Dosimetric comparison of different treatment modalities for stereotactic radiosurgery of arteriovenous malformations and acoustic neuromas.

PURPOSE: We investigated the influence of beam modulation on treatment planning by comparing four available stereotactic radiosurgery (SRS) modalities: Gamma-Knife-Perfexion, Novalis-Tx Dynamic-Conformal-Arc (DCA) and Dynamic-Multileaf-Collimation-Intensity-Modulated-radiotherapy (DMLC-IMRT), and Cyberknife. MATERIAL AND METHODS: Patients with arteriovenous malformation (n = 10) or acoustic neuromas (n = 5) were planned with different treatment modalities. Paddick conformity index (CI), dose heterogeneity (DH), gradient index (GI) and beam-on time were used as dosimetric indices. RESULTS: Gamma-Knife-Perfexion can achieve high degree of conformity (CI = 0.77 ± 0.04) with limited low-doses (GI = 2.59 ± 0.10) surrounding the inhomogeneous dose distribution (D(H) = 0.84 ± 0.05) at the cost of treatment time (68.1 min ± 27.5). Novalis-Tx-DCA improved this inhomogeneity (D(H) = 0.30 ± 0.03) and treatment time (16.8 min ± 2.2) at the cost of conformity (CI = 0.66 ± 0.04) and Novalis-TX-DMLC-IMRT improved the DCA CI (CI = 0.68 ± 0.04) and inhomogeneity (D(H) = 0.18 ± 0.05) at the cost of low-doses (GI = 3.94 ± 0.92) and treatment time (21.7 min ± 3.4) (p<0.01). Cyberknife achieved comparable conformity (CI = 0.77 ± 0.06) at the cost of low-doses (GI = 3.48 ± 0.47) surrounding the homogeneous (D(H) = 0.22 ± 0.02) dose distribution and treatment time (28.4min±8.1) (p<0.01). CONCLUSIONS: Gamma-Knife-Perfexion will comply with all SRS constraints (high conformity while minimizing low-dose spread). Multiple focal entries (Gamma-Knife-Perfexion and Cyberknife) will achieve better conformity than High-Definition-MLC of Novalis-Tx at the cost of treatment time. Non-isocentric beams (Cyberknife) or IMRT-beams (Novalis-Tx-DMLC-IMRT) will spread more low-dose than multiple isocenters (Gamma-Knife-Perfexion) or dynamic arcs (Novalis-Tx-DCA). Inverse planning and modulated fluences (Novalis-Tx-DMLC-IMRT and CyberKnife) will deliver the most homogeneous treatment. Furthermore, Linac-based systems (Novalis and Cyberknife) can perform image verification at the time of treatment delivery.

Ultrathin strut biodegradable polymer sirolimus-eluting stent versus durable polymer everolimus-eluting stent for percutaneous coronary revascularisation (BIOSCIENCE): a randomised, single-blind, non-inferiority trial.

