Site occupancy calibration of taxane pharmacology in live cells and tissues.

Drug receptor site occupancy is a central pharmacology parameter that quantitatively relates the biochemistry of drug binding to the biology of drug action. Taxanes and epothilones bind to overlapping sites in microtubules (MTs) and stabilize them. They are used to treat cancer and are under investigation for neurodegeneration. In cells, they cause concentration-dependent inhibition of MT dynamics and perturbation of mitosis, but the degree of site occupancy required to trigger different effects has not been measured. We report a live cell assay for taxane-site occupancy, and relationships between site occupancy and biological effects across four drugs and two cell lines. By normalizing to site occupancy, we were able to quantitatively compare drug activities and cell sensitivities independent of differences in drug affinity and uptake/efflux kinetics. Across all drugs and cells tested, we found that inhibition of MT dynamics, postmitotic micronucleation, and mitotic arrest required successively higher site occupancy. We also found interesting differences between cells and drugs, for example, insensitivity of the spindle assembly checkpoint to site occupancy. By extending our assay to a mouse xenograft tumor model, we estimated the initial site occupancy required for paclitaxel to completely prevent tumor growth as 80%. The most important cellular action of taxanes for cancer treatment may be formation of micronuclei, which occurs over a broad range of site occupancies.

[Spatial distribution and ecological structure of Thalassia testudinum (Hydrocharitaceae) in two reefs of Veracruz Reef System National Park, Mexico]. / Distribución espacial y estructura morfométrica de las praderas de Thalassia testudinum (Hydrocharitaceae) en dos arrecifes del Parque Nacional Sistema Arrecifal Veracruzano, México.

Seagrasses in coastal environments have been threatened by increased human activities; these have negatively altered processes and environmental services, and have decreased grassland areas. The aim of this study was to generate knowledge of Thalassia testudinum distribution, state of the structure and fragmentation level in two reefs of the Veracruz Reef System National Park (PNSAV). Two different reefs were selected: Sacrificios in the North and near the coast, and Cabezo in the South and away from the coast. Shoot-specific and area-specific characteristics of submerged macrophytes meadows present were determined, and four morpho-functional groups were identified. Significant differences between plant coverage were tested through nonparametric ANOVA, Kruskal-Wallis test. A supervised classification of spatial high-resolution image verified with field data was performed (55 Sacrificios and 290 Cabezo). The fragmentation level was calculated using landscape metrics, class level and thematic maps were made based on four covers. The meadows were dominated by Thalassia testudinum; maximum densities were 208 shoot/m2 in Cabezo, and 176 shoot/m2 in Sacrificios. Cabezo presented grasses with short (9 cm) and thin leaves (0.55 cm) on average; while Sacrificios showed longer (23.5 cm) and thicker (1 cm) leaves. Sacrificios showed lower fragmentation degree than Cabezo; in both cases, the vegetation cover fragmentation corresponded to less than 50 %. Although Cabezo reef presents further fragmentation, which creates a large number of microenvironments, being recognized for its importance as recruitment area. This work serves as a baseline for the creation of an adequate management plan (formation of a core area of Cabezo). It is necessary to complement this work with new efforts for the recognition of seagrass prairies in all PNSAV reefs, as well as periodic monitoring and recognition of ecosystem services. .

Promotion Criteria for Medical Educators: Are We Climbing a Ladder with Invisible Rungs?

