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Owing to their ultra-high accelerating gradients, combined with injection inside micrometer-scale accelerating wakefield buckets, plasma-based accelerators hold great potential to drive a new generation of free-electron lasers (FELs). Indeed, the first demonstration of plasma-driven FEL gain was reported recently, representing a major milestone for the field. Several groups around the world are pursuing these novel light sources, with methodology varying in the use of wakefield driver (laser-driven or beam-driven), plasma structure, phase-space manipulation, beamline design, and undulator technology, among others. This paper presents our best attempt to provide a comprehensive overview of the global community efforts towards plasma-based FEL research and development.
Neuropsychological deficits are considered endophenotypes for schizophrenia, because they are not only found in patients but also in many of their unaffected relatives, albeit in attenuated form. It is not yet clear which of these deficits in relatives are related to genetic or to environmental causes. We tested effects of inferred genetic liability for schizophrenia on neurocognitive variables to address this problem.
Method:
Twenty-eight patients with schizophrenia, 129 non-affected biological parents and 143 matched controls were assessed with an extensive neuropsychological test battery including tests of attention, memory, executive functioning and motor soft signs. Twenty-two parents had an ancestral history of schizophrenia and therefore were hypothesized to be more likely than their spouses without such a history (n = 17) to carry a genetic risk for schizophrenia.
Results:
Unaffected parents of schizophrenic patients showed significant deficits in a wide array of neuropsychological tasks and task domains. However, comparison of more likely and less likely carriers of illness-related genes showed specifically attentional and executive functioning, but not memory, to vary with degree of inferred genetic loading.
Conclusions:
Attentional and executive (frontal) impairments vary with genetic loading for schizophrenia and can be considered true endophenotypes for this disorder. Consequently, these functions are particularly suited to evaluate the functional impact of candidate genes for schizophrenia in future studies.
Disturbances of the oculomotor system are promising endophenotypes for schizophrenia. In two separate studies, we examined antisaccade task performance, a measure of inhibitory control, in first degree relatives of schizophrenic patients (genetic risk without manifest disorder) and in clinical high risk subjects with symptoms suggestive of a prodromal phase of schizophrenia.
Methods:
In the first study, 41 parents of schizophrenia patients and 22 controls were tested with with a prosaccade task and an antisaccade task. Parents were grouped into more likely, less likely, and indeterminate risk carriers. The second study involved 160 subjects clinically at risk for schizophrenia, 32 first episode schizophrenic patients, and 76 healthy controls.
Results:
In study 1 we found an increase of antisaccade latencies and error rates in parents of schizophrenics which varied with inferred genetic load, more likely gene carriers performing worst. In study 2, antisaccade performance varied with symptom load: subjects at risk with basic symptoms only were unimpaired, while at-risk subjects who had experienced brief psychotic episodes (BLIPS) showed deficits similar to first episode patients.
Conclusions:
Reduced inhibitory control of oculomotor performance is associated with genetic loading for schizophrenia, and also with symptoms placing subjects at imminent risk of psychosis.
Implicit memories like consumption habits and conditioned reactions to drug-related stimuli are operational in addiction and relapse. The affective startle paradigm is an attractive tool for the measurement of the incentive salience of drug-related cues. We tested whether the stronger appetitive valence of drug cues, shown in two recent startle studies in smokers, does persist after prolonged abstinence, and may thus contribute to relapse.
Method:
We examined the auditory startle reflex magnitude of mildly deprived (4-6 hours) heavy smokers (n = 24), former smokers (n = 16, mean abstinence interval 18 months), and non-smokers (n = 24) while they viewed smoking-related scenes or standardized unpleasant, neutral and pleasant control scenes from the International Affective Picture System.
Results:
As expected, non-smokers showed no appetitive reactions toward smoking-cues. In smokers, smoking-cues had both appetitive implicit (startle suppression) and explicit (ratings for valence and craving) motivational effects, resembling those of pleasant scenes and differing from neutral and unpleasant scenes. This effect was more pronounced in smokers who later relapsed after a smoking cessation program, and in smokers consuming less than 20 cigarettes per day. Former smokers, despite reporting no craving and negative reactions to smoking cues, still showed evidence of implicit appetitive valence of these cues.
Conclusions:
Nicotine addiction results in automatic appetitive reactions to drug-cues, which does not vanish after prolonged abstinence and which may thus contribute to relapses. Heavy smoking may result in a progressive internalization of smoking habits and a decline in reactivity towards external smoking-associated cues.
