Influence of EMS-physician presence on survival after out-of-hospital cardiopulmonary resuscitation: systematic review and meta-analysis

BACKGROUND Evidence suggests that EMS-physician-guided cardiopulmonary resuscitation (CPR) in out-of-hospital cardiac arrest (OOHCA) may be associated with improved outcomes, yet randomized controlled trials are not available. The goal of this meta-analysis was to determine the association between EMS-physician- versus paramedic-guided CPR and survival after OOHCA. METHODS AND RESULTS Studies that compared EMS-physician- versus paramedic-guided CPR in OOHCA published until June 2014 were systematically searched in MEDLINE, EMBASE and Cochrane databases. All studies were required to contain survival data. Data on study characteristics, methods, and as well as survival outcomes were extracted. A random-effects model was used for the meta-analysis due to a high degree of heterogeneity among the studies (I (2)  = 44 %). Return of spontaneous circulation [ROSC], survival to hospital admission, and survival to hospital discharge were the outcome measures. Out of 3,385 potentially eligible studies, 14 met the inclusion criteria. In the pooled analysis (n = 126,829), EMS-physician-guided CPR was associated with significantly improved outcomes compared to paramedic-guided CPR: ROSC 36.2 % (95 % confidence interval [CI] 31.0 - 41.7 %) vs. 23.4 % (95 % CI 18.5 - 29.2 %) (pooled odds ratio [OR] 1.89, 95 % CI 1.36 - 2.63, p < 0.001); survival to hospital admission 30.1 % (95 % CI 24.2 - 36.7 %) vs. 19.2 % (95 % CI 12.7 - 28.1 %) (pooled OR 1.78, 95 % CI 0.97 - 3.28, p = 0.06); and survival to discharge 15.1 % (95 % CI 14.6 - 15.7 %) vs. 8.4 % (95 % CI 8.2 - 8.5 %) (pooled OR 2.03, 95 % CI 1.48 - 2.79, p < 0.001). CONCLUSIONS This systematic review suggests that EMS-physician-guided CPR in out-of-hospital cardiac arrest is associated with improved survival outcomes.

Investigation of robotics-assisted tilt table technology for cardiopulmonary exercise testing in stroke patients

Due to the lack of exercise testing devices that can be employed in stroke patients with severe disability, the aim of this PhD research was to investigate the clinical feasibility of using a robotics-assisted tilt table (RATT) as a method for cardiopulmonary exercise testing (CPET) and exercise training in stroke patients. For this purpose, the RATT was augmented with force sensors, a visual feedback system and a work rate calculation algorithm. As the RATT had not been used previously for CPET, the first phase of this project focused on a feasibility study in 11 healthy able-bodied subjects. The results demonstrated substantial cardiopulmonary responses, no complications were found, and the method was deemed feasible. The second phase was to analyse validity and test-retest reliability of the primary CPET parameters obtained from the RATT in 18 healthy able-bodied subjects and to compare the outcomes to those obtained from standard exercise testing devices (a cycle ergometer and a treadmill). The results demonstrated that peak oxygen uptake (V'O2peak) and oxygen uptake at the submaximal exercise thresholds on the RATT were ̴20% lower than for the cycle ergometer and ̴30% lower than on the treadmill. A very high correlation was found between the RATT vs the cycle ergometer V'O2peak and the RATT vs the treadmill V'O2peak. Test-retest reliability of CPET parameters obtained from the RATT were similarly high to those for standard exercise testing devices. These findings suggested that the RATT is a valid and reliable device for CPET and that it has potential to be used in severely impaired patients. Thus, the third phase was to investigate using the RATT for CPET and exercise training in 8 severely disabled stroke patients. The method was technically implementable, well tolerated by the patients, and substantial cardiopulmonary responses were observed. Additionally, all patients could exercise at the recommended training intensity for 10 min bouts. Finally, an investigation of test-retest reliability and four-week changes in cardiopulmonary fitness was carried out in 17 stroke patients with various degrees of disability. Good to excellent test-retest reliability and repeatability were found for the main CPET variables. There was no significant difference in most CPET parameters over four weeks. In conclusion, based on the demonstrated validity, reliability and repeatability, the RATT was found to be a feasible and appropriate alternative exercise testing and training device for patients who have limitations for use of standard devices.