OBJECTIVE: In 2006 the Association of American Medical Colleges recommended standardization of documentation of the contributions of medical educators and guidelines for their academic promotion. The authors characterized current United States (US) medical school promotion guidelines for medical educators. METHODS: Authors collected publicly available data from medical school promotion websites from March through July 2022 after determining categories by traditional-set domains as well as peer-reviewed standards. Extracted data were analyzed using descriptive and inferential statistics, and frequencies were calculated for nominal and categorical data. RESULTS: Of 155 medical schools identified, promotion criteria were publicly available for 143 (92%) schools. Ninety-one (64%) schools identified a distinct educator track. Of those with a defined educator track, 44 (48%) schools consider workshops or other media when evaluating candidates for promotion, and only 52 (57%) of schools with a specified educational track require additional documentation of teaching or education as part of their promotion process. Notably, 34 (37%) of the 91 schools with an educator track specifically require an Educational Portfolio, compared to 27 (52%) of the 52 schools that do not have a specific educator track for promotion. CONCLUSION: This study describes the current lack of clarity and consistency of the promotion criteria for medical educators and indicates that the guidelines proposed by the Association of American Medical Colleges over 15 years ago have not been widely adopted. These data amplify previous calls for a more objective set of criteria for evaluating and recognizing the contributions of medical educators.

Biomechanical Assessments in Woodwind Musicians: A Systematic Review.

Biomechanical methods are frequently used to provide information about the kinematics and kinetics of posture and movement during musical performance. The aim of this review was to identify and analyze the biomechanical methods performed on woodwind musicians to understand their musculoskeletal demands. A systemic review was carried out following the guidelines of the document Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). It was registered in PROSPERO (code 430304).The databases PubMed, Cochrane, CINAHL, Scopus, and Web of Science were consulted between January 2000 and March 2022. The search in the databases identified 1625 articles, and 16 different studies were finally included in the review, with a sample size of 390 participants. Pressure sensors, surface electromyography, infrared thermography, goniometry in two dimensions, and ultrasound topometry in three dimensions were biomechanical methods useful to broaden the knowledge of musculoskeletal demands during musical practice. Piezoresistive pressure sensors were the most widely used method. The great heterogeneity of the studies limited the comparability of the results. The findings raised the need to increase both the quantity and the quality of studies in future research.

Impact of Age at the Time of the First ST-Elevation Myocardial Infarction on 10-Year Outcomes (from the EXAMINATION-EXTEND Trial).

The aim of this substudy of the EXAMINATION-EXTEND was to analyze 10-year outcomes according to the patient's age at the time of the first ST-elevation myocardial infarction (STEMI). Of 1,498 patients with STEMI included in the EXAMINATION-EXTEND study, those with a previous history of coronary ischemic even or ischemic stroke were excluded from this analysis. The remaining 1,375 patients were divided into 4 age groups: <55, 55 to 65, 65 to 75, and >75 years. The primary end point was 10-year patient-oriented composite end point (POCE) of all-cause death, any MI, or any revascularization. At 10-year follow-up, patients aged <55 years (adjusted hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.18 to 0.31, p = 0.001), 55 to 65 years (adjusted HR 0.26, 95% CI 0.20 to 0.34, p = 0.001), and 65 to 75 years (adjusted HR 0.38, 95% CI 0.30 to 0.50, p = 0.001) showed lower risk of POCE than those aged >75 years, led by a lower incidence of all-cause death (<55 : 6% vs 55 to 65: 11.9% vs 65 to 75: 25.7% vs >75 years: 61.6%, p = 0.001). Cardiac death was more prevalent in the older group (<55: 3.7% vs 55 to 65: 5.8% vs 65 to 75: 10.9% vs >75 years: 35.5%, p = 0.001). In the landmark analyses, between 5- and 10-year follow-up, young patients exhibited a higher incidence of any revascularization (<55: 7.4% vs 55 to 65: 4.9% vs 65 to 75: 1.8% vs >65 years: 1.6%, p = 0.001). In conclusion, in patients with a first STEMI, advanced age was associated with high rates of POCE at 10-year follow-up due to all-cause and cardiac death. Conversely, younger patients exhibited a high risk of revascularization at long-term follow-up.

Do coronary stents suffer long-term deterioration after repeated intracoronary lithotripsy for rebel underexpansion treatment?

