Simultaneous EEG-fMRI at ultra-high field: Artifact prevention and safety assessment.

The simultaneous recording of scalp electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) can provide unique insights into the dynamics of human brain function, and the increased functional sensitivity offered by ultra-high field fMRI opens exciting perspectives for the future of this multimodal approach. However, simultaneous recordings are susceptible to various types of artifacts, many of which scale with magnetic field strength and can seriously compromise both EEG and fMRI data quality in recordings above 3T. The aim of the present study was to implement and characterize an optimized setup for simultaneous EEG-fMRI in humans at 7T. The effects of EEG cable length and geometry for signal transmission between the cap and amplifiers were assessed in a phantom model, with specific attention to noise contributions from the MR scanner coldheads. Cable shortening (down to 12cm from cap to amplifiers) and bundling effectively reduced environment noise by up to 84% in average power and 91% in inter-channel power variability. Subject safety was assessed and confirmed via numerical simulations of RF power distribution and temperature measurements on a phantom model, building on the limited existing literature at ultra-high field. MRI data degradation effects due to the EEG system were characterized via B0 and B1(+) field mapping on a human volunteer, demonstrating important, although not prohibitive, B1 disruption effects. With the optimized setup, simultaneous EEG-fMRI acquisitions were performed on 5 healthy volunteers undergoing two visual paradigms: an eyes-open/eyes-closed task, and a visual evoked potential (VEP) paradigm using reversing-checkerboard stimulation. EEG data exhibited clear occipital alpha modulation and average VEPs, respectively, with concomitant BOLD signal changes. On a single-trial level, alpha power variations could be observed with relative confidence on all trials; VEP detection was more limited, although statistically significant responses could be detected in more than 50% of trials for every subject. Overall, we conclude that the proposed setup is well suited for simultaneous EEG-fMRI at 7T.

Horizontal, but not vertical, biotic interactions affect fine-scale plant distribution patterns in a low-energy system

Studies of species range determinants have traditionally focused on abiotic variables (typically climatic conditions), and therefore the recent explicit consideration of biotic interactions represents an important advance in the field. While these studies clearly support the role of biotic interactions in shaping species distributions, most examine only the influence of a single species and/or a single interaction, failing to account for species being subject to multiple concurrent interactions. By fitting species distribution models (SDMs), we examine the influence of multiple vertical (i.e., grazing, trampling, and manuring by mammalian herbivores) and horizontal (i.e., competition and facilitation; estimated from the cover of dominant plant species) interspecific interactions on the occurrence and cover of 41 alpine tundra plant species. Adding plant-plant interactions to baseline SDMs (using five field-quantified abiotic variables) significantly improved models' predictive power for independent data, while herbivore-related variables had only a weak influence. Overall, abiotic variables had the strongest individual contributions to the distribution of alpine tundra plants, with the importance of horizontal interaction variables exceeding that of vertical interaction variables. These results were consistent across three modeling techniques, for both species occurrence and cover, demonstrating the pattern to be robust. Thus, the explicit consideration of multiple biotic interactions reveals that plant-plant interactions exert control over the fine-scale distribution of vascular species that is comparable to abiotic drivers and considerably stronger than herbivores in this low-energy system.

Social and medical vulnerability factors of frequent users at the emergency department: a case-control study

