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In a prospective cohort design, we investigated: i) diagnostic stability of initially antipsychotic-naïve schizophrenia patients, ii) symptom severity including symptomatic remission, and iii) functional remission including full recovery.
We included 143 antipsychotic-naïve patients with first-episode schizophrenia or schizoaffective disorder. After 4–18 years, we clinically re-evaluated diagnosis, symptom severity and functioning for 70 patients. From the nationwide Danish registers, we extracted pragmatic outcome measures for 142 patients. We examined associations between baseline variables (age at diagnosis, sex, and premorbid intelligence) and long-term outcome status (symptomatic and functional remission).
At 4–18 years follow-up, 80% met the criteria for schizophrenia or schizoaffective disorder, however, despite the high diagnostic stability 53% met the criteria of symptomatic and/or functional remission. Symptomatic remission characterized 34% of the patients and was associated with female sex, better premorbid intelligence, and a younger age at schizophrenia diagnosis. Functional remission characterized 41% of the patients and 17% of patients met criteria for full recovery both of which were associated with female sex. The clinically re-evaluated patients did not differ from the drop-outs on key register-based variables.
We confirm the emerging evidence of a decreasing long-term diagnostic stability of schizophrenia, and a protective role of female sex. The association between premorbid intelligence and symptomatic remission underscores the pertinence of including cognitive deficits in the diagnostic category of schizophrenia. The association between younger age at diagnosis and symptomatic remission may reflect positive effects of early detection or a drift in the interpretation of the diagnostic classification system.
Poor response to dopaminergic antipsychotics constitutes a major challenge in the treatment of psychotic disorders and markers for non-response during first-episode are warranted. Previous studies have found increased levels of glutamate and γ-aminobutyric acid (GABA) in non-responding first-episode patients compared to responders, but it is unknown if non-responders can be identified using reference levels from healthy controls (HCs).
Thirty-nine antipsychotic-naïve patients with first-episode psychosis and 36 matched HCs underwent repeated assessments with the Positive and Negative Syndrome Scale and 3T magnetic resonance spectroscopy. Glutamate scaled to total creatine (/Cr) was measured in the anterior cingulate cortex (ACC) and left thalamus, and levels of GABA/Cr were measured in ACC. After 6 weeks, we re-examined 32 patients on aripiprazole monotherapy and 35 HCs, and after 26 weeks we re-examined 30 patients on naturalistic antipsychotic treatment and 32 HCs. The Andreasen criteria defined non-response.
Before treatment, thalamic glutamate/Cr was higher in the whole group of patients but levels normalized after treatment. ACC levels of glutamate/Cr and GABA/Cr were lower at all assessments and unaffected by treatment. When compared with HCs, non-responders at week 6 (19 patients) and week 26 (16 patients) had higher baseline glutamate/Cr in the thalamus. Moreover, non-responders at 26 weeks had lower baseline GABA/Cr in ACC. Baseline levels in responders and HCs did not differ.
Glutamatergic and GABAergic abnormalities in antipsychotic-naïve patients appear driven by non-responders to antipsychotic treatment. If replicated, normative reference levels for glutamate and GABA may aid estimation of clinical prognosis in first-episode psychosis patients.
Polymer additives can substantially reduce the drag of turbulent flows and the upper limit, the so-called state of ‘maximum drag reduction’ (MDR), is to a good approximation independent of the type of polymer and solvent used. Until recently, the consensus was that, in this limit, flows are in a marginal state where only a minimal level of turbulence activity persists. Observations in direct numerical simulations at low Reynolds numbers (
) using minimal sized channels appeared to support this view and reported long ‘hibernation’ periods where turbulence is marginalized. In simulations of pipe flow at
near transition we find that, indeed, with increasing Weissenberg number (
), turbulence expresses long periods of hibernation if the domain size is small. However, with increasing pipe length, the temporal hibernation continuously alters to spatio-temporal intermittency and here the flow consists of turbulent puffs surrounded by laminar flow. Moreover, upon an increase in
, the flow fully relaminarizes, in agreement with recent experiments. At even larger
, a different instability is encountered causing a drag increase towards MDR. Our findings hence link earlier minimal flow unit simulations with recent experiments and confirm that the addition of polymers initially suppresses Newtonian turbulence and leads to a reverse transition. The MDR state on the other hand results at these low
from a separate instability and the underlying dynamics corresponds to the recently proposed state of elasto-inertial turbulence.
