Acute coronary syndromes in young patients: Presentation, treatment and outcome

Background: Acute coronary syndromes (ACS) in very young patients have been poorly described. We therefore evaluate ACS in patients aged 35 years and younger. Methods: In this prospective cohort study, 76 hospitals treating ACS in Switzerland enrolled 28,778 patients with ACS between January 1, 1997, and October 1, 2008. ACS definition included ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina (UA). Results: 195 patients (0.7%) were 35 years old or younger. Compared to patients N35 years, these patients were more likely to present with chest pain (91.6% vs. 83.7%; P=0.003) and less likely to have heart failure (Killip class II to IV in 5.2% vs. 23.0%; Pb0.001). STEMI was more prevalent in younger than in older patients (73.1% vs. 58.3%; Pb0.001). Smoking, family history of CAD, and/or dyslipidemia were important cardiovascular risk factors in young patients (prevalence 77.2%, 55.0%, and 44.0%). The prevalence of overweight among young patients with ACS was high (57.8%). Cocaine abuse was associated with ACS in some young patients. Compared to older patients, young patients were more likely to receive early percutaneous coronary interventions and had better outcome with fewer major adverse cardiac events. Conclusions: Young patients with ACS differed from older patients in that the younger often presented with STEMI, received early aggressive treatment, and had favourable outcomes. Primary prevention of smoking, dyslipidemia and overweight should be more aggressively promoted in adolescence.

Optimizing the success of cell transplantation therapy for stroke

Stem cell transplantation has evolved as a promising experimental treatment approach for stroke. In this review, we address the major hurdles for successful translation from basic research into clinical applications and discuss possible strategies to overcome these issues. We summarize the results from present pre-clinical and clinical studies and focus on specific areas of current controversy and research: (i) the therapeutic time window for cell transplantation; (ii) the selection of patients likely to benefit from such a therapy; (iii) the optimal route of cell delivery to the ischemic brain; (iv) the most suitable cell types and sources; (v) the potential mechanisms of functional recovery after cell transplantation; and (vi) the development of imaging techniques to monitor cell therapy.

Periosteal Distraction Osteogenesis and Barrier Membrane Application: An Experimental Study in the Rat Calvaria

Background: Distraction of the periosteum results in the formation of new bone in the gap between the periosteum and the original bone. We postulate that the use of a barrier membrane would be beneficial for new bone formation in periosteal distraction. Methods: To selectively influence the contribution of the periosteum, a distraction plate with perforations was used alone or covered by a collagen barrier membrane. All animals were subjected to a 7-day latency period and a 10-day distraction period with a rate of 0.1 mm/day. Four animals per group with or without a barrier membrane were sacrificed at 2, 4, and 6 weeks after the end of the distraction. The height of new bone generated relative to the areas bound by the parent bone and the periosteum was determined by histomorphometric methods. Results: New bone was found in all groups. At the periphery of the distraction plate, significant differences in bone height were found between the hinge and the distraction screw for the group without barrier membrane at 2 weeks (0.39 ± 0.19 mm) compared to 4 weeks (0.84 ± 0.44 mm; P = 0.002) and 6 weeks (1.06 ± 0.39 mm; P = 0.004). Differences in maximum bone height with and without a barrier membrane were observed laterally to the distraction plate at 2 weeks (1.22 ± 0.64 versus 0.55 ± 0.14 mm; P = 0.019) and 6 weeks (1.61 ± 0.56 versus 0.73 ± 0.33 mm; P = 0.003) of the consolidation period. Conclusion: Within the limitations of the present study, the application of a barrier membrane may be considered beneficial for new bone formation induced by periosteal distraction.

Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study

The aim of this study was to describe the clinical and PSG characteristics of narcolepsy with cataplexy and their genetic predisposition by using the retrospective patient database of the European Narcolepsy Network (EU-NN). We have analysed retrospective data of 1099 patients with narcolepsy diagnosed according to International Classification of Sleep Disorders-2. Demographic and clinical characteristics, polysomnography and multiple sleep latency test data, hypocretin-1 levels, and genome-wide genotypes were available. We found a significantly lower age at sleepiness onset (men versus women: 23.74 ± 12.43 versus 21.49 ± 11.83, P = 0.003) and longer diagnostic delay in women (men versus women: 13.82 ± 13.79 versus 15.62 ± 14.94, P = 0.044). The mean diagnostic delay was 14.63 ± 14.31 years, and longer delay was associated with higher body mass index. The best predictors of short diagnostic delay were young age at diagnosis, cataplexy as the first symptom and higher frequency of cataplexy attacks. The mean multiple sleep latency negatively correlated with Epworth Sleepiness Scale (ESS) and with the number of sleep-onset rapid eye movement periods (SOREMPs), but none of the polysomnographic variables was associated with subjective or objective measures of sleepiness. Variant rs2859998 in UBXN2B gene showed a strong association (P = 1.28E-07) with the age at onset of excessive daytime sleepiness, and rs12425451 near the transcription factor TEAD4 (P = 1.97E-07) with the age at onset of cataplexy. Altogether, our results indicate that the diagnostic delay remains extremely long, age and gender substantially affect symptoms, and that a genetic predisposition affects the age at onset of symptoms.

Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis

BACKGROUND: Clinical outcomes of chronic hepatitis C infection in patients with advanced fibrosis include liver failure, hepatocellular carcinoma, and death. OBJECTIVE: To investigate whether sustained virologic response to treatment for hepatitis C is associated with improved clinical outcomes. DESIGN: Retrospective cohort study. SETTING: 5 hepatology units of tertiary care centers in Europe and Canada caring for patients with chronic hepatitis C treated between 1990 and 2003. PATIENTS: Consecutively treated patients with chronic hepatitis C who had biopsy-proven advanced fibrosis or cirrhosis (Ishak score, 4 to 6). MEASUREMENTS: Sustained virologic response, defined as absence of detectable hepatitis C virus RNA at 24 weeks after the end of treatment, and clinical outcomes, defined as death (liver-related or non-liver-related), liver failure, and hepatocellular carcinoma. RESULTS: Of 479 patients, 29.6% had sustained virologic response and 70.3% did not. Median follow-up was 2.1 years (interquartile range, 0.8 to 4.9 years). Four patients with and 83 without sustained virologic response had at least 1 outcome event. Sustained virologic response was associated with a statistically significant reduction in the hazard of events (adjusted hazard ratio, 0.21 [95% CI, 0.07 to 0.58]; P = 0.003). The effect was largely attributable to a reduction in liver failure, which developed in no patients with and 42 patients without sustained virologic response (5-year occurrence, 0% vs. 13.3% [CI, 8.4% to 18.2%]; unadjusted hazard ratio, 0.03 [CI, 0.00 to 0.91]). LIMITATIONS: Because few events occurred in the sustained virologic response group, the study had limited ability to detect differences between groups in individual outcomes. In addition, the study was retrospective; selection and survival biases may therefore influence estimates of effect. CONCLUSION: Sustained virologic response to treatment is associated with improved clinical outcomes, mainly prevention of liver failure, in patients with chronic hepatitis C and advanced fibrosis.

Comparison of intraarterial and intravenous thrombolysis for ischemic stroke with hyperdense middle cerebral artery sign

BACKGROUND AND PURPOSE: It is unclear whether intraarterial (IAT) or intravenous (IVT) thrombolysis is more effective for ischemic stroke with hyperdense middle cerebral artery sign (HMCAS) on computed tomography (CT). The aim of this study was to compare IAT and IVT in stroke patients with HMCAS. METHODS: Comparison of data from 2 stroke units with similar management of stroke associated with HMCAS, except that 1 unit performed IAT with urokinase and the other IVT with plasminogen activator. Time to treatment was up to 6 hours for IAT and up to 3 hours for IVT. Outcome was measured by mortality and the modified Rankin Scale (mRS), dichotomized at 3 months into favorable (mRS 0 to 2) and unfavorable (mRS 3 to 6). RESULTS: One hundred twelve patients exhibited a HMCAS, 55 of 268 patients treated with IAT and 57 of 249 patients who underwent IVT. Stroke severity at baseline and patient age were similar in both groups. Mean time to treatment was longer in the IAT group (244+/-63 minutes) than in the IVT group (156+/-21 minutes; P=0.0001). However, favorable outcome was more frequent after IAT (n=29, 53%) than after IVT (n=13, 23%; P=0.001), and mortality was lower after IAT (n=4, 7%) than after IVT (n=13, 23%; P=0.022). After multiple regression analysis IAT was associated with a more favorable outcome than IVT (P=0.003) but similar mortality (P=0.192). CONCLUSIONS: In this observational study intraarterial thrombolysis was more beneficial than IVT in the specific group of stroke patients presenting with HMCAS on CT, even though IAT was started later. Our results indicate that a randomized trial comparing both thrombolytic treatments in patients with middle cerebral artery occlusion is warranted.