BACKGROUND: Up to 5% of patients presenting to the emergency department (ED) four or more times within a 12 month period represent 21% of total ED visits. In this study we sought to characterize social and medical vulnerability factors of ED frequent users (FUs) and to explore if these factors hold simultaneously. METHODS: We performed a case-control study at Lausanne University Hospital, Switzerland. Patients over 18 years presenting to the ED at least once within the study period (April 2008 toMarch 2009) were included. FUs were defined as patients with four or more ED visits within the previous 12 months. Outcome data were extracted from medical records of the first ED attendance within the study period. Outcomes included basic demographics and social variables, ED admission diagnosis, somatic and psychiatric days hospitalized over 12 months, and having a primary care physician.We calculated the percentage of FUs and non-FUs having at least one social and one medical vulnerability factor. The four chosen social factors included: unemployed and/or dependence on government welfare, institutionalized and/or without fixed residence, either separated, divorced or widowed, and under guardianship. The fourmedical vulnerability factors were: ≥6 somatic days hospitalized, ≥1 psychiatric days hospitalized, ≥5 clinical departments used (all three factors measured over 12 months), and ED admission diagnosis of alcohol and/or drug abuse. Univariate and multivariate logistical regression analyses allowed comparison of two JGIM ABSTRACTS S391 random samples of 354 FUs and 354 non-FUs (statistical power 0.9, alpha 0.05 for all outcomes except gender, country of birth, and insurance type). RESULTS: FUs accounted for 7.7% of ED patients and 24.9% of ED visits. Univariate logistic regression showed that FUs were older (mean age 49.8 vs. 45.2 yrs, p=0.003),more often separated and/or divorced (17.5%vs. 13.9%, p=0.029) or widowed (13.8% vs. 8.8%, p=0.029), and either unemployed or dependent on government welfare (31.3% vs. 13.3%, p<0.001), compared to non-FUs. FUs cumulated more days hospitalized over 12 months (mean number of somatic days per patient 1.0 vs. 0.3, p<0.001; mean number of psychiatric days per patient 0.12 vs. 0.03, p<0.001). The two groups were similar regarding gender distribution (females 51.7% vs. 48.3%). The multivariate linear regression model was based on the six most significant factors identified by univariate analysis The model showed that FUs had more social problems, as they were more likely to be institutionalized or not have a fixed residence (OR 4.62; 95% CI, 1.65 to 12.93), and to be unemployed or dependent on government welfare (OR 2.03; 95% CI, 1.31 to 3.14) compared to non-FUs. FUs were more likely to need medical care, as indicated by involvement of≥5 clinical departments over 12 months (OR 6.2; 95%CI, 3.74 to 10.15), having an ED admission diagnosis of substance abuse (OR 3.23; 95% CI, 1.23 to 8.46) and having a primary care physician (OR 1.70;95%CI, 1.13 to 2.56); however, they were less likely to present with an admission diagnosis of injury (OR 0.64; 95% CI, 0.40 to 1.00) compared to non-FUs. FUs were more likely to combine at least one social with one medical vulnerability factor (38.4% vs. 12.1%, OR 7.74; 95% CI 5.03 to 11.93). CONCLUSIONS: FUs were more likely than non-FUs to have social and medical vulnerability factors and to have multiple factors in combination.

Species distribution models reveal apparent competitive and facilitative effects of a dominant species on the distribution of tundra plants

Abiotic factors are considered strong drivers of species distribution and assemblages. Yet these spatial patterns are also influenced by biotic interactions. Accounting for competitors or facilitators may improve both the fit and the predictive power of species distribution models (SDMs). We investigated the influence of a dominant species, Empetrum nigrum ssp. hermaphroditum, on the distribution of 34 subordinate species in the tundra of northern Norway. We related SDM parameters of those subordinate species to their functional traits and their co-occurrence patterns with E. hermaphroditum across three spatial scales. By combining both approaches, we sought to understand whether these species may be limited by competitive interactions and/or benefit from habitat conditions created by the dominant species. The model fit and predictive power increased for most species when the frequency of occurrence of E. hermaphroditum was included in the SDMs as a predictor. The largest increase was found for species that 1) co-occur most of the time with E. hermaphroditum, both at large (i.e. 750 m) and small spatial scale (i.e. 2 m) or co-occur with E. hermaphroditum at large scale but not at small scale and 2) have particularly low or high leaf dry matter content (LDMC). Species that do not co-occur with E. hermaphroditum at the smallest scale are generally palatable herbaceous species with low LDMC, thus showing a weak ability to tolerate resource depletion that is directly or indirectly induced by E. hermaphroditum. Species with high LDMC, showing a better aptitude to face resource depletion and grazing, are often found in the proximity of E. hermaphroditum. Our results are consistent with previous findings that both competition and facilitation structure plant distribution and assemblages in the Arctic tundra. The functional and co-occurrence approaches used were complementary and provided a deeper understanding of the observed patterns by refinement of the pool of potential direct and indirect ecological effects of E. hermaphroditum on the distribution of subordinate species. Our correlative study would benefit being complemented by experimental approaches.

