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For patients with major depressive disorder (MDD) experiencing side-effects or non-response to their first antidepressant, little is known regarding the effect of switching between a tricyclic antidepressant (TCA) and a selective serotonin reuptake inhibitor (SSRI).
To compare the switch between the TCA nortriptyline and the SSRI escitalopram.
Among 811 adults with MDD treated with nortriptyline or escitalopram for up to 12 weeks, 108 individuals switched from nortriptyline to escitalopram or vice versa because of side-effects or non-response (trial registration: EudraCT No.2004-001723-38 (https://eudract.ema.europa.eu/) and ISRCTN No.03693000 (http://www.controlled-trials.com)). Patients were followed for up to 26 weeks after switching and response was measured with the Montgomery–Åsberg Depression Rating scale (MADRS). We performed adjusted mixed-effects linear regression models with full information maximum likelihood estimation reporting β-coefficients with 95% CIs.
Switching antidepressants resulted in a significant decrease in MADRS scores. This was present for switchers from escitalopram to nortriptyline (n = 36, β = −0.38, 95% CI −0.51 to −0.25, P<0.001) and from nortriptyline to escitalopram (n = 72, β = −0.34, 95% CI −0.41 to −0.26, P<0.001). Both switching options resulted in significant improvement among individuals who switched because of non-response or side-effects. The results were supported by analyses on other rating scales and symptom dimensions.
These results suggest that switching from a TCA to an SSRI or vice versa after non-response or side-effects to the first antidepressant may be a viable approach to achieve response among patients with MDD.
Declarations of interest
K.J.A. holds an Alberta Centennial Addiction and Mental Health Research Chair, funded by the Government of Alberta. K.J.A. has been a member of various advisory boards, received consultancy fees and honoraria, and has received research grants from various companies including Johnson and Johnson Pharmaceuticals Research and Development and Bristol-Myers Squibb Pharmaceuticals Limited. D.S. has served on advisory boards for, and received unrestricted grants from, Lundbeck and AstraZeneca. A.F. and P.M. have received honoraria for participating in expert panels for Lundbeck and GlaxoSmithKline.
Depression and obesity are highly prevalent, and major impacts on public health frequently co-occur. Recently, we reported that having depression moderates the effect of the FTO gene, suggesting its implication in the association between depression and obesity.
To confirm these findings by investigating the FTO polymorphism rs9939609 in new cohorts, and subsequently in a meta-analysis.
The sample consists of 6902 individuals with depression and 6799 controls from three replication cohorts and two original discovery cohorts. Linear regression models were performed to test for association between rs9939609 and body mass index (BMI), and for the interaction between rs9939609 and depression status for an effect on BMI. Fixed and random effects meta-analyses were performed using METASOFT.
In the replication cohorts, we observed a significant interaction between FTO, BMI and depression with fixed effects meta-analysis (β=0.12, P = 2.7 × 10−4) and with the Han/Eskin random effects method (P = 1.4 × 10−7) but not with traditional random effects (β = 0.1, P = 0.35). When combined with the discovery cohorts, random effects meta-analysis also supports the interaction (β = 0.12, P = 0.027) being highly significant based on the Han/Eskin model (P = 6.9 × 10−8). On average, carriers of the risk allele who have depression have a 2.2% higher BMI for each risk allele, over and above the main effect of FTO.
This meta-analysis provides additional support for a significant interaction between FTO, depression and BMI, indicating that depression increases the effect of FTO on BMI. The findings provide a useful starting point in understanding the biological mechanism involved in the association between obesity and depression.
