Trimester-specific diagnostic accuracy of ultrasound for detection of placenta accreta spectrum: systematic review and meta-analysis.

OBJECTIVE: To assess the diagnostic accuracy of ultrasound for detecting placenta accreta spectrum (PAS) during the first trimester of pregnancy and compare it with the accuracy of second- and third-trimester ultrasound examination in pregnancies at risk for PAS. METHODS: PubMed, EMBASE and Web of Science databases were searched to identify relevant studies published from inception until 10 March 2023. Inclusion criteria were cohort, case-control or cross-sectional studies that evaluated the accuracy of ultrasound examination performed at < 14 weeks of gestation (first trimester) or ≥ 14 weeks of gestation (second/third trimester) for the diagnosis of PAS in pregnancies with clinical risk factors. The primary outcome was the diagnostic accuracy of sonography in detecting PAS in the first trimester, compared with the accuracy of ultrasound examination in the second and third trimesters. The secondary outcome was the diagnostic accuracy of each sonographic marker individually across the trimesters of pregnancy. The reference standard was PAS confirmed at pathological or surgical examination. The potential of ultrasound and different ultrasound signs to detect PAS was assessed by computing summary estimates of sensitivity, specificity, diagnostic odds ratio and positive and negative likelihood ratios. RESULTS: A total of 37 studies, including 5764 pregnancies at risk of PAS, with 1348 cases of confirmed PAS, were included in our analysis. The meta-analysis demonstrated that ultrasound had a sensitivity of 86% (95% CI, 78-92%) and specificity of 63% (95% CI, 55-70%) during the first trimester, and a sensitivity of 88% (95% CI, 84-91%) and specificity of 92% (95% CI, 85-96%) during the second/third trimester. Regarding sonographic markers examined in the first trimester, lower uterine hypervascularity exhibited the highest sensitivity (97% (95% CI, 19-100%)), and uterovesical interface irregularity demonstrated the highest specificity (99% (95% CI, 96-100%)). In the second/third trimester, loss of clear zone had the highest sensitivity (80% (95% CI, 72-86%)), and uterovesical interface irregularity exhibited the highest specificity (99% (95% CI, 97-100%)). CONCLUSIONS: First-trimester ultrasound examination has similar accuracy to second- and third-trimester ultrasound examinations for the diagnosis of PAS. Routine first-trimester ultrasound screening for patients at high risk of PAS may improve detection rates and allow earlier referral to tertiary care centers for pregnancy management. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Elective delivery at 34 weeks vs routine obstetric care in fetal gastroschisis: randomized controlled trial.