A wealth of clinical studies have identified objective biomarkers, which separate schizophrenia patients from healthy controls on a group level, but current diagnostic systems solely include clinical symptoms. In this study, we investigate if machine learning algorithms on multimodal data can serve as a framework for clinical translation.
Forty-six antipsychotic-naïve, first-episode schizophrenia patients and 58 controls underwent neurocognitive tests, electrophysiology, and magnetic resonance imaging (MRI). Patients underwent clinical assessments before and after 6 weeks of antipsychotic monotherapy with amisulpride. Nine configurations of different supervised machine learning algorithms were applied to first estimate the unimodal diagnostic accuracy, and next to estimate the multimodal diagnostic accuracy. Finally, we explored the predictability of symptom remission.
Cognitive data significantly classified patients from controls (accuracies = 60–69%; p values = 0.0001–0.009). Accuracies of electrophysiology, structural MRI, and diffusion tensor imaging did not exceed chance level. Multimodal analyses with cognition plus any combination of one or more of the remaining three modalities did not outperform cognition alone. None of the modalities predicted symptom remission.
In this multivariate and multimodal study in antipsychotic-naïve patients, only cognition significantly discriminated patients from controls, and no modality appeared to predict short-term symptom remission. Overall, these findings add to the increasing call for cognition to be included in the definition of schizophrenia. To bring about the full potential of machine learning algorithms in first-episode, antipsychotic-naïve schizophrenia patients, careful a priori variable selection based on independent data as well as inclusion of other modalities may be required.
Cognitive deficits are already present in early stages of schizophrenia. P3a and P3b event-related potentials (ERPs) are believed to underlie the processes of attention and working memory (WM), yet limited research has been performed on the associations between these parameters. Therefore, we explored possible associations between P3a/b amplitudes and cognition in a large cohort of antipsychotic-naïve, first-episode schizophrenia (AN-FES) patients and healthy controls (HC).
Seventy-three AN-FES patients and 93 age- and gender-matched HC were assessed for their P3a/b amplitude with an auditory oddball paradigm. In addition, subjects performed several subtests from the Cambridge Neuropsychological Test Automated Battery (CANTAB).
AN-FES patients had significantly reduced P3a/b amplitudes, as well as significantly lower scores on all cognitive tests compared with HC. Total group correlations revealed positive associations between P3b amplitude and WM and sustained attention and negative associations with all reaction time measures. These associations appeared mainly driven by AN-FES patients, where we found a similar pattern. No significant associations were found between P3b amplitude and cognitive measures in our HC. P3a amplitude did not correlate significantly with any cognitive measures in either group, nor when combined.
Our results provide further evidence for P3a/b amplitude deficits and cognitive deficits in AN-FES patients, which are neither due to antipsychotics nor to disease progress. Furthermore, our data showed significant, yet weak associations between P3b and cognition. Therefore, our data do not supply evidence for deficient P3a/b amplitudes as direct underlying factors for cognitive deficits in schizophrenia.
Schizophrenia has been associated with changes in both cortical thickness and surface area, but antipsychotic exposure, illness progression and substance use may confound observations. In antipsychotic-naïve schizophrenia patients, we investigated cortical thickness and surface area as well as mean curvature before and after monotherapy with amisulpride, a relatively selective dopamine D2/3 receptor antagonist.
Fifty-six patients and 59 matched healthy controls (HCs) underwent T1-weighted 3T magnetic resonance imaging. Forty-one patients and 51 HCs were re-scanned. FreeSurfer-processed baseline, follow-up values and symmetrized percentage changes (SPC) in cortical structures were analysed using univariate analysis of variance. Clinical measures comprised psychopathology ratings, assessment of functioning and tests of premorbid and current intelligence. We applied false discovery rate correction to account for multiple comparisons.
At baseline, groups did not differ in cortical thickness or surface area; however, curvature in the left hemisphere was higher in patients (p = 0.015). In both patients and HCs, higher curvature was associated with lower premorbid (p = 0.009) and current intelligence (p < 0.001). Lower surface area was associated with lower premorbid intelligence (p = 0.017). After 6 weeks, the cortical structures did not differ between groups. Amisulpride dose (275.0 mg/day) did not correlate with any cortical structures (p > 0.43). Cortical thickness SPC was negatively associated with symptom improvement (p = 0.002).
Schizophrenia appears associated with subtle, yet clinically relevant aberrations in cortical structures. Mean curvature holds promise as a sensitive supplement to cortical thickness and surface area to detect complex structural brain abnormalities.
