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Despite advances in identifying the genetic basis of psychiatric and neurological disorders, fundamental questions about their evolutionary origins remain elusive. Here, introgressed variants from archaic humans such as Neandertals can serve as an intriguing research paradigm. We compared the number of associations for Neandertal variants to the number of associations of frequency-matched non-archaic variants with regard to human CNS disorders (neurological and psychiatric), nervous system drug prescriptions (as a proxy for disease), and related, non-disease phenotypes in the UK biobank (UKBB). While no enrichment for Neandertal genetic variants were observed in the UKBB for psychiatric or neurological disease categories, we found significant associations with certain behavioral phenotypes including pain, chronotype/sleep, smoking and alcohol consumption. In some instances, the enrichment signal was driven by Neandertal variants that represented the strongest association genome-wide. SNPs within a Neandertal haplotype that was associated with smoking in the UKBB could be replicated in four independent genomics datasets.Our data suggest that evolutionary processes in recent human evolution like admixture with Neandertals significantly contribute to behavioral phenotypes but not psychiatric and neurological diseases. These findings help to link genetic variants in a population to putative past beneficial effects, which likely only indirectly contribute to pathology in modern day humans

Cherenkov telescopes play a crucial role in testing possible consequences of Quantum Gravity (QG), such as violations or deformations of Lorentz symmetry. In both cases, the photon dispersion relation is modified, making the photon group velocity energy dependent. This tiny effect, if real, could be measured using very high energy (VHE, E > 100 GeV) gamma rays crossing cosmological distances. The so-called time of flight measurements were up to now performed on individual sources with single instruments. No deviations from the special relativistic predictions have been detected, although strong constraints have been set on modified dispersion relations. In order to increase the sensitivity of QG analyses, and to perform the most robust searches for the energy-dependent photon group velocity up to date, researchers from the three major imaging Cherenkov telescopes (IACTs) experiments (H.E.S.S., MAGIC, and VERITAS) have joined forces. It is the first attempt at merging data from different instruments for this purpose, thus creating exceptionally large statistics. Moreover, combining observations from various gamma-ray sources at different redshifts alleviates the entanglement between the effects of QG and the source intrinsic time-delays. In addition, the influence of different theoretical formalisms for distance contribution were investigated and compared for the first time. In this talk, we will describe the likelihood-based analysis method developed for this purpose, and present the results obtained from simulated data. However, this is only the first part of the anticipated work. We will introduce our plans for the continuation and future endeavours in this field, specifically, for performing our analysis on real data sets.

Converging evidence indicates that major depressive disorder (MDD) and metabolic disorders might be mediated by shared (patho)biological pathways. However, the converging cellular and molecular signatures remain unknown. Here, we investigated metabolic dysfunction on a systemic, cellular, and molecular level in unmedicated patients with MDD compared with matched healthy controls (HC). Despite comparable BMI scores and absence of cardiometabolic disease, patients with MDD presented with significant dyslipidemia. On a cellular level, T cells obtained from patients with MDD exhibited reduced respiratory and glycolytic capacity. Gene expression analysis revealed increased carnitine palmitoyltransferase IA (CPT1a) levels in T cells, the rate-limiting enzyme for mitochondrial long-chain fatty acid oxidation. Together, our results indicate metabolic dysfunction in unmedicated, non-overweight patients with MDD on a systemic, cellular, and molecular level. This evidence for reduced mitochondrial respiration in T cells of patients with MDD provides translation of previous animal studies regarding a putative role of altered immunometabolism in depression pathobiology.