Informed application of habitat management measures is crucial, especially in saltmarshes that function as last refuges for breeding waders in Europe. Despite a reduction in agricultural use of saltmarshes since the establishment of the Wadden Sea National Parks at the end of the 1980s, there remains controversy regarding management measures such as the timing of mowing. We modelled the proportion of nests and chicks that would be jeopardised by mowing at different dates, using long-term breeding data of the Common Redshank Tringa totanus – an endangered and widespread indicator species of saltmarshes – from four study sites in the German Wadden Sea. At two study sites in the western Jadebusen, the proportion of broods that were at risk of being killed when mowing began on 1 July ranged between 78% in early, to 96% in late, breeding years, averaging 87%. Although Common Redshanks in the eastern Jadebusen started breeding one week earlier, the model still predicted a loss of 73% of chicks; while 97% of broods were at risk on the island of Wangerooge. Postponement of mowing to 1 August reduced these proportions to 21%, 11% and 32%, respectively. This study is the first to model the positive effects of delayed mowing of saltmarshes on ground-nesting birds. By implementing adjusted mowing dates in addition to previously suggested reductions in artificial drainage, direct and indirect adverse effects caused by mowing and drainage, such as an increased predation risk, are likely to be reduced, such that a ’favourable conservation status’ according to the EC Habitats Directive may be achieved.
Health nudge interventions to steer people into healthier lifestyles are increasingly applied by governments worldwide, and it is natural to look to such approaches to improve health by altering what people choose to eat. However, to produce policy recommendations that are likely to be effective, we need to be able to make valid predictions about the consequences of proposed interventions, and for this, we need a better understanding of the determinants of food choice. These determinants include dietary components (e.g. highly palatable foods and alcohol), but also diverse cultural and social pressures, cognitive-affective factors (perceived stress, health attitude, anxiety and depression), and familial, genetic and epigenetic influences on personality characteristics. In addition, our choices are influenced by an array of physiological mechanisms, including signals to the brain from the gastrointestinal tract and adipose tissue, which affect not only our hunger and satiety but also our motivation to eat particular nutrients, and the reward we experience from eating. Thus, to develop the evidence base necessary for effective policies, we need to build bridges across different levels of knowledge and understanding. This requires experimental models that can fill in the gaps in our understanding that are needed to inform policy, translational models that connect mechanistic understanding from laboratory studies to the real life human condition, and formal models that encapsulate scientific knowledge from diverse disciplines, and which embed understanding in a way that enables policy-relevant predictions to be made. Here we review recent developments in these areas.
Large outbreaks of Q fever have recently increased the awareness of this disease as a public health issue. Knowledge of the general impact of Q fever relies mainly on seroprevalence studies and it is fundamental that seroprevalence is assessed accurately. Therefore we evaluated the few enzyme-linked immunosorbent assays (ELISAs) commercially available for this purpose. An outbreak in 2005 in Jena, a city of 100 000 inhabitants, gave us the opportunity for the evaluation. However, we found disappointingly low sensitivities for two (42% and 51%) of three commercial ELISAs for detecting past infection. Nevertheless, all assays had good classification potential but cut-off adaptation is needed. Based on the unequal worldwide distribution of the differently performing tests in studies, Q fever seroprevalence is likely to be underestimated in studies from Europe whereas the data from North America and Australia are likely to be more reliable.
We describe three approaches to identify novel product affordances: affordance of absence; insights from lead users, specifically do-it-yourselfers (DIYers); and natural-language searches. While these approaches were separately pursued, we show their connection to each other in this paper. We begin by describing the affordance of absence, inspired by insights on affordances arising from a lack of resources. For example, in the absence of specialized tools, more general tools are used to accomplish similar tasks. Such absence clarifies how other tools could be modified to add relevant features and identifies critical features of the absent tool. In addition, the temporary removal of physical features and objects enables user interaction in ways that may not emerge in their presence. Affordance of absence has the potential to more fully specify affordances for a given object and to help overcome functional fixedness. For the second approach, we describe insights from DIYers obtained from the “IKEA hackers” online community. We consider DIYers lead users for seeking out and exploiting product affordances, often transforming product functions dramatically. We also discuss their projects through the lens of affordance of absence. For the third approach, we outline our natural-language approach to affordance extraction, beginning with consumer product reviews provided for Canadian Tire, a major Canadian retailer. We describe efforts toward automatically identifying less common affordances, and the use of cue phrases to highlight insightful DIY transformations from the IKEA hackers community. Finally, we comment on the potential value of this work for product design in general.