ADAPTATION OF INTESTINAL MUSCLE IN THE RAT AFTER INTESTINAL BYPASS

After intestinal bypass, the mucosa of the in-continuity segment (ICS) of intestine undergoes adaptive hyperplasia which results in increased absorptive function per length of intestine. In the present study, 70% of the small intestine was bypassed in rats to determine if intestinal muscle also adapts after bypass. To determine the effect of bypass on intestinal transit, a poorly absorbed marker substance was introduced into the orad portion of the ICS or bypassed loop (BL). Significantly less marker (P < 0.05) was passed from the ICS into the colon in 50 minutes in fed rats at 14 days compared to at 3 days after bypass. In 150 minutes there was more marker in the colon of fed rats at 3 and 14 days but not at 35 days after bypass than in control. In the BL, transit was slowed significantly in fed rats at 3 and 35 days and in fasted rats at 3 days but not 35 days after bypass compared to control. The circular muscle from the BL and the distal but not proximal portion of the ICS developed significantly more carbachol-stimulated force in vitro at 35 but not 3 days after bypass compared to unoperated but not sham-operated controls. At 35 days after bypass, the muscle layers had a greater muscle wet weight and protein content compared to both unoperated and sham-operated control in both the proximal and distal portions of the ICS. Similarly, there was more muscle in histological sections of the BL and distal portion of the ICS at 35 days after bypass compared to either control. Nonetheless, at 35 days after bypass actomyosin content as a fraction of muscle weight or total protein content was not different from control. The results support the hypothesis that there was a functional adaptation, i.e. slowed transit in fed rats that allowed more time for absorption. Feeding caused slowed transit in the BL as well as the ICS. Other results suggest that an increased amount of functional muscle formed in the distal portion of the ICS after bypass. ^

Multiple pathways to bypass the enhancer requirement of sigma 54 RNA polymerase: Roles for DNA and protein determinants

Sigma 54 is a required factor for bacterial RNA polymerase to respond to enhancers and directs a mechanism that is a hybrid between bacterial and eukaryotic transcription. Three pathways were found that bypass the enhancer requirement in vitro. These rely on either deletion of the sigma 54 N terminus or destruction of the DNA consensus −12 promoter recognition element or altering solution conditions to favor transient DNA melting. Each of these allows unstable heparin-sensitive pre-initiation complexes to form that can be driven to transcribe in the absence of both enhancer protein and ATP β–γ hydrolysis. These disparate pathways are proposed to have a common basis in that multiple N-terminal contacts may mediate the interactions between the polymerase and the DNA region where melting originates. The results raise possibilities for common features of open complex formation by different RNA polymerases.

Pleiotropic Alterations in Lipid Metabolism in Yeast sac1 Mutants: Relationship to “Bypass Sec14p” and Inositol Auxotrophy

SacIp dysfunction results in bypass of the requirement for phosphatidylinositol transfer protein (Sec14p) function in yeast Golgi processes. This effect is accompanied by alterations in inositol phospholipid metabolism and inositol auxotrophy. Elucidation of how sac1 mutants effect “bypass Sec14p” will provide insights into Sec14p function in vivo. We now report that, in addition to a dramatic accumulation of phosphatidylinositol-4-phosphate, sac1 mutants also exhibit a specific acceleration of phosphatidylcholine biosynthesis via the CDP-choline pathway. This phosphatidylcholine metabolic phenotype is sensitive to the two physiological challenges that abolish bypass Sec14p in sac1 strains; i.e. phospholipase D inactivation and expression of bacterial diacylglycerol (DAG) kinase. Moreover, we demonstrate that accumulation of phosphatidylinositol-4-phosphate in sac1 mutants is insufficient to effect bypass Sec14p. These data support a model in which phospholipase D activity contributes to generation of DAG that, in turn, effects bypass Sec14p. A significant fate for this DAG is consumption by the CDP-choline pathway. Finally, we determine that CDP-choline pathway activity contributes to the inositol auxotrophy of sac1 strains in a novel manner that does not involve obvious defects in transcriptional expression of the INO1 gene.

Two modes of transvection: Enhancer action in trans and bypass of a chromatin insulator in cis

Ed Lewis introduced the term “transvection” in 1954 to describe mechanisms that can cause the expression of a gene to be sensitive to the proximity of its homologue. Transvection since has been reported at an increasing number of loci in Drosophila, where homologous chromosomes are paired in somatic tissues, as well as at loci in other organisms. At the Drosophila yellow gene, transvection can explain intragenic complementation involving the yellow2 allele (y2). Here, transvection was proposed to occur by enhancers of one allele acting in trans on the promoter of a paired homologue. In this report, we describe two yellow alleles that strengthen this model and reveal an unexpected, second mechanism for transvection. Data suggest that, in addition to enhancer action in trans, transvection can occur by enhancer bypass of a chromatin insulator in cis. We propose that bypass results from the topology of paired genes. Finally, transvection at yellow can occur in genotypes not involving y2, implying that it is a feature of yellow itself and not an attribute of one particular allele.

As seen on TV: observational study of cardiopulmonary resuscitation in British television medical dramas

Objective: To determine the frequency and accuracy with which cardiopulmonary resuscitation is portrayed in British television medical dramas.