Coronary intravascular lithotripsy (IVL) is the latest developed technique available for stent underexpansion treatment, although it is unclear if this therapy causes stent structure damage. We present the case of a patient with severe, refractory stent underexpansion after primary angioplasty, which was resolved with a double session of IVL. Elective angiographic and optical coherence tomography (OCT) follow-up was performed 1 year after the procedure, which demonstrated the absence of any damage in the stent platform. Paradoxically, the study revealed a critical restenotic lesion in an area distant from the one of interest. Review of the first OCT after the primary procedure revealed 78% underexpansion in that area, which went by unnoticed and could be the cause of restenosis. Repeated IVL therapy may be helpful in cases of rebel stent underexpansion, and it conveys the impression of being safe in the long term in relation to the integrity and effectiveness of the drug-eluting coronary stents.

Impact of Diabetes on 10-Year Outcomes Following ST-Segment-Elevation Myocardial Infarction: Insights From the EXAMINATION-EXTEND Trial.

Background Long-term outcomes of ST-segment-elevation myocardial infarction in patients with diabetes have been barely investigated. The objective of this analysis from the EXAMINATION-EXTEND (10-Years Follow-Up of the EXAMINATION trial) trial was to compare 10-year outcomes of patients with ST-segment-elevation myocardial infarction with and without diabetes. Methods and Results Of the study population, 258 patients had diabetes and 1240 did not. The primary end point was patient-oriented composite end point of all-cause death, any myocardial infarction, or any revascularization. Secondary end points were the individual components of the primary combined end point, cardiac death, target vessel myocardial infarction, target lesion revascularization, and stent thrombosis. All end points were adjusted for potential confounders. At 10 years, patients with diabetes showed a higher incidence of patient-oriented composite end point compared with those without (46.5% versus 33.0%; adjusted hazard ratio [HR], 1.31 [95% CI, 1.05-1.61]; P=0.016) mainly driven by a higher incidence of any revascularization (24.4% versus 16.6%; adjusted HR, 1.61 [95% CI, 1.19-2.17]; P=0.002). Specifically, patients with diabetes had a higher incidence of any revascularization during the first 5 years of follow-up (20.2% versus 12.8%; adjusted HR, 1.57 [95% CI, 1.13-2.19]; P=0.007) compared with those without diabetes. No statistically significant differences were found with respect to the other end points. Conclusions Patients with ST-segment-elevation myocardial infarction who had diabetes had worse clinical outcome at 10 years compared with those without diabetes, mainly driven by a higher incidence of any revascularizations in the first 5 years. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04462315.

Sex Differences in 10-Year Outcomes Following STEMI: A Subanalysis From the EXAMINATION-EXTEND Trial.

BACKGROUND: Short-term outcomes following ST-segment elevation myocardial infarction (STEMI) in women are worse than in men, with a higher mortality rate. It is unknown whether sex plays a role in very long term outcomes. OBJECTIVES: The aim of this study was to assess whether very long term outcomes following STEMI treatment are influenced by sex. METHODS: EXAMINATION-EXTEND (10-Year Follow-Up of the EXAMINATION Trial) was an investigator-driven 10-year follow-up of the EXAMINATION (A Clinical Evaluation of Everolimus Eluting Coronary Stents in the Treatment of Patients With ST-Segment Elevation Myocardial Infarction) trial, which randomly 1:1 assigned 1,498 patients with STEMI to receive either everolimus-eluting stents or bare-metal stents. The present study was a subanalysis according to sex. The primary endpoint was the composite patient-oriented endpoint (all-cause death, any myocardial infarction, or any revascularization) at 10 years. Secondary endpoints were individual components of the primary endpoint. All endpoints were adjusted for age. RESULTS: Among 1,498 patients with STEMI, 254 (17%) were women. Overall, women were older, with more arterial hypertension and less smoking history than men. At 10 years, no difference was observed between women and men for the patient-oriented composite endpoint (40.6% vs 34.2%; adjusted HR: 1.14; 95% CI: 0.91-1.42; P = 0.259). There was a trend toward higher all-cause death in women vs men (27.6% vs 19.4%; adjusted HR: 1.30; 95% CI: 0.99-1.71; P = 0.063), with no difference in cardiac death or other endpoints. CONCLUSIONS: At very long term follow-up, there were no differences in the combined patient-oriented endpoint between women and men, with a trend toward higher all-cause death in women not driven by cardiac death. The present findings underline the need for focused personalized medicine in women after percutaneous revascularization aimed at both cardiovascular and sex-specific risk factor control and targeted treatment. (10-Years Follow-Up of the EXAMINATION Trial [EXAMINAT10N]; NCT04462315).