Little is known about potential harmful effects as a consequence of self-guided internet-based cognitive behaviour therapy (iCBT), such as symptom deterioration rates. Thus, safety concerns remain and hamper the implementation of self-guided iCBT into clinical practice. We aimed to conduct an individual participant data (IPD) meta-analysis to determine the prevalence of clinically significant deterioration (symptom worsening) in adults with depressive symptoms who received self-guided iCBT compared with control conditions. Several socio-demographic, clinical and study-level variables were tested as potential moderators of deterioration.
Randomised controlled trials that reported results of self-guided iCBT compared with control conditions in adults with symptoms of depression were selected. Mixed effects models with participants nested within studies were used to examine possible clinically significant deterioration rates.
Thirteen out of 16 eligible trials were included in the present IPD meta-analysis. Of the 3805 participants analysed, 7.2% showed clinically significant deterioration (5.8% and 9.1% of participants in the intervention and control groups, respectively). Participants in self-guided iCBT were less likely to deteriorate (OR 0.62, p < 0.001) compared with control conditions. None of the examined participant- and study-level moderators were significantly associated with deterioration rates.
Self-guided iCBT has a lower rate of negative outcomes on symptoms than control conditions and could be a first step treatment approach for adult depression as well as an alternative to watchful waiting in general practice.
Vulnerability of satellite-based navigation signals to intentional and unintentional interference calls for a high-level overview of Global Navigation Satellite System (GNSS) threats occurring globally to understand the magnitude and evolution of the problem. Therefore, a mechanism needs to be developed whereby disparate monitoring systems will be capable of contributing to a common entity of basic information about the threat scenarios they experience. This paper begins with a literature survey of 37 state-of-the-art GNSS threat monitoring systems, which have been analysed based on their respective operational features - constellations monitored and whether they possess the capability to perform interference-type classification, spoofing detection, and interference localisation. Also described is a comparative analysis of four GNSS threat reporting formats in use today. Based on these studies, the paper describes the Horizon2020 Standardisation of GNSS Threat Reporting and Receiver Testing through International Knowledge Exchange, Experimentation and Exploitation (STRIKE3) proposed integrated threat monitoring demonstration system and related standardised threat reporting message, to enable a high-level overview of the prevailing international GNSS threat scenarios and its evolution over time.
Strategies for the involvement of primary care in the management of patients with presumed or diagnosed dementia are heterogeneous across Europe. We wanted to explore attitudes of primary care physicians (PCPs) when managing dementia: (i) the most popular cognitive tests, (ii) who had the right to initiate or continue cholinesterase inhibitor or memantine treatment, and (iii) the relationship between the permissiveness of these rules/guidelines and PCP's approach in the dementia investigations and assessment.
Key informant survey. Setting: Primary care practices across 25 European countries. Subjects: Four hundred forty-five PCPs responded to a self-administered questionnaire. Two-step cluster analysis was performed using characteristics of the informants and the responses to the survey. Main outcome measures: Two by two contingency tables with odds ratios and 95% confidence intervals were used to assess the association between categorical variables. A multinomial logistic regression model was used to assess the association of multiple variables (age class, gender, and perceived prescription rules) with the PCPs’ attitude of “trying to establish a diagnosis of dementia on their own.”
Discrepancies between rules/guidelines and attitudes to dementia management was found in many countries. There was a strong association between the authorization to prescribe dementia drugs and pursuing dementia diagnostic work-up (odds ratio, 3.45; 95% CI 2.28–5.23).
Differing regulations about who does what in dementia management seemed to affect PCP's engagement in dementia investigations and assessment. PCPs who were allowed to prescribe dementia drugs also claimed higher engagement in dementia work-up than PCPs who were not allowed to prescribe.
Improvements in colorectal cancer (CRC) detection and treatment have led to greater numbers of CRC survivors, for whom there is limited evidence on which to provide dietary guidelines to improve survival outcomes. Higher intake of red and processed meat and lower intake of fibre are associated with greater risk of developing CRC, but there is limited evidence regarding associations with survival after CRC diagnosis. Among 3789 CRC cases in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, pre-diagnostic consumption of red meat, processed meat, poultry and dietary fibre was examined in relation to CRC-specific mortality (n 1008) and all-cause mortality (n 1262) using multivariable Cox regression models, adjusted for CRC risk factors. Pre-diagnostic red meat, processed meat or fibre intakes (defined as quartiles and continuous grams per day) were not associated with CRC-specific or all-cause mortality among CRC survivors; however, a marginal trend across quartiles of processed meat in relation to CRC mortality was detected (P 0·053). Pre-diagnostic poultry intake was inversely associated with all-cause mortality among women (hazard ratio (HR)/20 g/d 0·92; 95 % CI 0·84, 1·00), but not among men (HR 1·00; 95 % CI 0·91, 1·09) (Pfor heterogeneity=0·10). Pre-diagnostic intake of red meat or fibre is not associated with CRC survival in the EPIC cohort. There is suggestive evidence of an association between poultry intake and all-cause mortality among female CRC survivors and between processed meat intake and CRC-specific mortality; however, further research using post-diagnostic dietary data is required to confirm this relationship.