OBJECTIVE: To evaluate whether elective preterm delivery (ED) at 34 weeks is of postnatal benefit to infants with isolated gastroschisis compared with routine obstetric care (RC). METHODS: Between May 2013 and September 2015, all women with a sonographic diagnosis of fetal gastroschisis referred to a single tertiary center, before 34 weeks' gestation, were invited to participate in this study. Eligible patients were randomized to ED (induction of labor at 34 weeks) or RC (spontaneous labor or delivery by 37-38 weeks, based on standard obstetric indications). The primary outcome measure was length of time on total parenteral nutrition (TPN). Secondary outcomes were time to closure of gastroschisis and length of stay in hospital. Outcome variables were compared using appropriate statistical methods. Analysis was based on intention-to-treat. RESULTS: Twenty-five women were assessed for eligibility, of whom 21 (84%; 95% CI, 63.9-95.5%) agreed to participate in the study; of these, 10 were randomized to ED and 11 to RC. The trial was stopped at the first planned interim analysis due to patient safety concerns and for futility; thus, only 21 of the expected 86 patients (24.4%; 95% CI, 15.8-34.9%) were enrolled. Median gestational age at delivery was 34.3 (range, 34-36) weeks in the ED group and 36.7 (range, 27-38) weeks in the RC group. One patient in the ED group delivered at 36 weeks following unsuccessful induction at 34 weeks. Neonates of women who underwent ED, compared to those in the RC group, showed no difference in the median number of days on TPN (54 (range, 17-248) vs 21 (range, 9-465) days; P = 0.08), number of days to closure of gastroschisis (7 (range, 0-15) vs 5 (range, 0-8) days; P = 0.28) and length of stay in hospital (70.5 (range, 22-137) vs 31 (range, 19-186) days; P = 0.15). However, neonates in the ED group were significantly more likely to experience late-onset sepsis compared with those in the RC group (40% (95% CI, 12.2-73.8%) vs 0%; P = 0.03). CONCLUSION: This study demonstrates no benefit of ED of fetuses with gastroschisis when postnatal gastroschisis management is similar to that used in routine care. Rather, the data suggest that ED is detrimental to infants with gastroschisis. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Parto inducido a las 34 semanas versus atención obstétrica rutinaria en la gastrosquisis fetal: ensayo controlado aleatorizado OBJETIVO: Evaluar si el parto pretérmino inducido (PI) a las 34 semanas es beneficioso para los recién nacidos con gastrosquisis aislada en comparación con la atención obstétrica rutinaria (AR). MÉTODOS: Entre mayo de 2013 y septiembre de 2015, se invitó a participar en este estudio a todas las mujeres con diagnóstico ecográfico de gastrosquisis fetal remitidas a un mismo centro terciario, antes de las 34 semanas de gestación. Las pacientes elegibles fueron asignadas al azar al PI (inducción del parto a las 34 semanas) o a la AR (parto espontáneo a las 37-38 semanas, en función de los indicios obstétricos estándar). La medida de resultado primaria fue la duración de la nutrición parenteral total (NPT). Las medidas de resultado secundarias fueron el tiempo hasta el cierre de la gastrosquisis y la duración de la estancia hospitalaria. Las variables de resultado se compararon mediante métodos estadísticos apropiados. El análisis se basó en la intención de tratar. RESULTADOS: Se evaluó la elegibilidad de 25 mujeres, de las cuales 21 (84%; IC 95%, 63,9-95,5%) aceptaron participar en el estudio; de ellas, 10 fueron asignadas al azar al PI y 11 a la AR. El ensayo se detuvo después del primer análisis provisional planificado debido a preocupaciones sobre la seguridad de las pacientes y por su intrascendencia; por lo tanto, sólo se reclutaron 21 de las 86 pacientes esperadas (24,4%; IC 95%, 15,8-34,9%). La mediana de la edad gestacional en el momento del parto fue de 34,3 (rango: 34-36) semanas en el grupo de PI y 36,7 (rango: 27-38) semanas en el grupo de AR. Una paciente del grupo de PI tuvo un parto a las 36 semanas, después de una inducción infructuosa a las 34 semanas. Los neonatos de las mujeres que se sometieron a PI, comparados con los del grupo de AR, no mostraron diferencias en la mediana del número de días de NPT (54 (rango: 17-248) vs 21 (rango: 9-465) días; P=0,08), número de días hasta el cierre de la gastrosquisis (7 (rango: 0-15) vs 5 (rango: 0-8) días; P=0,28) y duración de la estancia hospitalaria (70,5 (rango: 22-137) vs 31 (rango: 19-186) días; P=0,15). Sin embargo, la probabilidad de experimentar sepsis de inicio tardío fue mayor en los neonatos del grupo de PI en comparación el grupo de AR (40% (IC 95%, 12,2-73,8%) vs 0%; P=0,03). CONCLUSIÓN: Este estudio demuestra que el PI no presenta ningún beneficio para los fetos con gastrosquisis cuando el tratamiento de la gastrosquisis postnatal es similar al utilizado en la atención rutinaria. Más bien, los datos sugieren que el PI es perjudicial para los lactantes con gastrosquisis.

Placental growth factor blunts uterine artery responses to angiotensin II.

OBJECTIVE: Changes in maternal serum concentration of placental growth factor (PlGF) and vascular response to intravascular infusion of Angiotensin II (Ang II) follow a bell-shaped curve pattern during gestation. This study evaluates the effects of PlGF and soluble vascular endothelial growth factor receptor-1 (sFlt-1) on responses of human uterine arteries (UA) to Ang II. DESIGN: Experimental. SETTING: Baylor College of Medicine and Texas Children's Hospital-Pavilion for Women. SAMPLE: Uterine arteries samples (n = 14) were obtained from normotensive women undergoing caesarean hysterectomy at ≥32 weeks. METHODS: Uterine arteries rings were incubated with (1) Krebs solution; (2) PlGF at 1.45, 14.5, and 500 pg/ml; (3) sFlt-1 at 2 ng/ml; and (4) a combination of sFlt-1, and PlGF. Dose-contraction responses to Ang II were determined in UA rings incubated in the above-mentioned conditions. Responses were also measured in presence of L-NAME or inhibitors of endothelium-derived hyperpolarising factor: apamine and charybdotoxin. The t-test was used for comparisons. MAIN OUTCOME MEASURE: Changes in vascular reactivity of UA rings. RESULTS: PlGF blunted (P = 0.03) and sFlt-1 increased (P <0.01) the UA maximum responses to Ang II. A combination of sFlt-1 and PlGF blunted UA responses to Ang II (P < 0.05). l-NAME, apamine, and charybdotoxin reversed the relaxation effects of PlGF on UA responses to Ang II (P < 0.05). CONCLUSIONS: PlGF contributes to the blunted vascular response to Angiotensin II during normotensive pregnancies and sFlt-1 appears to attenuate this effect. PlGF and sFlt-1 may contribute to the regulation of vascular tone during pregnancy by altering the vascular response to Angiotensin II. FUNDING: Baylor College of Medicine. TWEETABLE ABSTRACT: Placental growth factor and soluble vascular endothelial growth factor receptor-1 modulate the uterine artery response to Angiotensin II in normotensive pregnant women.