Photodynamic therapy enhances liposomal doxorubicin distribution in tumors during isolated perfusion of rodent lungs.

BACKGROUND: Photodynamic therapy (PDT) at low drug-light conditions can enhance the transport of intravenously injected macromolecular therapeutics through the tumor vasculature. Here we determined the impact of PDT on the distribution of liposomal doxorubicin (Liporubicin™) administered by isolated lung perfusion (ILP) in sarcomas grown on rodent lungs. METHODS: A syngeneic methylcholanthrene-induced sarcoma cell line was implanted subpleurally in the left lung of Fischer rats. Treatment schemes consisted in ILP alone (400 μg of Liporubicin), low-dose (0.0625 mg/kg Visudyne®, 10 J/cm(2) and 35 mW/cm(2)) and high-dose left lung PDT (0.125 mg/kg Visudyne, 10 J/cm(2) and 35 mW/cm(2)) followed by ILP (400 μg of Liporubicin). The uptake and distribution of Liporubicin in tumor and lung tissues were determined by high-performance liquid chromatography and fluorescence microscopy in each group. RESULTS: Low-dose PDT significantly improved the distribution of Liporubicin in tumors compared to high-dose PDT (p < 0.05) and ILP alone (p < 0.05). However, both PDT pretreatments did not result in a higher overall drug uptake in tumors or a higher tumor-to-lung drug ratio compared to ILP alone. CONCLUSIONS: Intraoperative low-dose Visudyne-mediated PDT enhances liposomal doxorubicin distribution administered by ILP in sarcomas grown on rodent lungs which is predicted to improve tumor control by ILP.

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Interpersonal Power: A Review, Critique, and Research Agenda

Power is a fundamental force in social relationships and is pervasive throughout various types of interactions. Although research has shown that the possession of power can change the powerholder, the full extent of power's consequences on individuals' decision making capabilities and social interactions within organizations is not fully understood. The goal of this paper is to review, synthesize, and critique the literature on power with a focus on its organizational and managerial implications. Specifically, we propose a definition of power that takes into account its three defining characteristics-having the discretion and means to enforce one's will-and summarize the extant literature on how power influences individuals' thoughts, emotions, and actions both in terms of prosocial and antisocial outcomes. In addition, we highlight important moderators of power and describe ways in which it can be studied in a more rigorous manner by examining methodological issues and pitfalls with regard to its measurement and manipulation. We also provide future research directions to motivate and guide the study of power by management scholars. Our desire is to present a thorough and parsimonious account of power's influence on individuals within an organizational context, as well as provide a foundation that scholars can build upon as they continue to make consequential contributions to the study of power.

Predictors of HIV-protection behaviour in HIV-positive men who have sex with casual male partners: a test of the explanatory power of an extended Information-Motivation-Behavioural Skills model.

This prospective study applies an extended Information-Motivation-Behavioural Skills (IMB) model to establish predictors of HIV-protection behaviour among HIV-positive men who have sex with men (MSM) during sex with casual partners. Data have been collected from anonymous, self-administered questionnaires and analysed by using descriptive and backward elimination regression analyses. In a sample of 165 HIV-positive MSM, 82 participants between the ages of 23 and 78 (M=46.4, SD=9.0) had sex with casual partners during the three-month period under investigation. About 62% (n=51) have always used a condom when having sex with casual partners. From the original IMB model, only subjective norm predicted condom use. More important predictors that increased condom use were low consumption of psychotropics, high satisfaction with sexuality, numerous changes in sexual behaviour after diagnosis, low social support from friends, alcohol use before sex and habitualised condom use with casual partner(s). The explanatory power of the calculated regression model was 49% (p<0.001). The study reveals the importance of personal and social resources and of routines for condom use, and provides information for the research-based conceptualisation of prevention offers addressing especially people living with HIV ("positive prevention").

Pathological Reorganization of NMDA Receptors Subunits and Postsynaptic Protein PSD-95 Distribution in Alzheimer's Disease.

