Long term effect of a medical emergency team on cardiac arrests in a teaching hospital

INTRODUCTION: It is unknown whether the reported short-term reduction in cardiac arrests associated with the introduction of the medical emergency team (MET) system can be sustained. METHOD: We conducted a prospective, controlled before-and-after examination of the effect of a MET system on the long-term incidence of cardiac arrests. We included consecutive patients admitted during three study periods: before the introduction of the MET; during the education phase preceding the implementation of the MET; and a period of four years from the implementation of the MET system. Cardiac arrests were identified from a log book of cardiac arrest calls and cross-referenced with case report forms and the intensive care unit admissions database. We measured the number of hospital admissions and MET reviews during each period, performed multivariate logistic regression analysis to identify predictors of mortality following cardiac arrest and studied the correlation between the rate of MET calls with the rate of cardiac arrests. RESULTS: Before the introduction of the MET system there were 66 cardiac arrests and 16,246 admissions (4.06 cardiac arrests per 1,000 admissions). During the education period, the incidence of cardiac arrests decreased to 2.45 per 1,000 admissions (odds ratio (OR) for cardiac arrest 0.60; 95% confidence interval (CI) 0.43–0.86; p = 0.004). After the implementation of the MET system, the incidence of cardiac arrests further decreased to 1.90 per 1,000 admissions (OR for cardiac arrest 0.47; 95% CI 0.35–0.62; p < 0.0001). There was an inverse correlation between the number of MET calls in each calendar year and the number of cardiac arrests for the same year (r(2 )= 0.84; p = 0.01), with 17 MET calls being associated with one less cardiac arrest. Male gender (OR 2.88; 95% CI 1.34–6.19) and an initial rhythm of either asystole (OR 7.58; 95% CI 3.15–18.25; p < 0.0001) or pulseless electrical activity (OR 4.09; 95% CI 1.59–10.51; p = 0.003) predicted an increased risk of death. CONCLUSION: Introduction of a MET system into a teaching hospital was associated with a sustained and progressive reduction in cardiac arrests over a four year period. Our findings show sustainability and suggest that, for every 17 MET calls, one cardiac arrest might be prevented

Functional diversity and co-operativity between subclonal populations of paediatric glioblastoma and diffuse intrinsic pontine glioma cells

The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments

Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial

Background Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19.Methods The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 µg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 µg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (antispike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing.Findings Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6–77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3–214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030–27 162), which increased to 37 460 ELU/mL (31 996–43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41–1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996–30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826–64 452), with a geometric mean fold change of 2·19 (1·90–2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37–14·32) and 15·90 (12·92–19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24–16·54] in the BNT162b2 group and 6·22 [3·90–9·92] in the mRNA-1273 group).Interpretation Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose

Medical emergency team (MET) calls during periods 08:00–18:00 and 18:00–08:00 comparison

<p><b>Copyright information:</b></p><p>Taken from "Circadian pattern of activation of the medical emergency team in a teaching hospital"</p><p>Critical Care 2005;9(4):R303-R306.</p><p>Published online 28 Apr 2005</p><p>PMCID:PMC1269438.</p><p>Copyright © 2005 Jones et al.; licensee BioMed Central Ltd.</p> Shown is a comparison of the percentage of MET calls made during the periods 08:00–18:00 and 18:00–08:00 for the years 2000–2004

Adaptation to HIF-1 deficiency by upregulation of the AMP/ATP ratio and phosphofructokinase activation in hepatomas