BACKGROUND: Refinements in stent design affecting strut thickness, surface polymer, and drug release have improved clinical outcomes of drug-eluting stents. We aimed to compare the safety and efficacy of a novel, ultrathin strut cobalt-chromium stent releasing sirolimus from a biodegradable polymer with a thin strut durable polymer everolimus-eluting stent. METHODS: We did a randomised, single-blind, non-inferiority trial with minimum exclusion criteria at nine hospitals in Switzerland. We randomly assigned (1:1) patients aged 18 years or older with chronic stable coronary artery disease or acute coronary syndromes undergoing percutaneous coronary intervention to treatment with biodegradable polymer sirolimus-eluting stents or durable polymer everolimus-eluting stents. Randomisation was via a central web-based system and stratified by centre and presence of ST segment elevation myocardial infarction. Patients and outcome assessors were masked to treatment allocation, but treating physicians were not. The primary endpoint, target lesion failure, was a composite of cardiac death, target vessel myocardial infarction, and clinically-indicated target lesion revascularisation at 12 months. A margin of 3·5% was defined for non-inferiority of the biodegradable polymer sirolimus-eluting stent compared with the durable polymer everolimus-eluting stent. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01443104. FINDINGS: Between Feb 24, 2012, and May 22, 2013, we randomly assigned 2119 patients with 3139 lesions to treatment with sirolimus-eluting stents (1063 patients, 1594 lesions) or everolimus-eluting stents (1056 patients, 1545 lesions). 407 (19%) patients presented with ST-segment elevation myocardial infarction. Target lesion failure with biodegradable polymer sirolimus-eluting stents (69 cases; 6·5%) was non-inferior to durable polymer everolimus-eluting stents (70 cases; 6·6%) at 12 months (absolute risk difference -0·14%, upper limit of one-sided 95% CI 1·97%, p for non-inferiority <0·0004). No significant differences were noted in rates of definite stent thrombosis (9 [0·9%] vs 4 [0·4%], rate ratio [RR] 2·26, 95% CI 0·70-7·33, p=0·16). In pre-specified stratified analyses of the primary endpoint, biodegradable polymer sirolimus-eluting stents were associated with improved outcome compared with durable polymer everolimus-eluting stents in the subgroup of patients with ST-segment elevation myocardial infarction (7 [3·3%] vs 17 [8·7%], RR 0·38, 95% CI 0·16-0·91, p=0·024, p for interaction=0·014). INTERPRETATION: In a patient population with minimum exclusion criteria and high adherence to dual antiplatelet therapy, biodegradable polymer sirolimus-eluting stents were non-inferior to durable polymer everolimus-eluting stents for the combined safety and efficacy outcome target lesion failure at 12 months. The noted benefit in the subgroup of patients with ST-segment elevation myocardial infarction needs further study. FUNDING: Clinical Trials Unit, University of Bern, and Biotronik, Bülach, Switzerland.

Plasma lipoprotein-associated phospholipase A2 activity in Alzheimer's disease, amnestic mild cognitive impairment, and cognitively healthy elderly subjects: a cross-sectional study.

ABSTRACT: INTRODUCTION: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a circulating enzyme with pro-inflammatory and oxidative activities associated with cardiovascular disease and ischemic stroke. While high plasma Lp-PLA2 activity was reported as a risk factor for dementia in the Rotterdam study, no association between Lp-PLA2 mass and dementia or Alzheimer's disease (AD) was detected in the Framingham study. The objectives of the current study were to explore the relationship of plasma Lp-PLA2 activity with cognitive diagnoses (AD, amnestic mild cognitive impairment (aMCI), and cognitively healthy subjects), cardiovascular markers, cerebrospinal fluid (CSF) markers of AD, and apolipoprotein E (APOE) genotype. METHODS: Subjects with mild AD (n = 78) and aMCI (n = 59) were recruited from the Memory Clinic, University Hospital, Basel, Switzerland; cognitively healthy subjects (n = 66) were recruited from the community. Subjects underwent standardised medical, neurological, neuropsychological, imaging, genetic, blood and CSF evaluation. Differences in Lp-PLA2 activity between the cognitive diagnosis groups were tested with ANOVA and in multiple linear regression models with adjustment for covariates. Associations between Lp-PLA2 and markers of cardiovascular disease and AD were explored with Spearman's correlation coefficients. RESULTS: There was no significant difference in plasma Lp-PLA2 activity between AD (197.1 (standard deviation, SD 38.4) nmol/min/ml) and controls (195.4 (SD 41.9)). Gender, statin use and low-density lipoprotein cholesterol (LDL) were independently associated with Lp-PLA2 activity in multiple regression models. Lp-PLA2 activity was correlated with LDL and inversely correlated with high-density lipoprotein (HDL). AD subjects with APOE-ε4 had higher Lp-PLA2 activity (207.9 (SD 41.2)) than AD subjects lacking APOE-ε4 (181.6 (SD 26.0), P = 0.003) although this was attenuated by adjustment for LDL (P = 0.09). No strong correlations were detected for Lp-PLA2 activity and CSF markers of AD. CONCLUSION: Plasma Lp-PLA2 was not associated with a diagnosis of AD or aMCI in this cross-sectional study. The main clinical correlates of Lp-PLA2 activity in AD, aMCI and cognitively healthy subjects were variables associated with lipid metabolism.

To what extent does adding tobacco to cannabis expose young users to nicotine?

