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Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database.
The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared.
There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups.
These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.
Recent evidence points to a critical role of redox dysregulation induced oxidative stress in the pathophysiology of early phases of schizophrenia. An add-on trial with n-acetyl-cysteine (NAC) led to a reduction in negative symptoms in chronic schizophrenia patients. Aim of this study was to explore impact of addition of NAC to standard treatment in early psychosis (EP) patients.
Double-blind, randomized, placebo-controlled trial of addition of NAC, 2700 mg daily, to antipsychotic treatment over 6 months. Monthly assessment of PANSS, GAF, SOFAS and antipsychotics treatment; quantification of brain glutathione levels (GSHmPFC) by 1H-magnetic-resonance-spectroscopy and of blood cells glutathione (GSHBC) and glutathione peroxidase activity (GPxBC) as marker of oxidation status at the beginning and end of treatment.
Overall, 63 patients were included. Spectroscopy data showed that GSHmPFC increased by +23% in the NAC group, while it tended to decrease by −5% in the placebo group (P = 0.005). No significant difference between NAC and placebo was observed on global changes in negative symptoms, positive symptoms or functional outcome. However, in patients with high-baseline oxidation status (GPxBC>22.3U/gHb), subgroup explorations revealed an improvement of positive symptoms over time compared to patients with low-baseline GPx (P = 0.02).
While addition of NAC induced an increase of brain GSH, it had no impact on symptomatic and functional outcome in EP patients. However, in patients with high oxidation status, addition of NAC leads to significantly greater improvement in positive symptoms. Future studies on antioxidant interventions in EP should consider biomarker-guided treatment.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
During pregnancy, mothers-to-be should adapt their diet to meet increases in nutrient requirements. Pregnant women appear to be keener to adopt healthier diets, but are not always successful. The objective of the present study was to determine whether a guided, stepwise and tailored dietary counselling programme, designed using an optimisation algorithm, could improve the nutrient adequacy of the diet of pregnant women, beyond generic guidelines. Pregnant women (n 80) who attended Notre-Dame-de-Bon-Secours Maternity Clinic were randomly allocated to the control or intervention arm. Dietary data were obtained twice from an online 3-d dietary record. The nutrient adequacy of the diet was calculated using the PANDiet score, a 100-point diet quality index adapted to the specific nutrient requirements for pregnancy. Women were supplied with generic dietary guidelines in a reference booklet. In the intervention arm, they also received nine sets of tailored dietary advice identified by an optimisation algorithm as best improving their PANDiet score. Pregnant women (n 78) completed the 12-week dietary follow-up. Initial PANDiet scores were similar in the control and intervention arms (60·4 (sd 7·3) v. 60·3 (sd 7·3), P = 0·92). The PANDiet score increased in the intervention arm (+3·6 (sd 9·3), P = 0·02) but not in the control arm (−0·3 (sd 7·3), P = 0·77), and these changes differed between arms (P = 0·04). In the intervention arm, there were improvements in the probabilities of adequacy for α-linolenic acid, thiamin, folate and cholesterol intakes (P < 0·05). Tailored dietary counselling using a computer-based algorithm is more effective than generic dietary counselling alone in improving the nutrient adequacy of the diet of French women in mid-pregnancy.
We present a broad study of linear, clustered, noble gas puffs irradiated with the frequency doubled (527 nm) Titan laser at Lawrence Livermore National Laboratory. Pure Ar, Kr, and Xe clustered gas puffs, as well as two mixed-gas puffs consisting of KrAr and XeKrAr gases, make up the targets. Characterization experiments to determine gas-puff density show that varying the experimental parameter gas-delay timing (the delay between gas puff initialization and laser-gas-puff interaction) provides a simple control over the gas-puff density. X-ray emission (>1.4 keV) is studied as a function of gas composition, density, and delay timing. Xe gas puffs produce the strongest peak radiation in the several keV spectral region. The emitted radiation was found to be anisotropic, with smaller X-ray flux observed in the direction perpendicular to both laser beam propagation and polarization directions. The degree of anisotropy is independent of gas target type but increases with photon energy. X-ray spectroscopic measurements estimate plasma parameters and highlight their difference with previous studies. Electron beams with energy in excess of 72 keV are present in the noble gas-puff plasmas and results indicate that Ar plays a key role in their production. A drastic increase in harder X-ray emissions (X-ray flash effect) and multi-MeV electron-beam generation from Xe gas-puff plasma occurred when the laser beam was focused on the front edge of the linear gas puff.