Pregnancy after endometrial ablation: a systematic review.

BACKGROUND: Pregnancies have been reported after endometrial ablation but there is little data regarding subsequent pregnancy outcomes. OBJECTIVE: To review systematically the available evidence regarding pregnancy outcomes after endometrial ablation, in order to equip physicians effectively to counsel women considering endometrial ablation. SEARCH STRATEGY: MEDLINE, Embase, Cochrane, and ClinicalTrials.gov were searched through January 2017. SELECTION CRITERIA: Published and unpublished literature in any language describing pregnancy after endometrial ablation or resection was eligible. DATA COLLECTION AND ANALYSIS: Data about preconception characteristics and pregnancy outcomes were extracted and analysed according to study design of source and pregnancy viability. MAIN RESULTS: We identified 274 pregnancies from 99 sources; 78 sources were case reports. Women aged 26-50 years (mean 37.5 ± 5 years) conceived a median of 1.5 years after ablation (range: 3 weeks prior to 13 years after). When reported, 80-90% had not used contraception. In all, 85% of pregnancies from trial/observational studies ended in termination, miscarriage or ectopic pregnancy. Pregnancies that continued (case report and non-case report sources) had high rates of preterm delivery, caesarean delivery, caesarean hysterectomy, and morbidly adherent placenta. Case reports also frequently described preterm premature rupture of membranes, intrauterine growth restriction, intrauterine fetal demise, uterine rupture, and neonatal demise. CONCLUSIONS: An unexpectedly high rate of pregnancy complications is reported in the available literature (which may reflect publication bias) and high-quality evidence is lacking. However, based on the existing evidence, women undergoing endometrial ablation should be informed that subsequent pregnancy may have serious complications and should be counselled to use reliable contraception after the procedure. TWEETABLE ABSTRACT: Systematic review - pregnancies reported after endometrial ablation have an increased risk of adverse outcomes.

Experimental Transmission of Bighorn Sheep Sinus Tumors to Bighorn Sheep (Ovis canadensis canadensis) and Domestic Sheep.

Bighorn sheep sinus tumors are a recently described disease affecting the paranasal sinuses of Rocky Mountain bighorn sheep (Ovis canadensis canadensis). Several features of this disease suggest an infectious cause, although a specific etiologic agent has not been identified. To test the hypothesis that bighorn sheep sinus tumors are caused by an infectious agent, we inoculated 4 bighorn sheep lambs and 4 domestic sheep lambs intranasally with a cell-free filtrate derived from a naturally occurring bighorn sheep sinus tumor; we held 1 individual of each species as a control. Within 18 months after inoculation, all 4 inoculated domestic sheep (100%) and 1 of the 4 inoculated bighorn sheep (25%) developed tumors within the ethmoid sinuses or nasal conchae, with features similar to naturally occurring bighorn sheep sinus tumors. Neither of the uninoculated sheep developed tumors. Histologically, the experimentally transmitted tumors were composed of stellate to spindle cells embedded within a myxoid matrix, with marked bone production. Tumor cells stained positively with vimentin, S100, alpha smooth muscle actin, and osteocalcin, suggesting origin from a multipotent mesenchymal cell. A periosteal origin for these tumors is suspected. Immunohistochemical staining for the envelope protein of JSRV (with cross-reactivity to ENTV) was equivocal, and PCR assays specific for these agents were negative.

A cardiovascular disease policy model that predicts life expectancy taking into account socioeconomic deprivation.