Rescue angioplasty: characteristics and results in a single-center experience.

PURPOSE AND METHODS: Rescue angioplasty (RA) has demonstrated its efficacy for the treatment of failed thrombolysis after acute myocardial infarction (AMI). We analyzed clinical, angiographic, and procedural characteristics, and prognosis at 30 days of prospective cohort of unselected patients admitted for RA. RESULTS: From August 2004 to August 2009, 361 patients were included in a single center. The median time pain to the thrombolysis was 140 minutes (interquartile range [IQR] 90-210), delay transfer 100 minutes (IQR 65-120); pain to PCI was 330 minutes (IQR 270-400). Initial flow TIMI 3 (Thrombolysis in Myocardial Infarction) was presented in 102 (28.3%) of cases and blush grade 3 in 88 (24.4%). After the procedure, TIMI 3 flow was achieved in 286 (79.2%) and blush grade 3 in 256 (71%) (P < 0.001 and P < 0,001, respectively). A glycoprotein IIb/IIIa receptor inhibitor (Abciximab) was used in 115 patients (32%). Stents were implanted in 339 (94%) of patients, 137 (38%) of which were drug-eluting stent. Complete ST segment resolution was observed in 202 (64.5%) patients in 12-lead electrocardiogram (ECG) and procedural success was 77.6%. Adverse cardiac events and death after 30 days follow-up were 13.6% and 10.7%, respectively. Target vessel revascularization at 30 days was 1.9%. CONCLUSIONS: Routine application of RA in patients with persistent ST elevation 90 minutes after thrombolysis is a useful technique for achieving revascularization of the affected artery. In-hospital mortality remains high especially in patients with cardiac shock, despite new interventional techniques available, and adjunctive antithrombotic therapy.

Change over time in the iodine nutritional status of pregnant women from the Pamplona healthcare region. / Evolución del estado de nutrición de yodo en gestantes del area sanitaria de Pamplona.

INTRODUCTION: Adequate iodine intake is essential during pregnancy. A previous study of pregnant women from the Pamplona healthcare region showed mild iodine deficiency (mean urinary iodine level, 125 mcg/L). This study was intended to ascertain the iodine intake of pregnant women in our region and to analyze the change over time in their iodine nutritional status. METHODS: An observational study of 400 women in their first trimester of pregnancy. An iodine intake questionnaire was administered. To assess iodine status, urinary iodine concentration (UIC) was measured in a simple urine sample, and serum thyroglobulin levels were determined. In addition, thyroid volume was measured by cervical ultrasound examination. RESULTS: Iodized salt was used by 70.5% of all participants (55.3% since the pre-gestational period) and 98.5% of them received iodine-containing supplements (mean dose, 202.6±30.1 mcg/day). Mean urinary iodine concentration was 242 mcg/L (138.5-415.5 mcg/L) and the mean serum thyroglobulin level was 12.3 mcg/L (8.3-9 mcg/L). Iodized salt intake was associated with higher UICs and lower thyroid volume. No differences were found in any of the tested parameters regarding the intake of dairy products, fish, or eggs. CONCLUSIONS: Iodine intake by pregnant women in Pamplona has increased due to a greater use of iodized salt and to higher doses of iodine supplements. As a result of this, an adequate iodine status has been achieved in the last decade.

The extent of surgery for low-risk 1-4 cm papillary thyroid carcinoma: a catch-22 situation. A retrospective analysis of 497 patients based on the 2015 ATA Guidelines recommendation 35.