Improved safety and reduction in stent thrombosis associated with biodegradable polymer-based biolimus-eluting stents versus durable polymer-based sirolimus-eluting stents in patients with coronary artery disease: final 5-year report of the LEADERS (Limus Eluted From A Durable Versus ERodable Stent Coating) randomized, noninferiority trial

OBJECTIVES This study sought to report the final 5 years follow-up of the landmark LEADERS (Limus Eluted From A Durable Versus ERodable Stent Coating) trial. BACKGROUND The LEADERS trial is the first randomized study to evaluate biodegradable polymer-based drug-eluting stents (DES) against durable polymer DES. METHODS The LEADERS trial was a 10-center, assessor-blind, noninferiority, "all-comers" trial (N = 1,707). All patients were centrally randomized to treatment with either biodegradable polymer biolimus-eluting stents (BES) (n = 857) or durable polymer sirolimus-eluting stents (SES) (n = 850). The primary endpoint was a composite of cardiac death, myocardial infarction (MI), or clinically indicated target vessel revascularization within 9 months. Secondary endpoints included extending the primary endpoint to 5 years and stent thrombosis (ST) (Academic Research Consortium definition). Analysis was by intention to treat. RESULTS At 5 years, the BES was noninferior to SES for the primary endpoint (186 [22.3%] vs. 216 [26.1%], rate ratio [RR]: 0.83 [95% confidence interval (CI): 0.68 to 1.02], p for noninferiority <0.0001, p for superiority = 0.069). The BES was associated with a significant reduction in the more comprehensive patient-orientated composite endpoint of all-cause death, any MI, and all-cause revascularization (297 [35.1%] vs. 339 [40.4%], RR: 0.84 [95% CI: 0.71 to 0.98], p for superiority = 0.023). A significant reduction in very late definite ST from 1 to 5 years was evident with the BES (n = 5 [0.7%] vs. n = 19 [2.5%], RR: 0.26 [95% CI: 0.10 to 0.68], p = 0.003), corresponding to a significant reduction in ST-associated clinical events (primary endpoint) over the same time period (n = 3 of 749 vs. n = 14 of 738, RR: 0.20 [95% CI: 0.06 to 0.71], p = 0.005). CONCLUSIONS The safety benefit of the biodegradable polymer BES, compared with the durable polymer SES, was related to a significant reduction in very late ST (>1 year) and associated composite clinical outcomes. (Limus Eluted From A Durable Versus ERodable Stent Coating [LEADERS] trial; NCT00389220).

Relaxation in hypertrophic cardiomyopathy and hypertensive heart disease: relations between hypertrophy and diastolic function

AIM To determine the relation between the extent and distribution of left ventricular hypertrophy and the degree of disturbance of regional relaxation and global left ventricular filling. METHODS Regional wall thickness (rWT) was measured in eight myocardial regions in 17 patients with hypertrophic cardiomyopathy, 12 patients with hypertensive heart disease, and 10 age matched normal subjects, and an asymmetry index calculated. Regional relaxation was assessed in these eight regions using regional isovolumetric relaxation time (rIVRT) and early to late peak filling velocity ratio (rE/A) derived from Doppler tissue imaging. Asynchrony of rIVRT was calculated. Doppler left ventricular filling indices were assessed using the isovolumetric relaxation time, the deceleration time of early diastolic filling (E-DT), and the E/A ratio. RESULTS There was a correlation between rWT and both rIVRT and rE/A in the two types of heart disease (hypertrophic cardiomyopathy: r = 0.47, p < 0.0001 for rIVRT; r = -0.20, p < 0.05 for rE/A; hypertensive heart disease: r = 0.21, p < 0.05 for rIVRT; r = -0.30, p = 0.003 for rE/A). The degree of left ventricular asymmetry was related to prolonged E-DT (r = 0. 50, p = 0.001) and increased asynchrony (r = 0.42, p = 0.002) in all patients combined, but not within individual groups. Asynchrony itself was associated with decreased E/A (r = -0.39, p = 0.01) and protracted E-DT (r = 0.69, p < 0.0001) and isovolumetric relaxation time (r = 0.51, p = 0.001) in all patients. These correlations were still significant for E-DT in hypertrophic cardiomyopathy (r = 0.56, p = 0.02) and hypertensive heart disease (r = 0.59, p < 0.05) and for isovolumetric relaxation time in non-obstructive hypertrophic cardiomyopathy (n = 8, r = 0.87, p = 0.005). CONCLUSIONS Non-invasive ultrasonographic examination of the left ventricle shows that in both hypertrophic cardiomyopathy and hypertensive heart disease, the local extent of left ventricular hypertrophy is associated with regional left ventricular relaxation abnormalities. Asymmetrical distribution of left ventricular hypertrophy is indirectly related to global left ventricular early filling abnormalities through regional asynchrony of left ventricular relaxation.