OBJECTIVES: A policy model is a model that can evaluate the effectiveness and cost-effectiveness of interventions and inform policy decisions. In this study, we introduce a cardiovascular disease (CVD) policy model which can be used to model remaining life expectancy including a measure of socioeconomic deprivation as an independent risk factor for CVD. DESIGN: A state transition model was developed using the Scottish Heart Health Extended Cohort (SHHEC) linked to Scottish morbidity and death records. Individuals start in a CVD-free state and can transit to three CVD event states plus a non-CVD death state. Individuals who have a non-fatal first event are then followed up until death. Taking a competing risk approach, the cause-specific hazards of a first event are modelled using parametric survival analysis. Survival following a first non-fatal event is also modelled parametrically. We assessed discrimination, validation and calibration of our model. RESULTS: Our model achieved a good level of discrimination in each component (c-statistics for men (women)-non-fatal coronary heart disease (CHD): 0.70 (0.74), non-fatal cerebrovascular disease (CBVD): 0.73 (0.76), fatal CVD: 0.77 (0.80), fatal non-CVD: 0.74 (0.72), survival after non-fatal CHD: 0.68 (0.67) and survival after non-fatal CBVD: 0.65 (0.66)). In general, our model predictions were comparable with observed event rates for a Scottish randomised statin trial population which has an overlapping follow-up period with SHHEC. After applying a calibration factor, our predictions of life expectancy closely match those published in recent national life tables. CONCLUSIONS: Our model can be used to estimate the impact of primary prevention interventions on life expectancy and can assess the impact of interventions on inequalities.

The roles of geography and founder effects in promoting host-associated differentiation in the generalist bogus yucca moth Prodoxus decipiens.

There is ample evidence that host shifts in plant-feeding insects have been instrumental in generating the enormous diversity of insects. Changes in host use can cause host-associated differentiation (HAD) among populations that may lead to reproductive isolation and eventual speciation. The importance of geography in facilitating this process remains controversial. We examined the geographic context of HAD in the wide-ranging generalist yucca moth Prodoxus decipiens. Previous work demonstrated HAD among sympatric moth populations feeding on two different Yucca species occurring on the barrier islands of North Carolina, USA. We assessed the genetic structure of P. decipiens across its entire geographic and host range to determine whether HAD is widespread in this generalist herbivore. Population genetic analyses of microsatellite and mtDNA sequence data across the entire range showed genetic structuring with respect to host use and geography. In particular, genetic differentiation was relatively strong between mainland populations and those on the barrier islands of North Carolina. Finer scale analyses, however, among sympatric populations using different host plant species only showed significant clustering based on host use for populations on the barrier islands. Mainland populations did not form population clusters based on host plant use. Reduced genetic diversity in the barrier island populations, especially on the derived host, suggests that founder effects may have been instrumental in facilitating HAD. In general, results suggest that the interplay of local adaptation, geography and demography can determine the tempo of HAD. We argue that future studies should include comprehensive surveys across a wide range of environmental and geographic conditions to elucidate the contribution of various processes to HAD.

Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with non-valvular atrial fibrillation: results from ROCKET AF.

Two once-daily rivaroxaban dosing regimens were compared with warfarin for stroke prevention in patients with non-valvular atrial fibrillation in ROCKET AF: 20 mg for patients with normal/mildly impaired renal function and 15 mg for patients with moderate renal impairment. Rivaroxaban population pharmacokinetic (PK)/pharmacodynamic (PD) modeling data from ROCKET AF patients (n = 161) are reported and are used to confirm established rivaroxaban PK and PK/PD models and to re-estimate values of the models' parameters for the current AF population. An oral one-compartment model with first-order absorption adequately described rivaroxaban PK. Age, renal function, and lean body mass influenced the PK model. Prothrombin time and prothrombinase-induced clotting time exhibited a near-linear relationship with rivaroxaban plasma concentration; inhibitory effects were observed through to 24 hours post-dose. Rivaroxaban plasma concentration and factor Xa activity had an inhibitory maximum-effect (Emax ) relationship. Renal function (on prothrombin time; prothrombinase-induced clotting time) and age (on factor Xa activity) had moderate effects on PK/PD models. PK and PK/PD models were shown to be adequate for describing the current dataset. These findings confirm the modeling and empirical results that led to the selection of doses tested against warfarin in ROCKET AF.

Trends in hospital treatments, including revascularisation, following acute myocardial infarction, 2003-2010: a multilevel and relative survival analysis for the National Institute for Cardiovascular Outcomes Research (NICOR).