Psychosis is preceded by cognitive and physiological alterations. This may be useful in the risk assessment in subjects with putatively prodromal symptoms, and could contribute to better understand the temporal unfolding of the disease.
Methods
The early recognition and intervention program of the German Research Network on schizophrenia defines early and late prodromal stages according to psychopathological criteria. For concurrent and prospective validation of these risk stages, subjects undergo neurocognitive, electrophysiological and oculomotor assessments of putative vulnerability markers. About 125 early prodromal subjects (defined by the presence of basic symptoms, Klosterkoetter et al. 2001), and 90 late prodromal subjects (defined by attenuated positive symptoms or by brief occurrences of psychotic symptoms) have been assessed at inclusion.
Results
As compared to psychiatrically healthy matched controls, late prodromals have significantly inferior verbal memory, verbal fluency, visual motor skills, and working memory. Impairments are qualitatively similar, but less pronounced in subjects in an early prodromal stage, with deficits of immediate verbal memory, verbal fluency and visuomotor performance being significant. Both groups show reduced auditory startle prepulse inhibition. Impairments are not correlated with depression and general distress scores, and are also largely independent of prodromal and attenuated positive symptoms. In early prodromals, global cognitive performance is related to the occurrence of psychotic symptoms during follow-up. Auditory P 300 is reduced in both prodromal groups, and predicts transitions to psychosis.
Conclusions
Neurocognitive and neurophysiological assessments validate and improve psychopathological risk assessment, and allow to disentangle stable vulnerability markers from indicators of imminent risk.
Funded by the German Federal Ministry for Education and Research BMBF (grant 01 GI 9934).
Aim was to examine depressive symptoms in acutely ill schizophrenia patients on a single symptom basis and to evaluate their relationship with positive, negative and general psychopathological symptoms.
Methods:
Two hundred and seventy-eight patients suffering from a schizophrenia spectrum disorder were analysed within a naturalistic study by the German Research Network on Schizophrenia. Using the Calgary Depression Scale for Schizophrenia (CDSS) depressive symptoms were examined and the Positive and Negative Syndrome Scale (PANSS) was applied to assess positive, negative and general symptoms. Correlation and factor analyses were calculated to detect the underlying structure and relationship of the patient’s symptoms.
Results:
The most prevalent depressive symptoms identified were depressed mood (80%), observed depression (62%) and hopelessness (54%). Thirty-nine percent of the patients suffered from depressive symptoms when applying the recommended cut-off of a CDSS total score of > 6 points at admission. Negligible correlations were found between depressive and positive symptoms as well as most PANSS negative and global symptoms despite items on depression, guilt and social withdrawal. The factor analysis revealed that the factor loading with the PANSS negative items accounted for most of the data variance followed by a factor with positive symptoms and three depression-associated factors.
Limitations:
The naturalistic study design does not allow a sufficient control of study results for the effect of different pharmacological treatments possibly influencing the appearance of depressive symptoms.
Conclusion:
Results suggest that depressive symptoms measured with the CDSS are a discrete symptom domain with only partial overlap with positive or negative symptoms.
Obesity has been shown to be associated with depression and it has been suggested that higher body mass index (BMI) increases the risk of depression and other common mental disorders. However, the causal relationship remains unclear and Mendelian randomisation, a form of instrumental variable analysis, has recently been employed to attempt to resolve this issue.
Aims
To investigate whether higher BMI increases the risk of major depression.
Method
Two instrumental variable analyses were conducted to test the causal relationship between obesity and major depression in RADIANT, a large case–control study of major depression. We used a single nucleotide polymorphism (SNP) in FTO and a genetic risk score (GRS) based on 32 SNPs with well-established associations with BMI.
Results
Linear regression analysis, as expected, showed that individuals carrying more risk alleles of FTO or having higher score of GRS had a higher BMI. Probit regression suggested that higher BMI is associated with increased risk of major depression. However, our two instrumental variable analyses did not support a causal relationship between higher BMI and major depression (FTO genotype: coefficient −0.03, 95% CI −0.18 to 0.13, P = 0.73; GRS: coefficient −0.02, 95% CI −0.11 to 0.07, P = 0.62).