Major depressive disorder (MDD) is a highly heterogeneous condition in terms of symptom presentation and, likely, underlying pathophysiology. Accordingly, it is possible that only certain individuals with MDD are well-suited to antidepressants. A potentially fruitful approach to parsing this heterogeneity is to focus on promising endophenotypes of depression, such as neuroticism, anhedonia, and cognitive control deficits.
Within an 8-week multisite trial of sertraline v. placebo for depressed adults (n = 216), we examined whether the combination of machine learning with a Personalized Advantage Index (PAI) can generate individualized treatment recommendations on the basis of endophenotype profiles coupled with clinical and demographic characteristics.
Five pre-treatment variables moderated treatment response. Higher depression severity and neuroticism, older age, less impairment in cognitive control, and being employed were each associated with better outcomes to sertraline than placebo. Across 1000 iterations of a 10-fold cross-validation, the PAI model predicted that 31% of the sample would exhibit a clinically meaningful advantage [post-treatment Hamilton Rating Scale for Depression (HRSD) difference ⩾3] with sertraline relative to placebo. Although there were no overall outcome differences between treatment groups (d = 0.15), those identified as optimally suited to sertraline at pre-treatment had better week 8 HRSD scores if randomized to sertraline (10.7) than placebo (14.7) (d = 0.58).
A subset of MDD patients optimally suited to sertraline can be identified on the basis of pre-treatment characteristics. This model must be tested prospectively before it can be used to inform treatment selection. However, findings demonstrate the potential to improve individual outcomes through algorithm-guided treatment recommendations.
Introduction: Understanding the spatial distribution of opioid abuse at the local level may facilitate community intervention strategies. The purpose of this analysis was to apply spatial analytical methods to determine clustering of opioid-related emergency medical services (EMS) responses in the City of Calgary. Methods: Using opioid-related EMS responses in the City of Calgary between January 1st through October 31st, 2017, we estimated the dissemination area (DA) specific spatial randomness effects by incorporating the spatial autocorrelation using intrinsic Gaussian conditional autoregressive model and generalized linear mixed models (GLMM). Global spatial autocorrelation was evaluated by Morans I index. Both Getis-Ord Gi and the LISA function in Geoda were used to estimate the local spatial autocorrelation. Two models were applied: 1) Poisson regression with DA-specific non-spatial random effects; 2) Poisson regression with DA-specific G-side spatial random effects. A pseudolikelihood approach was used for model comparison. Two types of cluster analysis were used to identify the spatial clustering. Results: There were 1488 opioid-related EMS responses available for analysis. Of the responses, 74% of the individuals were males. The median age was 33 years ( IQR: 26-42 years) with 65% of individuals between 20 and 39 years, and 27% between 40 and 64 years. In 62% of EMS responses, poisoning/overdose was the chief complaint. The global Morans Index implied the presence of global spatial autocorrelation. Comparing the two models applied suggested that the spatial model provided a better fit for the adjusted opioid-related EMS response rate. Calgary Center and East were identified as hot spots by both types of cluster analysis. Conclusion: Spatial modeling has a better predictability to assess potential high risk areas and identify locations for community intervention strategies. The clusters identified in Calgarys Center and East may have implications for future response strategies.
Introduction: With a Canadian aging population, the prevalence of mild traumatic brain injury (mTBI) among elderly is increasing and the age criterion of the Canadian CT head rule (CCHR) is challenged by many emergency physicians. We evaluated if increasing the age criterion of the CCHR would maintain its validity. Methods: We conducted an historical cohort study using the medical charts of all patients 65 years old or more who consulted at a Level One Trauma Centre emergency department (ED) for a mTBI between 2010 and 2014. The main outcome measures were clinically important brain injury (CIBI) on Computed Tomography (CT) and the presence of the CCHR criteria. The clinical and radiological data collection was standardized. Univariate analysis was performed to measure the predictive capacities of modified age cut-offs at 70 and 75 years old. Results: Out of the 104 confirmed mTBI in this study, 32 (30,8%) had CIBI on CT scan. Sensitivity and specificity [C.I. 95%] of the CCHR were 100% [89.1 - 100] and 0% [0.0 5.0] for an age criterion of 65 years old and above; 100% [89.1 - 100] and 4,2% [0.9 11.7] for a modified criterion of 70 years old; 100% [89.1 - 100] and 13,9% [6.9 24.1] for 75 years old. Furthermore, for an age criterion of 80 and 85 years old, sensitivity was respectively 90,6% [75.0 98.0] and 75,0% [56.6 88.5]. Conclusion: In our cohort, increasing the age criterion of the CCHR for minor head injury to 75 years old would benefit ED by further reducing CT scans without missing CIBI. A larger prospective study is indicated to confirm the proposed modification.