OBJECTIVE: To investigate temporal changes in survival after acute myocardial infarction (AMI) by early invasive strategy. METHODS: Accelerated failure time and 6-month relative survival analyses stratified by thrombolysis or primary percutaneous coronary intervention (PPCI) for ST elevation myocardial infarction (STEMI) and coronary angiography for non-STEMI (NSTEMI) encompassing 583 466 patients across 247 hospitals in England and Wales over hospital admission periods 2003-2004, 2005-2006, 2007-2008 and 2009-2010. RESULTS: Survival improved significantly for STEMI patients who received reperfusion therapy (time ratio (TR) 1.47, 95% CI 1.22 to 2.78) and was stable for those who did not (TR 1.02, 95% CI 0.85 to 1.22). While there were significant improvements in survival for NSTEMI patients who underwent coronary angiography (TR 1.39, 95% CI 1.18 to 1.62), there was a significant decline for those who did not (TR 0.70, 95% CI 0.65 to 0.75). Patients without reperfusion therapy or coronary angiography had a greater number of comorbidities, but the use of secondary prevention medications was comparable with patients who received reperfusion therapy or coronary angiography. There was a significant hospital-level survival effect, with higher crude 6-month mortality in hospitals in the lowest coronary angiography and PPCI quartiles (angiography Q1: 16.4% vs Q4: 12.8%; PPCI Q1: 15.8% vs Q4: 12.4%). CONCLUSIONS: Survival rates after AMI have improved. Whereas survival estimates for STEMI patients who did not receive reperfusion therapy were stable, they worsened for NSTEMI patients not receiving coronary angiography.

An evaluation of composite indicators of hospital acute myocardial infarction care: a study of 136,392 patients from the Myocardial Ischaemia National Audit Project.

BACKGROUND: Hospital acute myocardial infarction (AMI) care is increasingly evaluated using composite quality scores. We investigated the influence of three aggregation methods for an AMI indicator on mortality and hospital rank. METHODS AND RESULTS: We studied 136,392 patients discharged alive from 199 hospitals with AMI recorded in the Myocardial Ischaemia National Audit Project, between 01/01/2008 and 31/12/2009. A composite of prescription of aspirin, thienopyridine inhibitor, ß-blocker, angiotensin converting enzyme inhibitor, HMG CoA reductase enzyme inhibitor and enrolment in cardiac rehabilitation at discharge was aggregated as opportunity based (OBCS), weighted opportunity-based (WOBCS) and all-or-nothing (ANCS) scores. We quantified adjusted 30-day, 6-month and 1-year mortality rates and hospital performance rank. Median (IQR) scores were OBCS: 95.0% (3.5), WOBCS: 94.7% (0.8) and ANCS: 80.9% (11.8). The three methods affected the proportion of hospitals outside 99.8% credible limits of the national median (OBCS: 52.2%, WOBCS: 64.3% and ANCS: 37.7%) and hospital rank. Each 1% increase in composite score was significantly associated with a 1 to 3% and a 4% reduction in 6-month and 1-year mortality, respectively. However, the ANCS had fewer cases and no significant association with 30-day mortality. CONCLUSIONS: A hospital composite score, incorporating 6 aspects of AMI care, was significantly inversely associated with mortality. However, composite aggregation method influenced hospital rank, number of cases available for analysis and size of the association with all-cause mortality, with the ANCS performing least well. The use and choice of composite scores in hospital AMI quality improvement requires careful evaluation.

What's new for ESC Congress 2013? (Amsterdam 30 August - 4 September 2013).

The innovative Spotlight of the Congress is "The heart interacting with systemic organs". For our patients, the interaction of cardiac conditions with other organs is fundamentally important to outcome, to safety and to clinical management. Related specialty areas have much to learn from each other and the ESC Congress 2013 will attract specialists from other organ systems to help understand disease mechanisms and improve the management of our patients.

Age-dependent inequalities in improvements in mortality occur early after acute myocardial infarction in 478,242 patients in the Myocardial Ischaemia National Audit Project (MINAP) registry.