In Alzheimer's disease (AD), synaptic alterations play a major role and are often correlated with cognitive changes. In order to better understand synaptic modifications, we compared alterations in NMDA receptors and postsynaptic protein PSD-95 expression in the entorhinal cortex (EC) and frontal cortex (FC; area 9) of AD and control brains. We combined immunohistochemical and image analysis methods to quantify on consecutive sections the distribution of PSD-95 and NMDA receptors GluN1, GluN2A and GluN2B in EC and FC from 25 AD and control cases. The density of stained receptors was analyzed using multivariate statistical methods to assess the effect of neurodegeneration. In both regions, the number of neuronal profiles immunostained for GluN1 receptors subunit and PSD-95 protein was significantly increased in AD compared to controls (3-6 fold), while the number of neuronal profiles stained for GluN2A and GluN2B receptors subunits was on the contrary decreased (3-4 fold). The increase in marked neuronal profiles was more prominent in a cortical band corresponding to layers 3 to 5 with large pyramidal cells. Neurons positive for GluN1 or PSD-95 staining were often found in the same localization on consecutive sections and they were also reactive for the anti-tau antibody AD2, indicating a neurodegenerative process. Differences in the density of immunoreactive puncta representing neuropile were not statistically significant. Altogether these data indicate that GluN1 and PSD-95 accumulate in the neuronal perikarya, but this is not the case for GluN2A and GluN2B, while the neuropile compartment is less subject to modifications. Thus, important variations in the pattern of distribution of the NMDA receptors subunits and PSD-95 represent a marker in AD and by impairing the neuronal network, contribute to functional deterioration.

Peroxisome proliferator-activated receptors (PPARs): from metabolic control to epidermal wound healing.

Peroxisome proliferator-activated receptors control many cellular and metabolic processes. They are transcription factors belonging to the family of ligand-inducible nuclear receptors. Three isotypes called PPARalpha, PPARbeta/delta and PPARgamma have been identified in lower vertebrates and mammals. They display differential tissue distribution and each of the three isotypes fulfills specific functions. PPARalpha and PPARgamma control energy homoeostasis and inflammatory responses. Their activity can be modulated by drugs such as the hypolipidaemic fibrates and the insulin sensitising thiazolidinediones (pioglitazone and rosiglitazone). Thus, these receptors are involved in the control of chronic diseases such as diabetes, obesity, and atherosclerosis. Little is known about the main function of PPARbeta, but it has been implicated in embryo implantation, tumorigenesis in the colon, reverse cholesterol transport, and recently in skin wound healing. Here, we present recent developments in the PPAR field with particular emphasis on both the function of PPARs in lipid metabolism and energy homoeostasis (PPARalpha and PPARgamma), and their role in epidermal maturation and skin wound repair (PPARalpha and PPARbeta).

Do pseudo-absence selection strategies influence species distribution models and their predictions? An information-theoretic approach based on simulated data

Background Multiple logistic regression is precluded from many practical applications in ecology that aim to predict the geographic distributions of species because it requires absence data, which are rarely available or are unreliable. In order to use multiple logistic regression, many studies have simulated "pseudo-absences" through a number of strategies, but it is unknown how the choice of strategy influences models and their geographic predictions of species. In this paper we evaluate the effect of several prevailing pseudo-absence strategies on the predictions of the geographic distribution of a virtual species whose "true" distribution and relationship to three environmental predictors was predefined. We evaluated the effect of using a) real absences b) pseudo-absences selected randomly from the background and c) two-step approaches: pseudo-absences selected from low suitability areas predicted by either Ecological Niche Factor Analysis: (ENFA) or BIOCLIM. We compared how the choice of pseudo-absence strategy affected model fit, predictive power, and information-theoretic model selection results. Results Models built with true absences had the best predictive power, best discriminatory power, and the "true" model (the one that contained the correct predictors) was supported by the data according to AIC, as expected. Models based on random pseudo-absences had among the lowest fit, but yielded the second highest AUC value (0.97), and the "true" model was also supported by the data. Models based on two-step approaches had intermediate fit, the lowest predictive power, and the "true" model was not supported by the data. Conclusion If ecologists wish to build parsimonious GLM models that will allow them to make robust predictions, a reasonable approach is to use a large number of randomly selected pseudo-absences, and perform model selection based on an information theoretic approach. However, the resulting models can be expected to have limited fit.