Conclusions
Our instrumental variable analyses did not support a causal relationship between higher BMI and major depression. The positive associations of higher BMI with major depression in probit regression analyses might be explained by reverse causality and/or residual confounding.
This article presents a new multiscale modeling approach proposed to predict the impact response of a biomedical niobium–zirconium alloy by incorporating both geometric and microstructural aspects. Specifically, the roles of both anisotropy and geometry-based distribution of stresses and strains upon loading were successfully taken into account by incorporating a proper multiaxial material flow rule obtained from crystal plasticity simulations into the finite element (FE) analysis. The simulation results demonstrate that the current approach, which defines a hardening rule based on the location-dependent equivalent stresses and strains, yields more reliable results as compared with the classical FE approach, where the hardening rule is based on the experimental uniaxial deformation response of the material. This emphasizes the need for proper coupling of crystal plasticity and FE analysis for the sake of reliable predictions, and the approach presented herein constitutes an efficient guideline for the design process of dental and orthopedic implants that are subject to impact loading in service.
As physical activity may modify the effect of the apolipoprotein E (APOE) ε4 allele on the risk of dementia and Alzheimer's disease (AD) dementia, we tested for such a gene–environment interaction in a sample of general practice patients aged ⩾75 years.
Method
Data were derived from follow-up waves I–IV of the longitudinal German study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe). The Kaplan–Meier survival method was used to estimate dementia- and AD-free survival times. Multivariable Cox regression was used to assess individual associations of APOE ε4 and physical activity with risk for dementia and AD, controlling for covariates. We tested for gene–environment interaction by calculating three indices of additive interaction.
Results
Among the randomly selected sample of 6619 patients, 3327 (50.3%) individuals participated in the study at baseline and 2810 (42.5%) at follow-up I. Of the 2492 patients without dementia included at follow-up I, 278 developed dementia (184 AD) over the subsequent follow-up interval of 4.5 years. The presence of the APOE ε4 allele significantly increased and higher physical activity significantly decreased risk for dementia and AD. The co-presence of APOE ε4 with low physical activity was associated with higher risk for dementia and AD and shorter dementia- and AD-free survival time than the presence of APOE ε4 or low physical activity alone. Indices of interaction indicated no significant interaction between low physical activity and the APOE ε4 allele for general dementia risk, but a possible additive interaction for AD risk.
Conclusions
Physical activity even in late life may be effective in reducing conversion to dementia and AD or in delaying the onset of clinical manifestations. APOE ε4 carriers may particularly benefit from increasing physical activity with regard to their risk for AD.
Emotional dysregulation is becoming increasingly recognized as an important feature of attention deficit hyperactivity disorder (ADHD). In this study, two experiments were conducted investigating the neural response to either verbally instructed fear (IF) or uninstructed (classically conditioned) fear (UF) using the skin conductance response (SCR) and functional magnetic resonance imaging (fMRI).
Method
In the conditioning phase of the UF experiment (17 ADHD and 17 healthy controls), subjects experienced an unconditioned stimulus (UCS, unpleasant electrodermal stimulation) paired with a former neutral conditioned stimulus (CS+), whereas a control stimulus (CS−) was never paired with the UCS. In the subsequent test phase, only the CS+ and the CS− were presented. In the IF experiment (13 ADHD and 17 healthy controls), subjects were only told that an independently experienced UCS might occur together with the CS+ but not the CS− during testing. No UCS was presented.
Results
Groups did not detectably differ in SCR or neural responses to UF. In IF, ADHD patients showed a trend-line decreased SCR and significantly decreased activation of the dorsal anterior cingulate cortex (dACC), a region prominently involved in fear responding, to the CS+. This was accompanied by higher amygdala activation to the CS−.
Conclusions
During IF, ADHD patients showed deficits in regions centrally involved in fear learning and expression in terms of diminished CS+-related dACC and increased CS−-related amygdala signals. This suggests an impaired processing of verbally transmitted aversive information, which is central for conveying fear information in social contexts. This result extends the growing literature on emotional alterations in ADHD.
Although usually thought of as external environmental stressors, a significant heritable component has been reported for measures of stressful life events (SLEs) in twin studies.
Method
We examined the variance in SLEs captured by common genetic variants from a genome-wide association study (GWAS) of 2578 individuals. Genome-wide complex trait analysis (GCTA) was used to estimate the phenotypic variance tagged by single nucleotide polymorphisms (SNPs). We also performed a GWAS on the number of SLEs, and looked at correlations between siblings.