We have lately documented the importance of N-terminal pro-brain natriuretic peptide in aiding the diagnosis of Kawasaki disease.
We sought to investigate the potential value of N-terminal pro-brain natriuretic peptide pertaining to the prediction of coronary artery dilatation (Z-score>2.5) and/or of resistance to intravenous immunoglobulin therapy. We hypothesised that increased serum N-terminal pro-brain natriuretic peptide level correlates with increased coronary artery dilatation and/or resistance to intravenous immunoglobulin.
We carried out a prospective study involving newly diagnosed patients treated with 2 g/kg intravenous immunoglobulin within 5–10 days of onset of fever. Echocardiography was performed in all patients at onset, then weekly for 3 weeks, then at month 2, and month 3. Coronary arteries were measured at each visit, and coronary artery Z-score was calculated. All the patients had N-terminal pro-brain natriuretic peptide serum level measured at onset, and the Z-score calculated.
There were 109 patients enrolled at 6.58±2.82 days of fever, age 3.79±2.92 years. High N-terminal pro-brain natriuretic peptide level was associated with coronary artery dilatation at onset in 22.2 versus 5.6% for normal N-terminal pro-brain natriuretic peptide levels (odds ratio 4.8 [95% confidence interval 1.05–22.4]; p=0.031). This was predictive of cumulative coronary artery dilatation for the first 3 months (p=0.04–0.02), but not during convalescence at 2–3 months (odds ratio 1.28 [95% confidence interval 0.23–7.3]; p=non-significant). Elevated N-terminal pro-brain natriuretic peptide levels did not predict intravenous immunoglobulin resistance, 15.3 versus 13.5% (p=1).
Elevated N-terminal pro-brain natriuretic peptide level correlates with acute coronary artery dilatation in treated Kawasaki disease, but not with intravenous immunoglobulin resistance.
Neuroimaging measures of behavioral and emotional dysregulation can yield biomarkers denoting developmental trajectories of psychiatric pathology in youth. We aimed to identify functional abnormalities in emotion regulation (ER) neural circuitry associated with different behavioral and emotional dysregulation trajectories using latent class growth analysis (LCGA) and neuroimaging.
A total of 61 youth (9–17 years) from the Longitudinal Assessment of Manic Symptoms study, and 24 healthy control youth, completed an emotional face n-back ER task during scanning. LCGA was performed on 12 biannual reports completed over 5 years of the Parent General Behavior Inventory 10-Item Mania Scale (PGBI-10M), a parental report of the child's difficulty regulating positive mood and energy.
There were two latent classes of PGBI-10M trajectories: high and decreasing (HighD; n = 22) and low and decreasing (LowD; n = 39) course of behavioral and emotional dysregulation over the 12 time points. Task performance was >89% in all youth, but more accurate in healthy controls and LowD versus HighD (p < 0.001). During ER, LowD had greater activity than HighD and healthy controls in the dorsolateral prefrontal cortex, a key ER region, and greater functional connectivity than HighD between the amygdala and ventrolateral prefrontal cortex (p's < 0.001, corrected).
Patterns of function in lateral prefrontal cortical–amygdala circuitry in youth denote the severity of the developmental trajectory of behavioral and emotional dysregulation over time, and may be biological targets to guide differential treatment and novel treatment development for different levels of behavioral and emotional dysregulation in youth.
Within the last ten years there has been increasing
interest in tritium behaviour and distribution in the environment.
This is based partly on empirical findings that tritium discharged
mostly as HTO can become transformed into organic forms in environmental
samples. An international workshop was convened in France in 2012 to
gather the scientific community interested in organically bound
tritium to share their experience and to establish a current state
of knowledge. This paper summarises the outcome of the workshop,
which aimed to improve skills concerning OBT (Organically
Bound Tritium) determination, transfer and behaviour in the environment.
In order to improve OBT measurement credibility,
it was decided to conduct and promote OBT analysis
through inter-laboratory exercises. This practice will reduce uncertainty
in OBT analysis results, providing better OBT model
validation data and public dose assessments.
This work deals with the influence of sodium on the properties of CZTSSe material and solar cells. For that purpose, two types of substrates are compared, one with low sodium content (borosilicate glass), the other one with higher sodium content (soda-lime glass). In each case the Na-content in the CZTSSe passing from the substrate through the Mo back contact is quantified by secondary ion mass spectroscopy analysis. Photoluminescence spectroscopy indicates that better quality material is achievable when increasing the Na-content in the CZTSSe. The material characterization results are compared to the photovoltaic properties. Index Terms — Cu2ZnSn(S1-xSex)4, CZTSSe, CZTS, CZTSe, Sodium, Kesterite, thin film, solar cell.