INTRODUCTION: To determine if mulling, the process of adding tobacco to cannabis for its consumption, exposes young cannabis users to significant levels of nicotine. METHODS: This observational study performed in 2009-2010 among Swiss youths aged 16-25 years involved the completion of a self-administrated questionnaire and the collection of a urine sample on the same day. Measures of urinary cotinine were blindly performed using liquid chromatography coupled-mass spectrometry. A total of 197 eligible participants were divided in 3 groups based on their consumption profile in the past 5 days: 70 abstainers (ABS) not having used cigarettes or cannabis, 57 cannabis users adding tobacco to the cannabis they smoke (MUL) but not having smoked cigarettes, and 70 cigarette smokers (CIG) not having smoked cannabis. RESULTS: Exposure to nicotine was at its lowest among ABS with a mean (SE) cotinine level of 3.2 (1.4) ng/ml compared, respectively, with 214.6 (43.8) and 397.9 (57.4) for MUL and CIG (p < .001). While consumption profile appeared as the only significant factor of influence when examining nicotine exposure from the ABS and MUL participants on multivariate analysis, it did not result in substantial differences among MUL and CIG groups. CONCLUSIONS: Urinary cotinine levels found among MUL are high enough to indicate a significant exposure to nicotine originating from the mulling process. In line with our results, health professionals should pay attention to mulling as it is likely to influence cannabis and cigarette use as well as the efficacy of cessation interventions.

Use of nanoparticles in Swiss industry: a targeted survey

A large number of applications using manufactured nanoparticles of less than 100 nm are currently being introduced into industrial processes. There is an urgent need to evaluate the risks of these novel particles to ensure their safe production, handling, use, and disposal. However, today we lack even rudimentary knowledge about type and quantity of industrially used manufactured nanoparticles and the level of exposure in Swiss industry. The goal of this study was to evaluate the use of nanoparticles, the currently implemented safety measures, and the number of potentially exposed workers in all types of industry. To evaluate this, a targeted telephone survey was conducted among health and safety representatives from 197 Swiss companies. The survey showed that nanoparticles are already used in many industrial sectors; not only in companies in the new field of nanotechnology, but also in more traditional sectors, such as paints. Forty-three companies declared to use or produce nanoparticles, and 11 imported and traded with prepackaged goods that contain nanoparticles. The following nanoparticles were found to be used in considerable quantities (> 1000 kg/year per company): Ag, Al-Ox, Fe-Ox, SiO2, TiO2, and ZnO. The median reported quantity of handled nanoparticles was 100 kg/year. The production of cosmetics, food, paints, powders, and the treatment of surfaces used the largest quantities of these nanoparticles. Generally, the safety measures were found to be higher in powder-based than in liquid-based applications. However, the respondents had many open questions about best practices, which points to the need for rapid development of guidelines and protection strategies

Immediate and delayed effects of subchronic Paraquat exposure during an early differentiation stage in 3D-rat brain cell cultures.

Xenobiotic exposure is a risk factor in the etiology of neurodegenerative disease. It was recently hypothesized that restricted exposure during brain development could predispose for a neurodegenerative disease later in life. As neuroinflammation contributes to progressive neurodegeneration, it is suspected that neurodevelopmental xenobiotic exposure could elicit a neuroinflammatory process, which over time may assume a detrimental character. We investigated the neurotoxic effects of paraquat (PQ) in three-dimensional whole rat brain cell cultures, exposed during an early differentiation stage, comparing immediate effects-directly post exposure-with long-term effects, 20 days after interrupted PQ-administration. Adverse effects and neuroinflammatory responses were assessed by measuring changes in gene- and protein-expression as well as by determining cell morphology changes. Differentiating neural cultures were highly susceptible to PQ and showed neuronal damage and strong astrogliosis. After the 20-day washout period, neurons partially recovered, whereas astrogliosis persisted, and was accompanied by microglial activation of a neurodegenerative phenotype. Our data shows that immediate and long-term effects of subchronic PQ-exposure differ. Also, PQ-exposure during this window of extensive neuronal differentiation led to a delayed microglial activation, of a character that could promote further pro-inflammatory signals that enable prolonged inflammation, thereby fueling further neurodegeneration.

SNP2GO: functional analysis of genome-wide association studies.

Genome-wide association studies (GWAS) are designed to identify the portion of single-nucleotide polymorphisms (SNPs) in genome sequences associated with a complex trait. Strategies based on the gene list enrichment concept are currently applied for the functional analysis of GWAS, according to which a significant overrepresentation of candidate genes associated with a biological pathway is used as a proxy to infer overrepresentation of candidate SNPs in the pathway. Here we show that such inference is not always valid and introduce the program SNP2GO, which implements a new method to properly test for the overrepresentation of candidate SNPs in biological pathways.