BACKGROUND: Mortality rates after acute myocardial infarction (AMI) have declined, but there is uncertainty regarding the extent of improvements in early mortality in the elderly. METHODS: Mixed-effects regression analysis of 30-day mortality using data from 478,242 patients with AMI at 215 hospitals in England and Wales stratified by STEMI/NSTEMI, sex, and age group. A hospital opportunity-based composite score (OBCS) for aspirin, ACE-inhibitor, statin, ß blocker, and referral for cardiac rehabilitation was used as measure of quality of hospital care. RESULTS: 30-day mortality rates (95% CI) fell from 10.7% (10.6 to 10.9%) in 2004/5 to 8.4% (8.3 to 8.6%) in 2008/9. The median (IQR) hospital OBCSs increased over time, 2004/5: 87.3 (7.2), 2006/7: 88.9 (6.3), 2008/9: 90.3 (6.1), P<0.001, and were similar between age groups (18 to <65 years, 65 to 79 years, and ≥ 80 years) for STEMI: 89.4 (6.5) vs. 89.4 (6.6), vs. 89.2 (6.5) and NSTEMI: 88.6 (7.3) vs. 88.8 (7.0) vs. 88.9 (7.0), respectively For males, all age groups except patients <65 years demonstrated a significant decrease in adjusted mortality. For females, only patients ≥ 80 years demonstrated a significant reduction in adjusted mortality. A 1% increase in hospital OBCS was associated with a 1% decrease in 30-day mortality (95% CI: 0.99 to 0.99, P<0.001). CONCLUSION: In England and Wales, for patients with AMI there are age and sex-dependent differences in improvements in 30-day mortality. Whereas young males with AMI have reached an acceptable performance plateau, all other groups are either improving or, more importantly, are yet to demonstrate this.

The impact of beta-blockers on mortality in stable angina: a meta-analysis.

Beta-blockers are recommended as first-line symptomatic treatment for stable angina. However, their impact on mortality outside the context of myocardial infarction is unknown. We performed a meta-analysis of all randomized trials of beta-blockers in stable angina. Medical databases and cardiology journals were searched for relevant randomized clinical trials. The primary outcome was cardiovascular mortality, separately considering trials of beta-blockers versus placebo and beta-blockers versus other antianginals. We conducted a subgroup analysis on cardioselective versus non-cardioselective beta-blockers and calcium channel antagonists versus nitrates. We calculated odds ratios (ORs) and confidence intervals (CIs) using Peto's method. We found no statistically significant evidence that beta-blockers impact on mortality when compared with placebo (OR, 0.42; CI , 0.15-1.21) or other antianginals (OR, 0.98; CI, 0.86-1.10), or all others (OR, 0.97; CI, 0.86-1.09). There was a trend for cardioselective beta-blockers to have a greater improvement in mortality when compared with placebo and to have greater impact than non-calcium channel antagonists. Beta-blockers do not have statistically significant impact on mortality versus placebo or versus other active comparators. The findings exclude a benefit of 15% or greater and a hazard of 10% or greater. The impact of cardioselectivity requires further study.

Platelet activation in patients with peripheral vascular disease: reproducibility and comparability of platelet markers.

BACKGROUND: Many markers of platelet activation have been described but their reproducibility and comparability in patient populations are poorly defined. OBJECTIVES: We sought to compare markers of platelet and monocyte activation with platelet-monocyte aggregates, a proposed gold standard of in vivo platelet activation, and assess their reproducibility in patients with peripheral arterial disease: a population with substantial platelet activation, inflammation and risk of thrombotic events. PATIENTS/METHODS: Thirty patients with peripheral vascular disease attended on two occasions to permit within-day and between-day comparisons. In vivo platelet and monocyte activation were determined by flow-cytometric quantification of platelet-monocyte aggregation, platelet surface expression of P-selectin and CD40L, platelet-derived microparticles, and monocyte surface expression of CD40 and CD11b. Plasma concentrations of platelet-derived microparticles, soluble P-selectin and CD40L were measured by enzyme-linked immunosorbant assays. RESULTS: Platelet-monocyte aggregation (36.7±7.86%), and platelet surface expression of P-selectin (5.8±1.65%) and CD40L (3.3±1.45%) demonstrated comparable within-day (mean difference±co-efficient of reproducibility; 0.9±15.4%, 0.21±1.65% and 0.2±2.8% respectively) and between-day reproducibility (2.0±12.4%, 0.10±2.25% and 0.9±6.4% respectively). Platelet-monocyte aggregates correlated well with other platelet (r=0.30-0.50, P<0.02) and monocyte (r=0.27-0.47, P<0.03) activation markers. Flow cytometric and assay quantified platelet-derived microparticles showed poorer reproducibility (co-efficient of reproducibility >40). CONCLUSIONS: In patients with peripheral arterial disease, measurements of platelet-monocyte aggregates have good reproducibility and consistently reflect other markers of platelet and monocyte activation.

