TIMI, GRACE and alternative risk scores in Acute Coronary Syndromes: A meta-analysis of 40 derivation studies on 216,552 patients and of 42 validation studies on 31,625 patients.

BACKGROUND: Acute coronary syndromes (ACS) represent a difficult challenge for physicians. Risk scores have become the cornerstone in clinical and interventional decision making. METHODS AND RESULTS: PubMed was systematically searched for ACS risk score studies. They were divided into ACS studies (evaluating Unstable Angina; UA, Non ST Segment Elevation Myocardial Infarction; NSTEMI, and ST Segment Elevation Myocardial Infarction; STEMI), UA/NSTEMI studies or STEMI studies. The c-statistics of validation studies were pooled when appropriate with random-effect methods. 7 derivation studies with 25,525 ACS patients and 15 validation studies including 257,654 people were formally appraised. Pooled analysis of GRACE scores, both at short (0.82; 0.80-0.89 I.C 95%) and long term follow up (0.84; 0.82-0.87; I.C 95%) showed the best performance, with similar results to Simple Risk Index (SRI) derivation cohorts at short term. For NSTEMI/UA, 18 derivation studies with 56,560 patients and 18 validation cohorts with 56,673 patients were included. Pooled analysis of validations studies showed c-statistics of 0.54 (95% CI = 0.52-0.57) and 0.67 (95% CI = 0.62-0.71) for short and long term TIMI validation studies, and 0.83 (95% CI = 0.79-9.87) and 0.80 (95% CI = 0.74-0.89) for short and long term GRACE studies. For STEMI, 15 studies with 134,557 patients with derivation scores, and 17 validation studies with 187,619 patients showed a pooled c-statistic of 0.77 (95% CI = 0.71-0.83) and 0.77 (95% CI = 0.72-0.85) for TIMI at short and long term, and a pooled c-statistic of 0.82 (95% CI = 0.81-0.83) and 0.81 (95% CI = 0.80-0.82) for GRACE at short and long terms respectively. CONCLUSIONS: TIMI and GRACE are the risk scores that up until now have been most extensively investigated, with GRACE performing better. There are other potentially useful ACS risk scores available however these have not undergone rigorous validation. This study suggests that these other scores may be potentially useful and should be further researched

Actin-Related Protein Arp6 Influences H2A.Z-Dependent and -Independent Gene Expression and Links Ribosomal Protein Genes to Nuclear Pores

Actin-related proteins are ubiquitous components of chromatin remodelers and are conserved from yeast to man. We have examined the role of the budding yeast actin-related protein Arp6 in gene expression, both as a component of the SWR1 complex (SWR-C) and in its absence. We mapped Arp6 binding sites along four yeast chromosomes using chromatin immunoprecipitation from wild-type and swr1 deleted (swr1Δ) cells. We find that a majority of Arp6 binding sites coincide with binding sites of Swr1, the catalytic subunit of SWR-C, and with the histone H2A variant Htz1 (H2A.Z) deposited by SWR-C. However, Arp6 binding detected at centromeres, the promoters of ribosomal protein (RP) genes, and some telomeres is independent of Swr1 and Htz1 deposition. Given that RP genes and telomeres both show association with the nuclear periphery, we monitored the ability of Arp6 to mediate the localization of chromatin to nuclear pores. Arp6 binding is sufficient to shift a randomly positioned locus to nuclear periphery, even in a swr1Δ strain. Arp6 is also necessary for the pore association of its targeted RP promoters possibly through cell cycle-dependent factors. Loss of Arp6, but not Htz1, leads to an up-regulation of these RP genes. In contrast, the pore-association of GAL1 correlates with Htz1 deposition, and loss of Arp6 reduces both GAL1 activation and peripheral localization. We conclude that Arp6 functions both together with the nucleosome remodeler Swr1 and also without it, to mediate Htz1-dependent and Htz1-independent binding of chromatin domains to nuclear pores. This association is shown to have modulating effects on gene expression

ICAR: endoscopic skull‐base surgery

n/