Results
A significant proportion of variance in SLEs was captured by SNPs (30%, p = 0.04). When events were divided into those considered to be dependent or independent, an equal amount of variance was explained for both. This ‘heritability’ was in part confounded by personality measures of neuroticism and psychoticism. A GWAS for the total number of SLEs revealed one SNP that reached genome-wide significance (p = 4 × 10−8), although this association was not replicated in separate samples. Using available sibling data for 744 individuals, we also found a significant positive correlation of R2 = 0.08 in SLEs (p = 0.03).
Conclusions
These results provide independent validation from molecular data for the heritability of reporting environmental measures, and show that this heritability is in part due to both common variants and the confounding effect of personality.
Whether late-onset depression is a risk factor for or a prodrome of dementia remains unclear. We investigated the impact of depressive symptoms and early- v. late-onset depression on subsequent dementia in a cohort of elderly general-practitioner patients (n = 2663, mean age = 81.2 years).
Method
Risk for subsequent dementia was estimated over three follow-ups (each 18 months apart) depending on history of depression, particularly age of depression onset, and current depressive symptoms using proportional hazard models. We also examined the additive prediction of incident dementia by depression beyond cognitive impairment.
Results
An increase of dementia risk for higher age cut-offs of late-onset depression was found. In analyses controlling for age, sex, education, and apolipoprotein E4 genotype, we found that very late-onset depression (aged ⩾70 years) and current depressive symptoms separately predicted all-cause dementia. Combined very late-onset depression with current depressive symptoms was specifically predictive for later Alzheimer's disease (AD; adjusted hazard ratio 5.48, 95% confidence interval 2.41–12.46, p < 0.001). This association was still significant after controlling for cognitive measures, but further analyses suggested that it was mediated by subjective memory impairment with worries.
Conclusions
Depression might be a prodrome of AD but not of dementia of other aetiology as very late-onset depression in combination with current depressive symptoms, possibly emerging as a consequence of subjectively perceived worrisome cognitive deterioration, was most predictive. As depression parameters and subjective memory impairment predicted AD independently of objective cognition, clinicians should take this into account.
To analyse insight of illness during the course of inpatient treatment, and to identify influencing factors and predictors of insight.
Methods
Insight into illness was examined in 399 patients using the item G12 of the Positive and Negative Syndrome Scale (“lack of insight and judgement”). Ratings of the PANSS, HAMD, UKU, GAF, SOFAS, SWN-K and Kemp's compliance scale were performed and examined regarding their potential association with insight. The item G12 was kept as an ordinal variable to compare insight between subgroups of patients.
Results
Almost 70% of patients had deficits in their insight into illness at admission. A significant improvement of impairments of insight during the treatment (p<0.0001) was observed. At admission more severe positive and negative symptoms, worse functioning and worse adherence were significantly associated with poorer insight. Less depressive symptoms (p = 0.0004), less suicidality (p = 0.0218), suffering from multiple illness-episodes (p<0.0001) and worse adherence (p = 0.0012) at admission were identified to be significant predictors of poor insight at discharge.
Conclusion
The revealed predictors might function as treatment targets in order to improve insight and with it outcome of schizophrenia.
It has been proposed that non-steroidal anti-inflammatory drugs (NSAIDs) may interfere with the efficacy of antidepressants and contribute to treatment resistance in major depressive disorder (MDD). This effect requires replication and a test of whether it is specific to serotonin-reuptake inhibiting (SRI) antidepressants.
Method
We tested the effect of concomitant medication with NSAIDs on the efficacy of escitalopram, a SRI antidepressant, and nortriptyline, a tricyclic antidepressant, among 811 subjects with MDD treated for up to 12 weeks in the GENDEP study. Effects of NSAIDs on improvement of depressive symptoms were tested in mixed-effect linear models. Effects on remission were tested in logistic regression. Age, sex, baseline severity and centre of recruitment were considered as potential confounding factors.
Results
Ten percent (n=78) of subjects were taking NSAIDs during the antidepressant treatment. Older subjects were significantly more likely to take NSAIDs. After controlling for age, sex, centre of recruitment and baseline severity, concomitant medication with NSAIDs did not significantly influence the efficacy of escitalopram [β=0.035, 95% confidence interval (CI) −0.145 to 0.215, p=0.704] or nortriptyline (β=0.075, 95% CI −0.131 to 0.281, p=0.476). Although slightly fewer subjects who took NSAIDs reached remission [odds ratio (OR) 0.80, 95% CI 0.49–1.31, p=0.383], this non-significant effect was reversed after controlling for age, sex, baseline severity and recruitment centre effects (OR 1.04, 95% CI 0.61–1.77, p=0.882).