We document characteristics of tephra, including facies and geochemistry, from 27 subsurface sites in the Sacramento–San Joaquin Delta, California, to obtain stratigraphic constraints in a complex setting. Analyzed tephra deposits correlate with: 1) an unnamed tephra from the Carlotta Formation near Ferndale, California, herein informally named the ash of Wildcat Grade (<~1.450 to >~ 0.780 Ma), 2) the Rockland ash bed (~ 0.575 Ma), 3) the Loleta ash bed (~ 0.390 Ma), and 4) middle Pleistocene volcanic ash deposits at Tulelake, California, and Pringle Falls, Bend, and Summer Lake, Oregon, herein informally named the dacitic ash of Hood (<~0.211 to >~ 0.180 Ma). All four tephra are derived from Cascades volcanic sources. The Rockland ash bed erupted from the southern Cascades and occurs in up to > 7-m-thick deposits in cores from ~ 40 m subsurface in the Sacramento–San Joaquin Delta. Tephra facies and tephra age constraints suggest rapid tephra deposition within fluvial channel and overbank settings, likely related to flood events shortly following volcanic eruption. Such rapidly deposited tephra are important chronostratigraphic markers that suggest varying sediment accumulation rates in Quaternary deposits below the modern Sacramento–San Joaquin Delta. This study provides the first steps in a subsurface Quaternary stratigraphic framework necessary for future hazard assessment.
Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability).
For investigating familiality, we used 691 families with 2–5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software.
Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity.
AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.
Objective: Patients with Parkinson’s disease (PD) can show impaired self-awareness of motor deficits (ISAm). We developed a new scale that measures ISAm severity of hyper- and hypokinetic movements in PD during medication on state and defined its psychometric criteria. Method: Included were 104 right-handed, non-depressed, non-demented patients. Concerning ISAm, 38 motor symptoms were assessed using seven tasks, which were performed and self-rated concerning presence of deficit (yes/no) by all patients. The whole procedure was videotaped. Motor symptoms were then evaluated by two independent experts, blinded for patient’s ratings, concerning presence, awareness of deficit, and severity. Exploratory principal component analysis (promax rotation) was applied to reduce items. Principal axis factoring was conducted to extract factors. Reliability was examined regarding internal consistency, split-half reliability, and interrater reliability. Validity was verified by applying two additional measures of ISAm. Results: Of the initial 38 symptoms, 15 remained, assessed in five motor tasks and merged to a total severity score. Factor analysis resulted in a four factor solution (dyskinesia, resting tremor right hand, resting tremor left hand, bradykinesia). For all subscales and the total score, measures of reliability (values 0.64–0.89) and validity (effect sizes>0.3) were satisfactory. Descriptive results showed that 66% of patients had signs of ISAm (median 2, range 0–15), with ISAm being most distinct for dyskinesia. Conclusions: We provide the first validation of a test for ISAm in PD. Using this instrument, future studies can further analyze the pathophysiology of ISAm, the psychosocial sequelae, therapeutic strategies and compliance with therapy. (JINS, 2015, 21, 1–10)
A relation between the stellar mass M and the gas-phase metallicity Z of galaxies, the MZR, is observed up to higher redshifts. It is a matter of debate, however, if the SFR is a second parameter in the MZR. To explore this issue at z > 1, we used VLT-SINFONI near-infrared (NIR) spectroscopy of eight zCOSMOS galaxies at 1.3 < z < 1.4 to measure the strengths of four emission lines: Hβ, [OIII]λ5007, Hα, and [NII]λ6584, additional to [OII]λ3727 measured from VIMOS. We derive reliable O/H metallicities based on five lines, and also SFRs from extinction corrected Hα measurements. We find that the MZR of these star-forming galaxies at z ≈ 1.4 is lower than the local SDSS MZR by a factor of three to five, a larger change than reported in the literature using [NII]/Hα-based metallicities from individual and stacked spectra. Correcting N2-based O/Hs using recent results by Newman et al. (2014), also the larger FMOS sample at z ∼ 1.4 of Zahid et al. (2014) shows a similar evolution of the MZR like the zCOSMOS objects. These observations seem also in agreement with a non-evolving FMR using the physically motivated formulation of the FMR from Lilly et al. (2013).