Novel micelle carriers for cyclosporin A topical ocular delivery: in vivo cornea penetration, ocular distribution and efficacy studies.

Cornea transplantation is one of the most performed graft procedures worldwide with an impressive success rate of 90%. However, for "high-risk" patients with particular ocular diseases in addition to the required surgery, the success rate is drastically reduced to 50%. In these cases, cyclosporin A (CsA) is frequently used to prevent the cornea rejection by a systemic treatment with possible systemic side effects for the patients. To overcome these problems, it is a challenge to prepare well-tolerated topical CsA formulations. Normally high amounts of oils or surfactants are needed for the solubilization of the very hydrophobic CsA. Furthermore, it is in general difficult to obtain ocular therapeutic drug levels with topical instillations due to the corneal barriers that efficiently protect the intraocular structures from foreign substances thus also from drugs. The aim of this study was to investigate in vivo the effects of a novel CsA topical aqueous formulation. This formulation was based on nanosized polymeric micelles as drug carriers. An established rat model for the prevention of cornea graft rejection after a keratoplasty procedure was used. After instillation of the novel formulation with fluorescent labeled micelles, confocal analysis of flat-mounted corneas clearly showed that the nanosized carriers were able to penetrate into all corneal layers. The efficacy of a 0.5% CsA micelle formulation was tested and compared to a physiological saline solution and to a systemic administration of CsA. In our studies, the topical CsA treatment was carried out for 14 days, and the three parameters (a) cornea transparency, (b) edema, and (c) neovascularization were evaluated by clinical observation and scoring. Compared to the control group, the treated group showed a significant higher cornea transparency and significant lower edema after 7 and 13 days of the surgery. At the end point of the study, the neovascularization was reduced by 50% in the CsA-micelle treated animals. The success rate of cornea graft transplantation was 73% in treated animals against 25% for the control group. This result was as good as observed for a systemic CsA treatment in the same animal model. This new formulation has the same efficacy like a systemic treatment but without the serious CsA systemic side effects. Ocular drug levels of transplanted and healthy rat eyes were dosed by UPLC/MS and showed a high CsA value in the cornea (11710 ± 7530 ng(CsA)/g(tissue) and 6470 ± 1730 ng(CsA)/g(tissue), respectively). In conclusion, the applied formulation has the capacity to overcome the ocular surface barriers, the micelles formed a drug reservoir in the cornea from, where a sustained release of CsA can take place. This novel formulation for topical application of CsA is clearly an effective and well-tolerated alternative to the systemic treatment for the prevention of corneal graft rejection.

Prevalence, treatment and control of dyslipidaemia in Switzerland: still a long way to go.

BACKGROUND: There is little information regarding the prevalence and management of dyslipidaemia in Switzerland. DESIGN: Cross-sectional population-based study of 3238 women and 2846 men aged 35-75. METHODS: Dyslipidaemia prevalence, treatment and control were defined according to PROCAM guidelines adapted to Switzerland. RESULTS: About 29% of the overall sample presented with dyslipidaemia, of which 39% were treated and 58% of those treated were controlled. Among the 710 patients with personal history of cardiovascular disease (CVD) and/or diabetes, 632 (89%) presented with dyslipidaemia, of which 278 (44%) and 134 (21%) patients were treated and adequately controlled, respectively. On multivariate analysis, hypolipidaemic drug treatment was positively related with age and body mass index (P for trend <0.001), and negatively related with smoking status (P for trend <0.002), whereas personal history of CVD and/or diabetes had no effect [odds ratio (OR)=1.12, 95% confidence interval (CI): 0.90-1.38]. Adequate control of lipid levels was negatively related with female sex (OR=0.65, 95% CI: 0.45-0.94) and personal history of CVD and/or diabetes (OR=0.42, 95% CI: 0.30-0.59). When personal history of CVD and/or diabetes was replaced by PROCAM risk categories, patients in the highest risk were also less well controlled. CONCLUSION: In this population-based study, one-third of the participants was dyslipidaemic, but less than half was treated and only one-fifth was adequately controlled. The low treatment and control levels among individuals at high risk for CVD calls for a better application of recommendations regarding personal preventive measures.