Impact of changes in haematocrit level and platelet count on thromboelastometry parameters

INTRODUCTION To what extent haematocrit levels (Hct) and platelet counts (PLT) influence the measurement of parameters of thromboelastometry when assessed with the ROTEM® device is unclear. We investigated to what extent thromboelastometry measurements depend on Hct and PLT. MATERIALS AND METHODS Whole blood samples were taken for in-vitro preparations of mixtures with three different levels of PLT and a varying Hct. Maximum clot firmness (MCF), clotting time (CT), clot formation time (CFT) and alpha angle (α) for INTEM, EXTEM, FIBTEM and APTEM was recorded. RESULTS Measurements depended substantially on Hct and PLT. MCF readings were systematically lower with increasing Hct (0.2 vs. 0.4: -7.8 (-8.3 to -7.2); p<0.001, 0.2 vs. 0.55: -14.5 (-17.3 to -14.3); p<0.001) but higher with increasing PLT (50 vs. 125×10(9)/l: 8.2 (4.2 to 12.3); p=0.005, 50 vs. 250×10(9)/l: 12.0 (7.2 to 16.8); p=0.002). CT readings were systematically higher with increasing Hct (0.2 vs. 0.4: 9.2 (6.2 to 12.1); p=0.001, 0.2 vs. 0.55: 38.2 (21.5 to 54.9); p=0.003) while increasing PLT had no influence. CFT readings were also systematically higher with increasing Hct (0.2 vs. 0.4: 83.8 (40.2 to 127.6); p=0.006, 0.2 vs. 0.55: 226.2 (110.7 to 341.7); p=0.006) but systematically lower with increasing PLT (50 vs. 125×10(9)/l: -144.0 (-272.3 to -15.6); p=0.036, 50 vs. 250×10(9)/l: -189.2 (-330.4 to -48.0); p=0.02); readings of the alpha angle showed a similar pattern. CONCLUSIONS Our results suggest that readings of thromboelastometry parameters need to be adjusted by Hct and PLT to avoid potential confounding and miss-interpretations in clinical practice.

Radiometrical, hormonal and biological correlates of skeletal growth in the female rat from birth to senescence

OBJECTIVE We investigated the skeletal growth profile of female rats from birth to senescence (100weeks) on the basis of sequential radiometrical, hormonal and biochemical parameters. DESIGN Weaning rats entered the study which was divided into two sections: a) sequential measurements of vertebral and tibial growths and bone mineral density (BMD), estimation of mineral content of the entire skeleton (BMC) and chemical analysis of vertebral Ca; and b) determination of basal and pulsatile growth hormone (rGH), insulin-like growth hormone (IGF-I), estradiol (E2), parathyroid hormone (PTH), osteocalcin (OC) and urinary d-pyridinoline (dp) throughout the experimental period. RESULTS Vertebral and tibial growths ceased at week 25 whereas BMD and BMC as well as total vertebral Ca exhibited a peak bone mass at week 40. rGH pulsatile profiles were significantly higher in younger animals coinciding with the period of active growth and IGF-I peaked at 7weeks, slowly declining thereafter and stabilizing after week 60. OC and dp closely paralleled IGF-I coinciding with the period of enhanced skeletal growth, remaining thereafter in the low range indicative of reduced bone turnover. E2 increased during reproductive life but the lower values subsequently recorded were still in the physiological range, strongly suggesting a protective role of this steroid on bone remodeling. PTH followed a similar profile to E2, but the significance of this after completion of growth remains unclear. CONCLUSIONS Mechanisms governing skeletal growth in the female rat appear similar to those in humans. Bone progression and attainment of peak bone mass are under simultaneous control of rGH, IGF-I and calciotropic hormones and are modulated by E2. This steroid seems to protect the skeleton from resorption before senescence whereas the role of PTH in this context remains uncertain.