Resolving inequalities in care? Reduced mortality in the elderly after acute coronary syndromes. The Myocardial Ischaemia National Audit Project 2003-2010.

AIMS: To examine age-dependent in-hospital mortality for hospitalization with acute coronary syndromes (ACS) in England and Wales. METHODS AND RESULTS: Mixed-effects regression analysis using data from 616 011 ACS events at 255 hospitals as recorded in the Myocardial Ischemia National Audit Project (MINAP) 2003-2010; 102 415 (16.7%) patients were aged <55 years and 72 721 (11.9%) ≥85 years. Patients ≥85 years with ST-elevation myocardial infarction (STEMI) were less likely to receive emergency reperfusion therapy than those <55 years (RR = 0.27, 95% CI: 0.25-0.28). Older patients had greater lengths of stay (P< 0.001) and higher in-hospital mortality (P< 0.001). For STEMI and non-ST-elevation myocardial infarction (NSTEMI), there were reductions in in-hospital mortality from 2003 to 2010 across all age groups including the very elderly. For STEMI ≥ 85 years, in-hospital mortality reduced from 30.1% in 2003 to 19.4% in 2010 (RR = 0.54, 95% CI: 0.38-0.75, P< 0.001), and for NSTEMI ≥ 85 years, from 31.5% in 2003 to 20.4% in 2010 (RR = 0.56, 95% CI: 0.42-0.73, P< 0.001). Findings were upheld after multi-level adjustment (base = 2003): male STEMI 2010 OR = 0.60, 95% CI: 0.48-0.75; female STEMI 2010 OR = 0.55, 95% CI: 0.42-0.71; male NSTEMI OR = 0.50, 95% CI: 0.42-0.60; female NSTEMI OR = 0.49, 95% CI: 0.40-0.59. CONCLUSION: For patients hospitalized with ACS in England and Wales, there have been substantial reductions in in-hospital mortality rates from 2003 to 2010 across all age groups. The temporal improvements in mortality were similar for sex and type of acute myocardial infarction. Age-dependent inequalities in the management of ACS were apparent.

Paranasal sinus masses of Rocky Mountain bighorn sheep (Ovis canadensis canadensis).

This article describes 10 cases of paranasal sinus masses in Rocky Mountain bighorn sheep (Ovis canadensis canadensis). Among 21 bighorns that were examined from 11 herds in Colorado, 10 individuals (48%) from 4 herds (36%) had masses arising from the paranasal sinuses. Affected animals included 9 of 17 females (53%) and 1 of 4 males (25%), ranging in age from approximately 2 years to greater than 10 years. Defining gross features of these masses included unilateral or bilateral diffuse thickening of the respiratory lining of the maxillary and/or frontal sinuses, with abundant seromucinous exudate in the affected sinus cavities. Defining histologic features of these masses included chronic inflammation and proliferation of mesenchymal and epithelial cells of the mucosa and submucosa. Epithelial changes included hyperplasia of mucosal epithelium, hyperplasia of submucosal glands and ducts, and neoplasia (adenocarcinoma). Mesenchymal changes included submucosal myxedema, submucosal fibroplasia/fibrosis, bone destruction, and neoplasia (myxomatous fibroma). Specific immunohistochemistry and polymerase chain reaction for Jaagsiekte sheep retrovirus and enzootic nasal tumor virus were performed with negative results.

The Global Registry of Acute Coronary Events, 1999 to 2009--GRACE.

The aim of GRACE was to provide a large multinational registry of the full spectrum of patients with acute coronary syndromes (ACS) in order to define patient characteristics and outcomes and derive predictive risk scores. The study was designed and administered by an independent steering committee; data analyses were performed under the guidance of the steering committee at the Center for Outcomes Research of the University of Massachusetts. Regular feedback regarding local, regional and international guideline and performance measures was provided to individual hospitals and clusters of hospitals. Regional and international benchmark data were available to all sites. Main GRACE involved 123 hospitals in 14 countries in North and South America, Europe, Australia and New Zealand. GRACE2 (Expanded GRACE) comprised 154 hospitals in Europe, North and South America, Asia, Australasia and China. Continuous recruitment and follow-up took place between 1999 and 2009. The first 10 -20 patients per site (depending on hospital size) were enrolled each month, resulting in the recruitment of 102 341 patients, who were categorized as having ST-segment elevation myocardial infarction, non-ST-elevation myocardial infarction or unstable angina. Standardized case report forms (datafax or electronic) were completed by trained study coordinators, and included fields relating to demographic factors, comorbid conditions, treatments and in-hospital and post-discharge (6-month) events. Blood sampling, genetic analyses and longer-term follow-up were undertaken in GRACE substudies. Prospective individual patient follow-up was carried out. All sites were audited locally; 10% of individual patient records were audited in a 2-year cycle. Less than 1% of 20 key baseline fields, and less than 1% of discharge diagnosis and discharge status data, were missing. Six-month follow-up was 85% complete. Publications and risk scores are available at http://www.outcome.org/grace. Proposals for specific analyses were considered, in competition, by an independent publications committee.