Mechanism of stimulation of the DNA glycosylase activity of hOGG1 by the major human AP endonuclease: bypass of the AP lyase activity step

The generation of reactive oxygen species in the cell provokes, among other lesions, the formation of 8-oxo-7,8-dihydroguanine (8-oxoG) in DNA. Due to mispairing with adenine during replication, 8-oxoG is highly mutagenic. To minimise the mutagenic potential of this oxidised purine, human cells have a specific 8-oxoG DNA glycosylase/AP lyase (hOGG1) that initiates the base excision repair (BER) of 8-oxoG. We show here that in vitro this first enzyme of the BER pathway is relatively inefficient because of a high affinity for the product of the reaction it catalyses (half-life of the complex is >2 h), leading to a lack of hOGG1 turnover. However, the glycosylase activity of hOGG1 is stimulated by the major human AP endonuclease, HAP1 (APE1), the enzyme that performs the subsequent step in BER, as well as by a catalytically inactive mutant (HAP1-D210N). In the presence of HAP1, the AP sites generated by the hOGG1 DNA glycosylase can be occupied by the endonuclease, avoiding the re-association of hOGG1. Moreover, the glycosylase has a higher affinity for a non-cleaved AP site than for the cleaved DNA product generated by HAP1. This would shift the equilibrium towards the free glycosylase, making it available to initiate new catalytic cycles. In contrast, HAP1 does not affect the AP lyase activity of hOGG1. This stimulation of only the hOGG1 glycosylase reaction accentuates the uncoupling of its glycosylase and AP lyase activities. These data indicate that, in the presence of HAP1, the BER of 8-oxoG residues can be highly efficient by bypassing the AP lyase activity of hOGG1 and thus excluding a potentially rate limiting step.

Metabolic Bypass of the Tricarboxylic Acid Cycle during Lipid Mobilization in Germinating Oilseeds1 : Regulation of NAD+-Dependent Isocitrate Dehydrogenase Versus Fumarase

Biosynthesis of sucrose from triacylglycerol requires the bypass of the CO2-evolving reactions of the tricarboxylic acid (TCA) cycle. The regulation of the TCA cycle bypass during lipid mobilization was examined. Lipid mobilization in Brassica napus was initiated shortly after imbibition of the seed and proceeded until 2 d postimbibition, as measured by in vivo [1-14C]acetate feeding to whole seedlings. The activity of NAD+-isocitrate dehydrogenase (a decarboxylative enzyme) was not detected until 2 d postimbibition. RNA-blot analysis of B. napus seedlings demonstrated that the mRNA for NAD+-isocitrate dehydrogenase was present in dry seeds and that its level increased through the 4 d of the experiment. This suggested that NAD+-isocitrate dehydrogenase activity was regulated by posttranscriptional mechanisms during early seedling development but was controlled by mRNA level after the 2nd or 3rd d. The activity of fumarase (a component of the nonbypassed section of the TCA cycle) was low but detectable in B. napus seedlings at 12 h postimbibition, coincident with germination, and increased for the next 4 d. RNA-blot analysis suggested that fumarase activity was regulated primarily by the level of its mRNA during germination and early seedling development. It is concluded that posttranscriptional regulation of NAD+-isocitrate dehydrogenase activity is one mechanism of restricting carbon flux through the decarboxylative section of the TCA cycle during lipid mobilization in germinating oilseeds.

Accuracy of lesion bypass by yeast and human DNA polymerase η

DNA polymerase η (Polη) functions in the error-free bypass of UV-induced DNA lesions, and a defect in Polη in humans causes the cancer-prone syndrome, the variant form of xeroderma pigmentosum. Both yeast and human Polη replicate through a cis-syn thymine-thymine dimer (TT dimer) by inserting two As opposite the two Ts of the dimer. Polη, however, is a low-fidelity enzyme, and it misinserts nucleotides with a frequency of ≈ 10−2 to 10−3 opposite the two Ts of the TT dimer as well as opposite the undamaged template bases. This low fidelity of nucleotide insertion seems to conflict with the role of Polη in the error-free bypass of UV lesions. To resolve this issue, we have examined the ability of human and yeast Polη to extend from paired and mispaired primer termini opposite a TT dimer by using steady-state kinetic assays. We find that Polη extends from mispaired primer termini on damaged and undamaged DNAs with a frequency of ≈ 10−2 to 10−3 relative to paired primer termini. Thus, after the incorporation of an incorrect nucleotide, Polη would dissociate from the DNA rather than extend from the mispair. The resulting primer-terminal mispair then could be subject to proofreading by a 3′→5′ exonuclease. Replication through a TT dimer by Polη then would be more accurate than that predicted from the fidelity of nucleotide incorporation alone.

Croatia and the structural funds – Doing without an Ottoman Empire bypass bridge. CEPS Commentary, 29 July 2013

In his latest commentary, Associate Senior Fellow Michael Emerson hails Croatia’s accession to the EU as a fine step forward towards the official goal of integration of the whole of the Balkans into the EU. At the same time, he warns of the folly underway of the serious attention being paid by the European Commission to the newest member state’s petition to construct a multi-million euro bridge over a 9-km stretch of Bosnian land (the ‘Neum corridor’) that inconveniently but temporarily interrupts a non-stop drive along Croatia’s Dalmatian coast.

Down the road to Dubrovnik – Doing without an Ottoman Empire bypass bridge. CEPS Commentary, 29 July 2013

As Europeans speed down the road to Dubrovnik, Croatia's treasured jewel of the Adriatic coast, Michael Emerson discusses in a seasonal commentary one topical issue: What to do now over the 9 km of Bosnian coastline that separates north and south Croatia? Several options are under consideration, one of which would mean a very expensive bridge and dubious use of EU structural funds.