Treatment modalities for T1N0 esophageal cancers: a comparative analysis of local therapy versus surgical resection

BACKGROUND To investigate the role of nonsurgical treatment for early-stage esophageal cancer, we compared the outcomes of local therapy to esophagectomy, using a large, national database. METHODS Five-year cancer-specific and overall survival (OS) of patients, with T1N0M0 squamous cell or adenocarcinoma of the mid or distal esophagus treated with either surgery or local therapy, with ablative and/or excision techniques, in the Surveillance Epidemiology and End Results cancer registry from 1998 to 2008, were compared using the Kaplan-Meier approach, and multivariable and propensity-score adjusted Cox proportional hazard, and competing risk models. RESULTS Of 1458 patients with T1N0 esophageal cancer, 1204 (83%) had surgery and 254 (17%) had local therapy only. The use of local therapy increased significantly from 8.1% in 1998 to 24.1% in 2008 (p < 0.001). The 5-year OS after local excisional therapy and surgery was not significantly different (55.5% versus 64.1% respectively, p = 0.07), and 5-year cancer-specific survival (CSS) also did not differ (81.7% versus 75.8%, p = 0.10). However, after propensity-score adjustment, CSS was better for patients who underwent local therapy compared with those who underwent surgery (hazard ratio: 0.46, 95% confidence interval: 0.27-0.77, p = 0.003), whereas OS remained similar. CONCLUSION The use of local therapy for T1N0 esophageal cancers increased significantly from 1998 to 2008. Compared with those treated with esophagectomy, patients treated with local therapy had similar OS but improved CSS, indicating a higher chance of dying from other causes. Further studies are needed to confirm the oncologic efficacy of local therapy when used in patients whose lifespans are not limited by conditions other than esophageal cancer.

Proactive motivation and engagement in career behaviors: Investigating direct, mediated, and moderated effects

Proactive career behaviors become increasingly important in today's career environment, but little is known about how and when motivational patterns affect individual differences. In a six-month longitudinal study among German university students (Study 1; N = 289) it was demonstrated that motivation in terms of “can do” (self-efficacy and context beliefs), “reason to” (autonomous career goals), and “energized to” (positive affect) significantly predicted career behaviors. Contrary to expectation, negative context beliefs had a positive effect when combined with other motivational states. Study 2 replicated and extended those results by investigating whether “can do” motivation mediates the effect of proactive personality and whether those effects are conditional upon the degree of career choice decidedness. We tested a moderated multiple mediation model with a unique sample of 134 German students, assessed three times, each interval being 6 weeks apart. The results showed that effects of proactivity were partially carried through higher self-efficacy beliefs but not context beliefs. Supporting a moderation model, indirect effects through self-efficacy beliefs were not present for students with very low decidedness.

Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis.

BACKGROUND Observational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC. METHODS AND FINDINGS Eligible studies measured HC exposure and incident HIV infection prospectively using standardized measures, enrolled women aged 15-49 y, recorded ≥15 incident HIV infections, and measured prespecified covariates. Our primary analysis estimated the adjusted hazard ratio (aHR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. We included 18 studies, including 37,124 women (43,613 woman-years) and 1,830 incident HIV infections. Relative to no HC use, the aHR for HIV acquisition was 1.50 (95% CI 1.24-1.83) for DMPA use, 1.24 (95% CI 0.84-1.82) for NET-EN use, and 1.03 (95% CI 0.88-1.20) for COC use. Between-study heterogeneity was mild (I2 < 50%). DMPA use was associated with increased HIV acquisition compared with COC use (aHR 1.43, 95% CI 1.23-1.67) and NET-EN use (aHR 1.32, 95% CI 1.08-1.61). Effect estimates were attenuated for studies at lower risk of methodological bias (compared with no HC use, aHR for DMPA use 1.22, 95% CI 0.99-1.50; for NET-EN use 0.67, 95% CI 0.47-0.96; and for COC use 0.91, 95% CI 0.73-1.41) compared to those at higher risk of bias (pinteraction = 0.003). Neither age nor herpes simplex virus type 2 infection status modified the HC-HIV relationship. CONCLUSIONS This IPD meta-analysis found no evidence that COC or NET-EN use increases women's risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.