Background HIF-1 deficiency has marked effects on tumour glycolysis and growth. We therefore investigated the consequences of HIF-1 deficiency in mice, using the well established Hepa-1 wild-type (WT) and HIF-1β-deficient (c4) model. These mechanisms could be clinically relevant, since HIF-1 is now a therapeutic target. Methods Hepa-1 WT and c4 tumours grown in vivo were analysed by 18FDG-PET and 19FDG Magnetic Resonance Spectroscopy for glucose uptake; by HPLC for adenine nucleotides; by immunohistochemistry for GLUTs; by immunoblotting and by DIGE followed by tandem mass spectrometry for protein expression; and by classical enzymatic methods for enzyme activity. Results HIF-1β deficient Hepa-1 c4 tumours grew significantly more slowly than WT tumours, and (as expected) showed significantly lower expression of many glycolytic enzymes. However, HIF-1β deficiency caused no significant change in the rate of glucose uptake in c4 tumours compared to WT when assessed in vivo by measuring fluoro-deoxyglucose (FDG) uptake. Immunohistochemistry demonstrated less GLUT-1 in c4 tumours, whereas GLUT-2 (liver type) was similar to WT. Factors that might upregulate glucose uptake independently of HIF-1 (phospho-Akt, c-Myc) were shown to have either lower or similar expression in c4 compared to WT tumours. However the AMP/ATP ratio was 4.5 fold higher (p < 0.01) in c4 tumours, and phosphofructokinase-1 (PFK-1) activity, measured at prevailing cellular ATP and AMP concentrations, was up to two-fold higher in homogenates of the deficient c4 cells and tumours compared to WT (p < 0.001), suggesting that allosteric PFK activation could explain their normal level of glycolysis. Phospho AMP-Kinase was also higher in the c4 tumours. Conclusions Despite their defective HIF-1 and consequent down-regulation of glycolytic enzyme expression, Hepa-1 c4 tumours maintain glucose uptake and glycolysis because the resulting low [ATP] high [AMP] allosterically activate PFK-1. This mechanism of resistance would keep glycolysis functioning and also result in activation of AMP-Kinase and growth inhibition; it may have major implications for the therapeutic activity of HIF inhibitors in vivo. Interestingly, this control mechanism does not involve transcriptional control or proteomics, but rather the classical activation and inhibition mechanisms of glycolytic enzymes

Tamoxifen decreases drug efflux from liposomes; relevance to its ability to reverse multidrug resistance in cancer cells

AbstractTamoxifen decreased the efflux of the fluorescent marker drug, chloroquine, from phosphatidylcholine liposomes. Tamoxifen is a known structural-mimic of cholesterol, which were both found to be similarly effective in preventing drug release from liposomes. This ability of tamoxifen and cholesterol to decrease drug efflux in a concentration-dependent manner is likely to arise from their known ability to decrease membrane fluidity both in liposomes and also in cancer cells. The possible importance of the ability of tamoxifen to inhibit drug efflux from liposomes in relation to its ability to reverse multidrug resistance in cancer patients caused by the efflux of cytotoxic therapeutic agents, is discussed

Active Oxygen Species Formation in Synaptosomes Exposed to an Aluminum Chelator

This study evaluates the potential of two chelators, 1,2-dimethyl-3-hydroxypyridine-4-one (Hdpp) and 1-n-butyl-2-methyl-3-hydroxypyridin-4-one (Hnbp), to modulate cerebral rates of free radical production. The fluorometric assay for 2',7'-dichlorofluorescein, which is formed by oxidation of a nonfluorescent precursor (2',7'-dichlorofluorescein diacetate), was used to assay reactive oxygen species (ROS) production. The chelator Hdpp alone and the aluminum complexes of each chelator, Al (dpp)3 and Al (nbp)3, all inhibited basal rates of generation of ROS within a rat cerebral synaptosomal fraction. In the presence of an iron salt (1 microM FeSO4), a major enhancement of synaptosomal ROS formation was apparent. However, with the addition of an equimolar concentration of Hdpp, Al(dpp)3, or Al(nbp)3, this stimulation was completely abolished. The N-substituted-3-hydroxy-4-pyridinones have been proposed to be of clinical utility for the removal of iron or aluminum from tissues. The clinical potential of this class of chelator may be enhanced by their ability to inhibit iron-related oxidative events