI-COII mitochondrial ...region and 10 polymorphic microsatellite loci. The western commercial breeding population (WCBP) and the southeastern commercial breeding population (SCBP) were sampled in 1993–1994 and again in 2004–2005. The goal of this study was to characterize the genetic composition of these populations and to measure potential changes in genetic diversity and composition across the sampling period. The mitochondrial DNA haplotypes C1 and C2, characteristic of the most popular bee strains (Italians and Carniolans, respectively) sold in the United States, were the dominant haplotypes at both sample dates. The frequency of Apis mellifera mellifera M haplotypes, M4, M7, and M7′, decreased during the 10-yr span. An A1 haplotype characteristic of Africanized bees was found in the SCBP from 2005. Microsatellite analysis showed there was a loss of alleles in both the WCBP and SCBP, but the losses were not significant due to simultaneous gains of new alleles into these populations between 1993 and 2005. Genetic differences that occurred between the 1993–1994 WCBP and SCBP were still detectable in these populations sampled a decade later, suggesting that these populations could be useful sources of diversity for each other in the future.
An experimental platform employing human derived intestinal epithelial cell (IEC) line monolayers grown on permeable Transwell® filters was previously investigated to differentiate between hazardous ...and innocuous proteins. This approach was effective at distinguishing these types of proteins and perturbation of monolayer integrity, particularly transepithelial electrical resistance (TEER), was the most sensitive indicator. In the current report, in vitro indicators of monolayer integrity, cytotoxicity, and inflammation were evaluated using primary (non-transformed) human polarized small intestinal epithelial barriers cultured on Transwell® filters to compare effects of a hazardous protein (Clostridium difficile Toxin A ToxA) and an innocuous protein (bovine serum albumin BSA). ToxA exerted a reproducible decrease on barrier integrity at doses comparable to those producing effects observed from cell line-derived IEC monolayers, with TEER being the most sensitive indicator. In contrast, BSA, tested at concentrations substantially higher than ToxA, did not cause changes in any of the tested variables. These results demonstrate a similarity in response to certain proteins between cell line-derived polarized IEC models and a primary human polarized small intestinal epithelial barrier model, thereby reinforcing the potential usefulness of cell line-derived polarized IECs as a valid experimental platform to differentiate between hazardous and non-hazardous proteins.
•Integrity of primary small intestinal epithelial cell barriers was decreased when cells were exposed to C. difficile Toxin A.•TEER was the most sensitive indicator of decreased barrier integrity.•No effect was observed when primary small intestinal barriers were exposed to bovine serum albumin (BSA).•Primary small intestinal barriers and cell line-derived intestinal epithelial barriers react to ToxA and BSA similarly.
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