BACKGROUND: Treatment resistant depression (TRD) characterizes a subgroup of 10-30% of patients with major depressive disorder, and is associated with considerable morbidity and mortality. A consensus treatment for TRD does not exist, which often leads to wide variations in treatment strategies. Real-world studies on treatment patterns and outcomes in TRD patients in Europe are lacking and could help elucidate current treatment strategies and their efficacy. METHODS: This non-interventional cohort study of patients with TRD (defined as treatment failure on ≥2 oral antidepressants given at adequate dose and duration) with moderate to severe depression collected real-world data on treatment patterns and outcomes in several European countries. Patients were started on a new treatment for depression according to routine clinical practice. RESULTS: Among 411 patients enrolled, after 6 months, only 16.7% achieved remission and 73.5% showed no response. At Month 12, while 19.2% achieved remission and 69.2% showed no response, 33.3% of those in remission at Month 6 were no longer in remission. Pharmacological treatments employed were heterogenous; 54 different drugs were recorded at baseline, and the top 5 treatment types according to drug classes accounted for 40.0% of patients. Even though remission rates were very low, at Month 12, 60.0% of patients had not changed treatment since enrolment. CONCLUSIONS: The heterogeneity of treatments highlights a lack of consensus. Moreover, despite low response rates, patients often remained on treatments for substantial periods of time. These data further support existence of an unmet treatment need for TRD patients in Europe. publishersversion published

Background: Treatment resistant depression (TRD) is diagnosed when patients experiencing a major depressive episode fail to respond to ≥2 treatments. Along with substantial indirect costs, patients with TRD have higher healthcare resource utilization (HCRU) than other patients with depression. However, research on the economic impact of this HCRU, and differences according to response to treatment, is lacking. Methods: This multicenter, observational study documented HCRU among patients with TRD in European clinical practice initiating new antidepressant treatments. Data regarding access to outpatient consultations and other healthcare resources for the first 6 months, collected using a questionnaire, were analyzed qualitatively according to response and remission status. The economic impact of HCRU, estimated using European costing data, was analyzed quantitatively. Results: Among 411 patients, average HCRU was higher in non-responders, attending five times more general practitioner (GP) consultations and spending longer in hospital (1.7 versus 1.1 days) than responders. Greater differences were observed according to remission status, with non-remitters attending seven times more GP consultations and spending approximately three times longer in hospital (1.7 versus 0.6 days) than remitters. Consequently, the estimated economic impacts of non-responders and non-remitters were significantly greater than those of responders and remitters, respectively. Limitations: Key limitations are small cohort size, absence of control groups and generalizability to different healthcare systems.

Background: Treatment resistant depression (TRD; failure to respond to ≥2 treatments) affects ~20% of patients with major depressive disorder (MDD). Real-world data could help describe patient characteristics and TRD disease burden, to assess the unmet needs of TRD patients in Europe. Methods: This observational study collected data from adults with moderate to severe TRD initiating a new treatment for depression, according to local standards of care. At baseline, socio-demographic characteristics, medical history, prior and current treatments were recorded. Disease severity, health-related quality of life (HRQoL), functionality and productivity were assessed. Results: Overall, 411 eligible patients were enrolled across seven European countries. Mean (standard deviation [SD]) patient age was 51.0 (10.8) years; 62.3% were female. Long-term sick leave was reported by 19.0% of patients; 30.2% were unemployed. The mean (SD) duration of the current episode was 2.6 (3.9) years. At baseline, mean (SD) HRQoL scores for EuroQoL 5-dimension 5-level (UK tariff) and EQ-Visual Analog Scale were 0.41 (0.25) and 41.1 (18.7), respectively. The Work Productivity and Activity Impairment questionnaire demonstrated mean (SD) absenteeism of 57.0% (44.9%) and presenteeism of 54.7% (29.5%); mean (SD) overall work impairment was 60.5% (29.9%). Limitations: Key limitations are small cohort size, absence of a control group and generalizability to countries with different healthcare models. Conclusions: TRD patients had a high disease burden, low HRQoL and reduced function and productivity, with a substantial proportion unable to work. This demonstrates an unmet treatment need in TRD patients that, if addressed, could reduce the heavy personal and societal burden

In this thesis, we first study how classical fields can be quantized on a curved spacetime. Interestingly, this provides a mechanism for purely gravitational particle production which we investigate against the background of scalar fields in the FLRW spacetime. Subsequently, this mechanism is used to produce DM particles at the end of inflation and during reheating which therefore will not interact with other particles except gravitatively. Finally, we disduss on a general ground how to construct models which describe purely gravitatively interacting particles.

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-Analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-Analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-Analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations. © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.