PURPOSE: The adequate extent of surgery for 1-4 cm low-risk papillary thyroid carcinoma (PTC) is unclear. Our objective was to analyze the applicability of the 2015 ATA Guidelines recommendation 35B (R35) for the management low-risk PTC. METHODS: This multicentre study included patients with low-risk PTC who had undergone total thyroidectomy (TT). Retrospectively we selected those who met the R35 criteria for the performance of a thyroid lobectomy (TL). The aim was to identify the proportion of low-risk PTC patients treated using TT who would have required reintervention had they had a TL in accordance with R35. RESULTS: We identified 497 patients (400 female; 80.5%). Median tumor size (mm): 21.2 (11-40). A tumor size ≥2 cm was found in 252 (50.7%). Most of them, 320 (64.4%), were in Stage I (AJCC 7th Edition). Following R35, 286 (57.5%) would have needed TT. Thus, they would have required a second surgery had they undergone TL. The indications for reintervention would have included lymph node involvement (35%), extrathyroidal extension (22.9%), aggressive subtype (8%), or vascular invasion (22.5%). No presurgical clinical data predict TT. CONCLUSIONS: The appropriate management of low-risk PTC is unclear. Adherence to ATA R35 could lead to a huge increase in reinterventions when a TL is performed, though the need for them would be questionable. In our sample, more than half of patients (57.5%) who may undergo a TL for a seemingly low-risk PTC would have required a second operation to satisfy international guidelines, until better preoperative diagnostic tools become available.

Antithrombin Cambridge II (A384S) supports a role for antithrombin deficiency in arterial thrombosis.

Although the control of thrombin in the microvasculature at the endothelial cell surface is crucial to prevent atherothrombosis, the role of antithrombin in arterial thrombosis is unclear. It is widely considered that antithrombin deficiency is unlikely to contribute to arterial thrombosis, but no convincing epidemiological study has been performed because of the low frequency of this deficiency. In this study we evaluated the role in myocardial infarction (MI) of a relatively common mutation affecting antithrombin gene (A384S: Antithrombin Cambridge II) that has functional features that may impair the right control of thrombogenic events caused by injury to the vascular wall. Moreover, this deficiency, which is not detected using common methods to diagnose antithrombin deficiency, also increases the risk of venous thrombosis. We included 1,224 patients with MI (691 consecutive patients and 533 survivors of a premature event), and 1,649 controls. The mutation was identified in 0.3% of controls, but 0.8% of MI patients. After adjusting for sex and other cardiovascular risk factors, the antithrombin Cambridge II significantly increased 5.66-fold the risk of MI (95% CI: 1.53-20.88; p = 0.009). Interestingly, young patients had the highest risk of MI associated with the mutation (OR: 9.98; 95%CI: 1.60-62.24; p = 0.009). This is the first epidemiological study that supports a role for antithrombin deficiency in arterial thrombosis. These results suggest that deficiency of antithrombin may be an independent risk factor for MI that has been underestimated, but larger studies are needed to confirm the relevance of inhibitors of thrombin in arterial thrombosis.

Replication Study: Wnt activity defines colon cancer stem cells and is regulated by the microenvironment.

As part of the Reproducibility Project: Cancer Biology we published a Registered Report (Evans et al., 2015), that described how we intended to replicate selected experiments from the paper 'Wnt activity defines colon cancer stem cells and is regulated by the microenvironment' (Vermeulen et al., 2010). Here, we report the results. Using three independent primary spheroidal colon cancer cultures that expressed a Wnt reporter construct we observed high Wnt activity was associated with the cell surface markers CD133, CD166, and CD29, but not CD24 and CD44, while the original study found all five markers were correlated with high Wnt activity (Figure 2F; Vermeulen et al., 2010). Clonogenicity was highest in cells with high Wnt activity and clonogenic potential of cells with low Wnt activity were increased by myofibroblast-secreted factors, including HGF. While the effects were in the same direction as the original study (Figure 6D; Vermeulen et al., 2010) whether statistical significance was reached among the different conditions varied. When tested in vivo, we did not find a difference in tumorigenicity between high and low Wnt activity, while the original study found cells with high Wnt activity were more effective in inducing tumors (Figure 7E; Vermeulen et al., 2010). Tumorigenicity, however, was increased with myofibroblast-secreted factors, which was in the same direction as the original study (Figure 7E; Vermeulen et al., 2010), but not statistically significant. Finally, we report meta-analyses for each results where possible.