Prior studies of adult post-traumatic stress disorder (PTSD) suggest abnormal functioning of prefrontal and limbic regions. Cumulative childhood and adult trauma exposures are major risk factors for developing adult PTSD, yet their contribution to neural dysfunction in PTSD remains poorly understood. This study aimed to examine the neural correlates of childhood and adult trauma exposure and post-traumatic stress symptoms (PTSS) within a single model.
Medication-free male combat veterans (n = 28, average age 26.6 years) with a wide range of PTSS were recruited from the community between 2010 and 2011. Subjects completed an emotional face-morphing task while undergoing functional magnetic resonance imaging (fMRI). Clinical ratings included the Clinician-Administered PTSD Scale (CAPS), Childhood Trauma Questionnaire (CTQ) and Combat Exposure Scale (CES). A priori regions were examined through multivariate voxelwise regression in SPM8, using depressive symptoms and IQ as covariates.
In the angry condition, CAPS scores correlated positively with activation in the medial prefrontal cortex [mPFC; Brodmann area (BA) 10, z = 3.51], hippocampus (z = 3.47), insula (z = 3.62) and, in earlier blocks, the amygdala. CES and CTQ correlated positively with activation in adjacent areas of the dorsal anterior cingulate cortex (dACC; BA 32, z = 3.70 and BA 24, z = 3.88 respectively). In the happy condition, CAPS, CTQ and CES were not correlated significantly with activation patterns.
dACC activation observed in prior studies of PTSD may be attributable to the cumulative effects of childhood and adult trauma exposure. By contrast, insula, hippocampus and amygdala activation may be specific to PTSS. The specificity of these results to threat stimuli, but not to positive stimuli, is consistent with abnormalities in threat processing associated with PTSS.
Patients with major depressive disorder (MDD) present with highly heterogeneous symptom profiles. We aimed to examine whether individual differences in amygdala activity to emotionally salient stimuli were related to heterogeneity in lifetime levels of depressive and subthreshold manic symptoms among adults with MDD.
We compared age- and gender-matched adults with MDD (n = 26) with healthy controls (HC, n = 28). While undergoing functional magnetic resonance imaging, participants performed an implicit emotional faces task: they labeled a color flash superimposed upon initially neutral faces that dynamically morphed into one of four emotions (angry, fearful, sad, happy). Region of interest analyses examined group differences in amygdala activity. For conditions in which adults with MDD displayed abnormal amygdala activity versus HC, within-group analyses examined amygdala activity as a function of scores on a continuous measure of lifetime depression-related and mania-related pathology.
Adults with MDD showed significantly greater right-sided amygdala activity to angry and happy conditions than HC (p < 0.05, corrected). Multiple regression analyses revealed that greater right-amygdala activity to the happy condition in adults with MDD was associated with higher levels of subthreshold manic symptoms experienced across the lifespan (p = 0.002).
Among depressed adults with MDD, lifetime features of subthreshold mania were associated with abnormally elevated amygdala activity to emerging happy faces. These findings are a first step toward identifying biomarkers that reflect individual differences in neural mechanisms in MDD, and challenge conventional mood disorder diagnostic boundaries by suggesting that some adults with MDD are characterized by pathophysiological processes that overlap with bipolar disorder.
Individuals with bipolar disorder demonstrate abnormal social function. Neuroimaging studies in bipolar disorder have shown functional abnormalities in neural circuitry supporting face emotion processing, but have not examined face identity processing, a key component of social function. We aimed to elucidate functional abnormalities in neural circuitry supporting face emotion and face identity processing in bipolar disorder.
Twenty-seven individuals with bipolar disorder I currently euthymic and 27 healthy controls participated in an implicit face processing, block-design paradigm. Participants labeled color flashes that were superimposed on dynamically changing background faces comprising morphs either from neutral to prototypical emotion (happy, sad, angry and fearful) or from one identity to another identity depicting a neutral face. Whole-brain and amygdala region-of-interest (ROI) activities were compared between groups.
There was no significant between-group difference looking across both emerging face emotion and identity. During processing of all emerging emotions, euthymic individuals with bipolar disorder showed significantly greater amygdala activity. During facial identity and also happy face processing, euthymic individuals with bipolar disorder showed significantly greater amygdala and medial prefrontal cortical activity compared with controls.
This is the first study to examine neural circuitry supporting face identity and face emotion processing in bipolar disorder. Our findings of abnormally elevated activity in amygdala and medial prefrontal cortex (mPFC) during face identity and happy face emotion processing suggest functional abnormalities in key regions previously implicated in social processing. This may be of future importance toward examining the abnormal self-related processing, grandiosity and social dysfunction seen in bipolar disorder.