Selective distribution of lactate dehydrogenase isoenzymes in neurons and astrocytes of human brain.

In vertebrates, the interconversion of lactate and pyruvate is catalyzed by the enzyme lactate dehydrogenase. Two distinct subunits combine to form the five tetrameric isoenzymes of lactate dehydrogenase. The LDH-5 subunit (muscle type) has higher maximal velocity (Vmax) and is present in glycolytic tissues, favoring the formation of lactate from pyruvate. The LDH-1 subunit (heart type) is inhibited by pyruvate and therefore preferentially drives the reaction toward the production of pyruvate. There is mounting evidence indicating that during activation the brain resorts to the transient glycolytic processing of glucose. Indeed, transient lactate formation during physiological stimulation has been shown by 1H-magnetic resonance spectroscopy. However, since whole-brain arteriovenous studies under basal conditions indicate a virtually complete oxidation of glucose, the vast proportion of the lactate transiently formed during activation is likely to be oxidized. These in vivo data suggest that lactate may be formed in certain cells and oxidized in others. We therefore set out to determine whether the two isoforms of lactate dehydrogenase are localized to selective cell types in the human brain. We report here the production and characterization of two rat antisera, specific for the LDH-5 and LDH-1 subunits of lactate dehydrogenase, respectively. Immunohistochemical, immunodot, and western-blot analyses show that these antisera specifically recognize their homologous antigens. Immunohistochemistry on 10 control cases demonstrated a differential cellular distribution between both subunits in the hippocampus and occipital cortex: neurons are exclusively stained with the anti-LDH1 subunit while astrocytes are stained by both antibodies. These observations support the notion of a regulated lactate flux between astrocytes and neurons.

Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study.

OBJECTIVE: To identify specific major congenital malformations associated with use of carbamazepine in the first trimester of pregnancy. DESIGN: A review of all published cohort studies to identify key indications and a population based case-control study to test these indications. SETTING: Review of PubMed, Web of Science, and Embase for papers about carbamazepine exposure in the first trimester of pregnancy and specific malformations, and the EUROCAT Antiepileptic Study Database, including data from 19 European population based congenital anomaly registries, 1995-2005. PARTICIPANTS: The literature review covered eight cohort studies of 2680 pregnancies with carbamazepine monotherapy exposure, and the EUROCAT dataset included 98 075 registrations of malformations covering over 3.8 million births. MAIN OUTCOME MEASURES: Overall prevalence for a major congenital malformation after exposure to carbamazepine monotherapy in the first trimester. Odds ratios for malformations with exposure to carbamazepine among cases (five types of malformation identified in the literature review) compared with two groups of controls: other non-chromosomal registrations of malformations and chromosomal syndromes. RESULTS: The literature review yielded an overall prevalence for a major congenital malformation of 3.3% (95% confidence interval 2.7 to 4.2) after exposure to carbamazepine monotherapy in the first trimester. In 131 registrations of malformations, the fetus had been exposed to carbamazepine monotherapy. Spina bifida was the only specific major congenital malformation significantly associated with exposure to carbamazepine monotherapy (odds ratio 2.6 (95% confidence interval 1.2 to 5.3) compared with no antiepileptic drug), but the risk was smaller for carbamazepine than for valproic acid (0.2, 0.1 to 0.6). There was no evidence for an association with total anomalous pulmonary venous return (no cases with carbamazepine exposure), cleft lip (with or without palate) (0.2, 0.0 to 1.3), diaphragmatic hernia (0.9, 0.1 to 6.6), or hypospadias (0.7, 0.3 to 1.6) compared with no exposure to antiepileptic drugs. Further exploratory analysis suggested a higher risk of single ventricle and atrioventricular septal defect. CONCLUSION: Carbamazepine teratogenicity is relatively specific to spina bifida, though the risk is less than with valproic acid. Despite the large dataset, there was not enough power to detect moderate risks for some rare major congenital malformations.