Effect of the small molecule plasminogen activator inhibitor-1 (PAI-1) inhibitor, PAI-749, in clinical models of fibrinolysis.

BACKGROUND: The principal inhibitor of fibrinolysis in vivo is plasminogen activator inhibitor-1 (PAI-1). PAI-749 is a small molecule inhibitor of PAI-1 with proven antithrombotic efficacy in several preclinical models. OBJECTIVE: To assess the effect of PAI-749, by using an established ex vivo clinical model of thrombosis and a range of complementary in vitro human plasma-based and whole blood-based models of fibrinolysis. METHODS: In a double-blind, randomized, crossover study, ex vivo thrombus formation was assessed using the Badimon chamber in 12 healthy volunteers during extracorporeal administration of tissue-type plasminogen activator (t-PA) in the presence of PAI-749 or control. t-PA-mediated lysis of plasma clots and of whole blood model thrombi were assessed in vitro. The role of vitronectin was examined by assessing lysis of fibrin clots generated from purified plasma proteins. RESULTS: There was a dose-dependent reduction in ex vivo thrombus formation by t-PA (P < 0.0001). PAI-749 had no effect on in vitro or ex vivo thrombus formation or fibrinolysis in the presence or absence of t-PA. Inhibition of PAI-1 with a blocking antibody enhanced fibrinolysis in vitro (P < 0.05). CONCLUSIONS: Despite its efficacy in a purified human system and in preclinical models of thrombosis, the current study suggests that PAI-749 does not affect thrombus formation or fibrinolysis in a range of established human plasma and whole blood-based systems.

Comparison of the anticoagulant intensities of fondaparinux and enoxaparin in the Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS)-5 trial.

BACKGROUND: In the OASIS-5 trial, fondaparinux reduced major bleeding with similar short-term efficacy as enoxaparin but lowered death and stroke during long-term follow-up. The mechanism of lower bleeding and improved efficacy with fondaparinux is uncertain. METHODS AND RESULTS: We compared the anti-Xa concentration (reflecting drug levels), Xa clot time (reflecting anticoagulant effect) and endogenous thrombin potential (ETP; a global test of hemostatic function) in plasma samples collected 6, 24 and 72 h after the first dose of the study drug in 48 patients randomly assigned fondaparinux 2.5 mg day(-1) and 42 patients assigned enoxaparin 1 mg kg(-1) twice daily in the OASIS-5 trial. Patients assigned to fondaparinux compared with enoxaparin had a significantly lower mean anti-Xa level [0.52 IU mL(-1) (SD 0.22 IU mL(-1)) vs. 1.2 IU mL(-1) (SD 0.45 IU mL(-1)), P<0.0001] and Xa clot time [64.9 s (SD 17.7 s) vs. 111.8 s (SD 29.6 s), P<0.0001], and significantly higher ETP area under the curve (AUC) [386.7 mA (SD 51.5 mA) vs. 206.4 mA (SD 90.6 mA), P<0.001] at 6 h, and these differences remained evident at 24 and 72 h. There was significantly less variability of the results of anti-Xa levels, Xa clot time and ETP AUC for fondaparinux compared with enoxaparin at 6 h (P<0.001 for each comparison). CONCLUSION: Fondaparinux 2.5 mg day(-1) compared with enoxaparin 1 mg kg(-1) twice daily produces less variable anticoagulant effect and lower mean anticoagulant intensity. These results most likely explain the reduced risk of bleeding seen with fondaparinux compared with enoxaparin in the OASIS-5 trial and suggest that a lower intensity of anticoagulation than used in the past may be sufficient to prevent recurrent ischemic events and death in patients with ACS who are concurrently treated with aspirin and clopidogrel.