Optimization of the follow-up of pregnant women with autoimmune thyroid disease. / Optimización del seguimiento de gestantes con enfermedad tiroidea autoinmune.

OBJECTIVE: To determine the risk of hypothyroidism in pregnant women with autoimmune thyroid disease and thyrotropin (TSH) < 2,5 mIU/l at the beginning of pregnancy. METHODS: Prospective longitudinal study of pregnant women with no personal history of thyroid disease, and with TSH < 2.5 mIU/l in the first trimester. TSH, free thyroxine (FT4), anti peroxidase (TPO) and anti thyroglobulin antibodies were measured in the 3 trimesters of pregnancy. We compared thyroid function throughout pregnancy, and the development of gestational hypothyroidism (TSH >4 mIU/l) among pregnant women with positive thyroid autoimmunity and those with negative autoimmunity. RESULTS: We included 300 pregnant women with mean baseline TSH 1.3 ± 0.6 mIU/l (9th gestational week). Positive thyroid autoinmunity was detected in 17.7% of women (n = 53) at the first trimester. Between the first and the third trimesters, TPO and anti thyroglobulin antibodies titers decreased 76.8% and 80.7% respectively. Thyroid function during pregnancy was similar among the group with positive autoimmunity and the group with negative autoimmunity, and the development of hypothyroidism was 1.9% (1/53) and 2% (5/247) respectively. Pregnant women in whom TSH increased above 4 mIU/l (n = 6), had higher baseline TSH levels compared to those who maintained TSH ≤4 mIU/l during pregnancy (1.8 vs. 1.3 mIU/l; p=.047). CONCLUSION: In our population, women with TSH levels <2.5 mIU/l at the beginning of pregnancy have a minimal risk of developing gestational hypothyroidism regardless of thyroid autoimmunity.

A Scalable Pipeline for High-Throughput Flow Cytometry.

Flow cytometry (FC) provides high-content data for a variety of applications, including phenotypic analysis of cell surface and intracellular markers, characterization of cell supernatant or lysates, and gene expression analysis. Historically, sample preparation, acquisition, and analysis have presented as a bottleneck for running such types of assays at scale. This article will outline the solutions that have been implemented at Novartis which have allowed high-throughput FC to be successfully conducted and analyzed for a variety of cell-based assays. While these experiments were generally conducted to measure phenotypic responses from a well-characterized and information-rich small molecular probe library known as the Mechanism-of-Action (MoA) Box, they are broadly applicable to any type of test sample. The article focuses on application of automated methods for FC sample preparation in 384-well assay plates. It also highlights a pipeline for analyzing large volumes of FC data, covering a visualization approach that facilitates review of screen-level data by dynamically embedding FlowJo (FJ) workspace images for each sample into a Spotfire file, directly linking them to the metric being observed. Finally, an application of these methods to a screen for MHC-I expression upregulators is discussed.

A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine.

Glioblastoma multiforme (GBM) is an aggressive primary brain cancer that includes focal amplification of PDGFRα and for which there are no effective therapies. Herein, we report the development of a genetically engineered mouse model of GBM based on autocrine, chronic stimulation of overexpressed PDGFRα, and the analysis of GBM signaling pathways using proteomics. We discover the tubulin-binding protein Stathmin1 (STMN1) as a PDGFRα phospho-regulated target, and that this mis-regulation confers sensitivity to vinblastine (VB) cytotoxicity. Treatment of PDGFRα-positive mouse and a patient-derived xenograft (PDX) GBMs with VB in mice prolongs survival and is dependent on STMN1. Our work reveals a previously unconsidered link between PDGFRα activity and STMN1, and highlight an STMN1-dependent cytotoxic effect of VB in GBM.