In the outskirts of massive high-redshift radio galaxies, powerful radio-jets often interact with ambient warm Lyα-emitting gas. We present the discovery of luminous reservoirs of cold molecular gas in these environments, based on CO(1-0) observations with the Australia Telescope Compact Array. The CO-emission is aligned with the radio jets, and found tens of kpc outside the host galaxy. These molecular gas reservoirs have CO luminosities in the range of those found in submm-galaxies (L'CO ~ 4-9 × 1010 K km/s pc2), but they lack any near-infrared counterpart in deep Spitzer imaging. These results suggest that jet-triggered feedback takes place in the circum-galactic environment of high-z radio galaxies. We prefer the interpretation that the CO-emitting gas is formed when the propagating jets enrich, shock and cool pre-existing dusty halo gas. We further argue that sensitive low-surface-brightness CO observations, using radio interferometers in very compact array-configurations, are essential to study the role of the cold molecular medium in the outskirts of massive high-z galaxies.
Commission 15 of the International Astronomical Union (IAU), entitled Physical Study of Comets and Minor Planets, was founded in 1935 and dissolved in 2015, following the reorganization of IAU. In 80 years of Commission 15, tremendous progress has been made on the knowledge of these objets, thanks to the combined efforts of ground- and space-based observations, space mission rendezvous and flybys, laboratory simulation and analyses of returned samples, and theoretical and numerical modeling. Together with dynamical studies of the Solar System, this discipline has provided a much deeper understanding of how the Solar System formed and evolved. We present a legacy report of Commission 15, which highlights key milestones in the exploration and knowledge of the small bodies of the Solar System.
Terrestrial radar interferometry (TRI) is a new technique for studying ice motion and volume change of glaciers. TRI is especially useful for temporally and spatially dense measurements of highly dynamic glacial termini. We conducted a TRI survey of Breiðamerkurjökull, a marine-terminating glacier in Iceland, imaging its terminus near the end of the melt season in 2011, 2012 and 2013. The ice velocities were as high as 5 m d−1, with the fastest velocities near the calving front. Retreat of the glacier over the 3 year observation period was accompanied by strong embayment formation. Iceberg tracking with the radar shows high current velocities near the embayment, probably indicating strong meltwater outflow and mixing with relatively warm lagoon water.
While management according to biological reference points is well established for many commercial marine fisheries, similar systems for more leisure based fisheries for freshwater fishes are less common. This paper describes the scientific foundation for management according to conservation limits and management targets for Norwegian populations of Atlantic salmon, a highly valued and heavily exploited anadromous fish species. Based on stock recruitment relationships during the freshwater phase, the biomass of females necessary to attain the carrying capacity (yielding average maximum recruitment) has been established as conservation limits for each of the 439 Norwegian populations. Using a simulation model based on reported catch and estimates of exploitation rates, the probability and percentage attainment of the conservation limits have been assessed annually since 2008, and exploitation advice provided for 176 of the largest populations. The number of populations that attained their conservation limits increased substantially after the new management scheme was introduced, despite that the number of returning salmon remained at historical low levels. Overall the populations evaluated in 2011 were at 95% of their conservation limits compared to 91% in 2008 and 85% in 2005. The improvement could largely be attributed to reduced exploitation rates, due to new restrictions in both the marine and river fisheries. The new management scheme also improved the catch statistics and stimulated data acquisition for management. Implementation of management according to conservation limits has been a success in terms of attaining the main management goal of protecting the Atlantic salmon populations by ensuring that an increasing number of the populations likely are at their maximum reproductive capacity. Long-term increases in fisheries yield, the secondary management goal, are likely to be attained, but remain to be documented. Reference point based management of Atlantic salmon exemplifies management within the intersection of fisheries management and conservation biology, borrowing principles from both sides.