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.
To investigate whether higher BMI increases the risk of major depression.
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.
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).
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.
Clinical and ethical implications of personality and mood changes in Parkinson's disease (PD) patients treated with subthalamic deep brain stimulation (STN-DBS) are under debate. Although subjectively perceived personality changes are often mentioned by patients and caregivers, few empirical studies concerning these changes exist. Therefore, we analysed subjectively perceived personality and mood changes in STN-DBS PD patients.
In this prospective study of the ELSA-DBS group, 27 PD patients were assessed preoperatively and 1 year after STN-DBS surgery. Two categories, personality and mood changes, were analysed with semi-structured interviews. Patients were grouped into personality change yes/no, as well as positive/negative mood change groups. Caregivers were additionally interviewed about patients’ personality changes. Characteristics of each group were assessed with standard neurological and psychiatric measurements. Predictors for changes were analysed.
Personality changes were perceived by six of 27 (22%) patients and by 10 of 23 caregivers (44%). The preoperative hypomania trait was a significant predictor for personality change perceived by patients. Of 21 patients, 12 (57%) perceived mood as positively changed. Higher apathy and anxiety ratings were found in the negative change group.
Our results show that a high proportion of PD patients and caregivers perceived personality changes under STN-DBS, emphasizing the relevance of this topic. Mood changed in positive and negative directions. Standard measurement scales failed to adequately reflect personality or mood changes subjectively perceived by patients. A more individualized preoperative screening and preparation for patients and caregivers, as well as postoperative support, could therefore be useful.
We studied the effect of a cross-conjugated bridging group (χC) on charge-transfer in a push-pull chromophore system. The hyperpolarizability of such molecules was found to be comparable to that of a fully π-conjugated molecule (πC) with the same donor and acceptor. The cross-conjugated moiety was then applied as a pendant to a fully π-conjugated chromophore containing a tricyanopyrroline acceptor (TCP). The addition of a χC moiety did not alter the intrinsic hyperpolarizability and provides an avenue for extending and aiding πC systems. The molecules were examined by X-ray diffraction (XRD), hyper-Raleigh scattering (HRS) and UV-visible (UV-vis) spectroscopy. Experimental results were compared with the predictions of density functional theory (DFT). Cross-conjugated molecules have comparable β values, relative to πC molecules, due to reduced spatial overlap between the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO). Thus, the χC architecture could facilitate independent modification of donor and acceptor strengths while minimizing unfavorable effects on electronic transitions and dipole moments.
Two methods for the fabrication of flexible and stretchable photonic crystal slabs are demonstrated and compared. In both cases a periodically nanostructured polydimethylsiloxane (PDMS) membrane is used as substrate. The first method is based on oblique-angle vapor deposition of SiO as a high refractive index material onto the nanostructured membrane. The deposition is made at an angle of 45° to the surface. The grooves of the nanostructure are aligned such that shading effects cause an inhomogeneous layer thickness distribution on the surface. This supports controlled, periodic cracking of the high index layer upon stretching. In the second approach ZnO nanoparticles are spin-coated on the nanostructured PDMS membrane. Here, the membrane can be stretched and serves as a photonic crystal slab without the need of any further treatment. For both types of flexible photonic crystal slabs a shift of the guided mode resonances to longer wavelengths is observed upon stretching. For a 20% strain perpendicular to the grating grooves a resonance shift of more than 50 nm is obtained.
It is well known that exposure to ultraviolet (UV) light can result in various physical and psychological diseases. Therefore, there is a strong demand for a reliable sensor to monitor UV exposure levels in the physiologically relevant intensity ranges of mW/cm2. Here, we demonstrate a UV sensor based on a silica whispering gallery mode microresonator. This UV sensor works over physiologically relevant intensity ranges with linear performance both in the forward and backward operating directions, with very high signal-to-noise ratio that can be utilized in monitoring the UV exposure for various applications.