La mesure précise des champs de contraintes autour de précipités inclus dans une matrice
cristalline est nécessaire à la compréhension de l’interaction entre les dislocations et
les précipités de matériaux structurellement durcis. Ces interactions contrôlent le
mouvement des dislocations, et donnent donc des informations sur les propriétés mécaniques
des matériaux. Les champs de contraintes autour des précipités de petite taille peuvent
être obtenus à partir d’images de microscopie électronique en transmission en haute
résolution (METHR) en utilisant la méthode des phases géométrique (GPA). Cette méthode est
utilisable de façon générale pour caractériser les contraintes à l’échelle nanométrique
autour des précipités de structure complexe ou inconnue et est appliquée ici dans les cas
de l’alliage d’aluminium 2198. Dans ce matériau, il est montré que les champs de
déformation autour d’un nanoprécipité en forme de disque et d’épaisseur faible peuvent
être modélisés par ceux d’une dislocation dissociée.
One aim of personalized medicine is to determine which treatment is to be preferred for an individual patient, given all patient information available. Particularly in mental health, however, there is a lack of a single objective, reliable measure of outcome that is sensitive to crucial individual differences among patients.
We examined the feasibility of quantifying the total clinical value provided by a treatment (measured by both harms and benefits) in a single metric. An expert panel was asked to compare 100 pairs of patients, one from each treatment group, who had participated in a randomized clinical trial (RCT) involving interpersonal psychotherapy (IPT) and escitalopram, selecting the patient with the preferred outcome considering both benefits and harms.
From these results, an integrated preference score (IPS) was derived, such that the differences between any two patients' IPSs would predict the clinicians' preferences. This IPS was then computed for all patients in the RCT. A second set of 100 pairs was rated by the panel. Their preferences were highly correlated with the IPS differences (r=0.84). Finally, the IPS was used as the outcome measure comparing IPT and escitalopram. The 95% confidence interval (CI) for the effect size comparing treatments indicated clinical equivalence of the treatments.
A metric that combines benefits and harms of treatments could increase the value of RCTs by making clearer which treatments are preferable and, ultimately, for whom. Such methods result in more precise estimation of effect sizes, without increasing the required sample size.
Radioactive releases in the environment around civilian nuclear facilities have significantly decreased over the last few decades, with the exception of tritium. In late 2007, papers published in the UK (RIFE 11 report, study by the HPA’s Advisory Group on Ionising Radiation (AGIR)) raised questions as to the behaviour of tritium in the environment. Given this context, ASN wanted to get a clear analysis of the existing studies into the issue and in early 2008 decided to establish two independent pluralistic working groups. Two main points of the discussions are on the bioaccumulation and the biological effects.
In the end of 2007, ASN launched an internal reflexion on the information of the public on the radioactivity levels in the environment. The aim was to develop a radioactivity environment scale or index, based on existing scales used for air pollution. After the presentation of a demonstration model by ASN in 2008 to HCTISN, a working group (WG) was constituted in the beginning of 2009 by ASN with stakeholders with the approval in March 2009 of the goals to be reached by this index: a communication instrument to qualify the information of the radioactivity levels in the environment, consistent with INES, particularly when sanitary consequences may occur, easy to elaborate from the available measured values of radioactivity and always usable for any location, independently of an incidental or accidental situation.
The United States Army is concerned that its installations face multiple resource issues, including water security. Critical water issues include supply, cost, and quality. Strategies are needed to mitigate any adverse affects. To develop these strategies, information was gathered from national watershed screenings and regional water budgets, including supply and demand data from regions containing Army installations. The information was then used to develop installation water-demand projections that look beyond the boundaries of an installation and out 30 years into the future to identify the potential for water scarcity. Fort Bragg, North Carolina, and Fort Bliss, Texas–New Mexico, were used as specific examples to illustrate the critical role that water plays in the future of Army installations. Fort Bragg is not likely to have water availability issues out to 2030, because it will be accessing municipal water supplies. Fort Bliss will likely face water availability issues because the aquifer from which it draws its potable water is being used by more and more other parties.
Since the detection of nanoparticles is a major issue in nano sciences, we have developed two instruments for the fast imaging of individual nano objects. The first one is based on a spatial modulation of the sample using an incoherent dark field illumination and a multiplexed lock in detection.
The second instrument uses digital heterodyne holography. Both instruments make it possible to achieve a high signal-to-noise ratio and therefore to detect very low signal.