The business meeting of IAU Commission 15 (C15) took place in Beijing on 29 August 2012, from 14:00 to 18:00, in room 405 of the China National Convention Center. This report of the business meeting of Commission 15 at the 2012 IAU GA is based on the report provided by Alberto Cellino, past president, and on the minutes taken by Daniel Hestroffer, secretary of Commission 15 in the triennium 2009 to 2012, and current secretary.
To screen biomaterials in a materiomics approach, libraries of materials are produced. Different materials are used, varying from metals and cements, to covalent polymers that can be either premixed or polymerized in situ, to supramolecular systems that can be applied in a modular approach. This chapter describes the generation of such libraries using different kinds of materials and chemistries. Additionally, the advantages and limitations of the application of these different systems/biomaterials in a materiomics approach are discussed.
Different synthetic biomaterials are used for many biomedical applications, varying from metals and ceramic cements, to polymers and supramolecular systems. To screen these biomaterials in a materiomics approach, as said above, libraries of materials are produced. Variations in biomaterials are screened as continuous gradients or in a discrete fashion. The properties that are varied and methods used to create variation within these libraries depend on the type of biomaterial. For the hard metal and ceramic-based biomaterials, the surface interaction with tissue is the property of most interest, and therefore properties such as surface roughness and topography are varied. Covalent polymers are diversified using combinatorial chemistry. The dynamic and self-assembling nature of supramolecular systems allows for the development of material libraries using a modular approach by mixing and matching of different compounds modified with supramolecular moieties.
The variable high-order multiblock overlapping (overset) grids method of Sjögreen & Yee [CiCP, Vol. 5, 2009] for a perfect gas has been extended to nonequilibrium flows. This work makes use of the recently developed high-order well-balanced shock-capturing schemes and their filter counterparts [Wang et al., J. Comput. Phys., 2009, 2010] that exactly preserve certain non-trivial steady state solutions of the chemical nonequilibrium governing equations. Multiscale turbulence with strong shocks and flows containing both steady and unsteady components is best treated by mixing of numerical methods and switching on the appropriate scheme in the appropriate subdomains of the flow fields, even under the multiblock grid or adaptive grid refinement framework. While low dissipative sixth- or higher-order shock-capturing filter methods are appropriate for unsteady turbulence with shocklets, second- and third- order shock-capturing methods are more effective for strong steady or nearly steady shocks in terms of convergence. It is anticipated that our variable high-order overset grid framework capability with its highly modular design will allow for an optimum synthesis of these new algorithms in such a way that the most appropriate spatial discretizations can be tailored for each particular region of the flow. In this paper some of the latest developments in single block high-order filter schemes for chemical nonequilibrium flows are applied to overset grid geometries. The numerical approach is validated on a number of test cases characterized by hypersonic conditions with strong shocks, including the reentry flow surrounding a 3D Apollo-like NASA Crew Exploration Vehicle that might contain mixed steady and unsteady components, depending on the flow conditions.
Due to its proximity, the neutral hydrogen belonging to Cen A can be observed at high resolution with good sensitivity. This allows us to study the morphology and kinematics in detail, in order to understand the evolution of this radio-loud source (e.g. merger history, AGN activity). At the same time, it is important to compare results to other sources of the same class (i.e. early-type galaxies in general and radio galaxies in particular) to see how Cen A fits into the global picture of early-type/radio galaxy evolution. The amount of Hi, the morphology of a warped disk with Hi clouds surrounding the disk and the regular kinematics of the inner part of the Hi disk are not unusual for early-type galaxies. The growing evidence that mergers are not necessarily responsible for AGN activity fits with the observational result that the recent merger event in Cen A is not directly connected to the current phase of activity. Based on these results, we conclude that Cen A has typical neutral hydrogen properties for an early-type and radio galaxy and it can therefore — from the perspective of Hi — be seen as a typical example of its class.
Over the past three decades, ultrashort laser pulses have been demonstrated to be a very powerful tool to investigate materials properties at the nanoscale. A key driving force is the high-time resolution required to study heat transfer across interfaces and in thin films. The Time-Domain Thermoreflectance (TDTR) is now widely used. This optical technique offers an interesting alternative to electrical approaches such as the 3ω method. We present a complete study of the TDTR signals. We investigate the influence of the modulation frequency on the measured signals and we show how this experimental parameter could be set to enhance or reduce the sensitivity to a specific thermal parameter. The dependence of the measured “apparent” thermal conductivity of the thin film as a function of the modulation frequency is discussed. Results are applied to investigate thermal properties of a series of InGaAs samples with embedded ErAs nanoparticles.