HIF activation causes synthetic lethality between the VHL tumor suppressor and the EZH1 histone methyltransferase.

Inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL) is the signature lesion in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC). pVHL loss causes the transcriptional activation of hypoxia-inducible factor (HIF) target genes, including many genes that encode histone lysine demethylases. Moreover, chromatin regulators are frequently mutated in this disease. We found that ccRCC displays increased H3K27 acetylation and a shift toward mono- or unmethylated H3K27 caused by an HIF-dependent increase in H3K27 demethylase activity. Using a focused short hairpin RNA library, as well as CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9) and a pharmacological inhibitor, we discovered that pVHL-defective ccRCC cells are hyperdependent on the H3K27 methyltransferase EZH1 for survival. Therefore, targeting EZH1 could be therapeutically useful in ccRCC.

Evaluation of a 'color coding' system for the assessment of patients undergoing primary percutaneous coronary intervention.

AIMS: The reduction of delay times as well as the rate of false alarms (FA) have become some of the main points of the different infarction networks. We propose a simple way of classifying patients derived for primary PCI (pPCI) into well-defined simple groups by colors, where we can assess real delays of each clinical presentation, define the FA and, furthermore, establish their immediate and short term prognosis. METHODS AND RESULTS: Prospective study of STEMI consecutive patients derived for pPCI during 2014. Patients were categorized into one of the 3 predesigned groups [(i) Green: diagnostic-ECG with compatible clinical presentation for pPCI; (ii) Yellow: LBBB, pacemaker rate or non-diagnostic ECG; and (iii) Red: very complex patients], always before performing the angiography in 518 patients. Delay times were highest in the Yellow group, with much longer first medical contact (FMC) to balloon time (median Green 118'; Yellow 163'; Red 130'; p<0.001) mainly due to higher times from the first medical contact to the diagnosis and team activation (median Green 30'; Yellow 70'; Red 39'; p<0.001). In the whole cohort, pPCI was performed in 80.2% of patients, with 11.9% of FA. The Green group had only a 2.5% FA rate, in contrast to the Yellow group where FA were 43.2%. CONCLUSIONS: This simple classification differentiates the 3 very clear groups in which delay times and prognosis are very different. This classification allows us to measure, evaluate and compare the performance of each of our pPCI networks with others and within different periods of times.

Synergistic association between hypercholesterolemia and the C46T factor XII polymorphism for developing premature myocardial infarction.

Factor XII (FXII) plays a key role in both coagulation and fibrinolysis, thus its role in thrombotic processes is uncertain. Both genetic and environmental factors determine FXII plasma levels. A common C46T polymorphism in the Kozak region of F12 gene disturbs the translation of the protein leading to a significant reduction of FXII levels although its clinical significance is conflictive. We studied the F12 C46T polymorphism in 281 patients who had suffered from an acute myocardial infarction (MI) before 45-year-old and 550 control subjects from the same area. Serum levels of cholesterol, HDL, LDL, triglycerides and C reactive protein (CRP) were assayed in the MI group. The 46T allele slightly increased the risk to suffer from premature MI (OR: 1.64; 95% CI: 1.14-2.37; p = 0.008). Moreover, patients carrying the 46T allele showed increased levels of CRP (p = 0.002). Interestingly, we found that the simultaneous presence of the 46T allele and hypercholesterolemia increases the risk to develop premature MI 2.26 times. The F12 C46T polymorphism, associated with a reduction of plasma FXII levels, seems to play a deleterious effect, predisposing the development of premature MI, especially in hypercholesterolemic patients. This effect could be associated with an increased pro-inflammatory state, as the 46T allele associates with high levels of CRP.