Conclusions
NSAIDs are unlikely to affect the efficacy of SRI or other antidepressants. Concurrent use of NSAIDs and antidepressants does not need to be avoided.
Young people with self-experienced cognitive thought and perception deficits (basic symptoms) may present with an early initial prodromal state (EIPS) of psychosis in which most of the disability and neurobiological deficits of schizophrenia have not yet occurred.
Aims
To investigate the effects of an integrated psychological intervention (IPI), combining individual cognitive–behavioural therapy, group skills training, cognitive remediation and multifamily psychoeducation, on the prevention of psychosis in the EIPS.
Method
A randomised controlled, multicentre, parallel group trial of 12 months of IPI v. supportive counselling (trial registration number: NCT00204087). Primary outcome was progression to psychosis at 12- and 24-month follow-up.
Results
A total of 128 help-seeking out-patients in an EIPS were randomised. Integrated psychological intervention was superior to supportive counselling in preventing progression to psychosis at 12-month follow-up (3.2% v. 16.9%; P = 0.008) and at 24-month follow-up (6.3% v. 20.0%; P = 0.019).
Conclusions
Integrated psychological intervention appears effective in delaying the onset of psychosis over a 24-month time period in people in an EIPS.
The study of molecules in space, known as astrochemistry or molecular astrophysics, is a rapidly growing field. Molecules exist in a wide range of environments in both gaseous and solid form, from our own solar system to the distant early universe. To astronomers, molecules are indispensable and unique probes of the physical conditions and dynamics of regions in which they are detected, especially the interstellar medium. In particular, the many stages of both low-mass and high-mass star formation are better understood today thanks to the analysis of molecular observations. Molecules can also yield a global picture of the past and present of sources. Moreover, molecules affect their environment by contributing to the heating and cooling processes that occur.
Early improvement with treatment is thought to be important in patients with first-episode schizophrenia, yet a valid definition is still outstanding.
Aims
To develop a valid definition of early improvement and test its predictive validity regarding response and remission.
Method
We examined 188 in-patients with first-episode schizophrenia. Early improvement was defined as improvement in Positive and Negative Syndrome Scale (PANSS) total score at week 2, response as a 40% PANSS total score improvement at end-point, and remission according to consensus criteria.
Results
Reasonable predictive validity of early improvement was found for a 46% PANSS total score improvement at week 2 and a 50% improvement for remission (area under the curve: response 0.707, remission 0.692). Estimated confidence intervals ranged from 26 to 62% PANSS reduction for response and remission.
Conclusions
Patients with a first episode of schizophrenia should improve by at least 30% in PANSS total score at week 2 to achieve response and remission.
Animal models of anxiety disorders emphasize the crucial role of locus ceruleus–noradrenergic (norepinephrine, NE) signaling, the basolateral amygdala (BLA) and their interactions in the expression of anxiety-like behavioral responses to stress. Despite clinical evidence for the efficacy of a β-noradrenergic receptor blockade with propranolol in the alleviation of anxiety symptoms and the secondary prevention of post traumatic stress disorder, preclinical evidence for a β-noradrenergic modulation of BLA activity in humans is missing.
Method
We combined functional magnetic resonance imaging in healthy volunteers with probabilistic mapping of intra-amygdalar responses to fearful, neutral and happy facial expressions to test the hypothesis that a β-noradrenergic receptor blockade with propranolol would inactivate the BLA.
Results
Consistent with our a priori hypothesis, propranolol diminished BLA responses to facial expressions, independent of their emotional valence. The absence of activity changes in probabilistically defined visual control regions underscores the specific action of propranolol in the BLA.
Conclusions
Our findings provide the missing link between the anxiolytic potential of propranolol and the biological basis of β-noradrenergic activation in the human BLA as a key target for the pharmacological inhibition of anxiety neurocircuitry. Moreover, our findings add to emerging evidence that NE modulates both the reactivity (sensitivity) and the operating characteristics (specificity) of the BLA via β-noradrenergic receptors.