Relationship between coronary endothelial function and coronary calcification in early atherosclerosis.

BACKGROUND: The relationship between coronary endothelial function and coronary calcification is not well established. METHODS: Forty-six patients 17 men [37%]; age, 47.4+/-11.4 years prospectively underwent testing for coronary endothelial function and measurement of coronary artery calcification (CAC). RESULTS: Log CAC scores were not significantly different between patients with normal (n=31) and abnormal (n=15) response of epicardial coronary artery diameter to acetylcholine (%CAD(Ach)) (median (25, 75 percentile) 1.1 (0.0, 3.7) vs. 0.3 (0.0, 2.4), P=.32) and with normal (n=28) and abnormal (n=18) response of coronary blood flow to acetylcholine (%CBF(Ach)) (0.5 (0.0, 3.6) vs. 0.5 (0.0, 3.2), P=.76). Log CAC scores did not correlate with %CAD(Ach) (r=0.08, P=.59), %CBF(Ach) (r=0.14, P=.35). CONCLUSIONS: In patients without significant coronary artery disease, coronary endothelial dysfunction showed no apparent association with coronary calcification. Our findings suggest that these 2 markers may represent separate, independent processes in the progression of coronary atherosclerosis.

How Much Does It Cost? Optimization of Costs in Sequence Analysis of Social Science Data

One major methodological problem in analysis of sequence data is the determination of costs from which distances between sequences are derived. Although this problem is currently not optimally dealt with in the social sciences, it has some similarity with problems that have been solved in bioinformatics for three decades. In this article, the authors propose an optimization of substitution and deletion/insertion costs based on computational methods. The authors provide an empirical way of determining costs for cases, frequent in the social sciences, in which theory does not clearly promote one cost scheme over another. Using three distinct data sets, the authors tested the distances and cluster solutions produced by the new cost scheme in comparison with solutions based on cost schemes associated with other research strategies. The proposed method performs well compared with other cost-setting strategies, while it alleviates the justification problem of cost schemes.

Safety of artemether-lumefantrine exposure in first trimester of pregnancy: an observational cohort.

BACKGROUND: There is limited data available regarding safety profile of artemisinins in early pregnancy. They are, therefore, not recommended by WHO as a first-line treatment for malaria in first trimester due to associated embryo-foetal toxicity in animal studies. The study assessed birth outcome among pregnant women inadvertently exposed to artemether-lumefantrine (AL) during first trimester in comparison to those of women exposed to other anti-malarial drugs or no drug at all during the same period of pregnancy. METHODS: Pregnant women with gestational age <20 weeks were recruited from Maternal Health clinics or from monthly house visits (demographic surveillance), and followed prospectively until delivery. RESULTS: 2167 pregnant women were recruited and 1783 (82.3%) completed the study until delivery. 319 (17.9%) used anti-malarials in first trimester, of whom 172 (53.9%) used (AL), 78 (24.4%) quinine, 66 (20.7%) sulphadoxine-pyrimethamine (SP) and 11 (3.4%) amodiaquine. Quinine exposure in first trimester was associated with an increased risk of miscarriage/stillbirth (OR 2.5; 1.3-5.1) and premature birth (OR 2.6; 1.3-5.3) as opposed to AL with (OR 1.4; 0.8-2.5) for miscarriage/stillbirth and (OR 0.9; 0.5-1.8) for preterm birth. Congenital anomalies were identified in 4 exposure groups namely AL only (1/164[0.6%]), quinine only (1/70[1.4%]), SP (2/66[3.0%]), and non-anti-malarial exposure group (19/1464[1.3%]). CONCLUSION: Exposure to AL in first trimester was more common than to any other anti-malarial drugs. Quinine exposure was associated with adverse pregnancy outcomes which was not the case following other anti-malarial intake. Since AL and quinine were used according to their availability rather than to disease severity, it is likely that the effect observed was related to the drug and not to the disease itself. Even with this caveat, a change of policy from quinine to AL for the treatment of uncomplicated malaria during the whole pregnancy period could be already envisaged.