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Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
We present the design steps of a coaxial dipole antenna for telemetry applications under extreme conditions of accelerations and centrifugal forces. Both, electromagnetic and mechanical designs are explained, as well as performance compromises that have to be made between both domains. The experimental results are given in the following part of the article, before some details on the instrumented firings and the receiving station; at last a few examples of projectiles equipped with such antennas are presented.
Changes in autonomic nervous system (ANS) function have been observed in a variety of psychological disorders, including posttraumatic stress disorder (PTSD). Analysis of heart rate variability (HRV) provides insight into the functioning of the ANS. Previous research on PTSD found lower HRV in PTSD patients compared to controls, indicating altered sympathetic and parasympathetic activity, but findings are inconsistent. The purpose of this meta-analysis was to examine differences in HRV indices between individuals with PTSD and healthy controls at baseline and during stress.
The included primary studies present an aggregate of studies analyzing different HRV indices. Examined HRV indices were standard deviation of the normalized NN-intervals (SDNN), root mean square of successive differences (RMSSD), low-frequency (LF) and high-frequency (HF) spectral components, LF/HF ratio, and heart rate (HR). Moderating effects of study design, HRV and PTSD assessment, and sample characteristics were examined via subgroup-analyses and meta-regressions.
Random-effects meta-analyses for HRV parameters at rest revealed significant group differences for RMSSD and HF-HRV, suggesting lower parasympathetic activity in PTSD. The aggregated effect size for SDNN was medium, suggesting diminished total variability in PTSD. A small effect was found for LF-HRV. A higher LF/HF ratio was found in the PTSD sample as compared to controls. Individuals with PTSD showed significantly higher HR. During stress, individuals with PTSD showed higher HR and lower HF-HRV, both indicated by small effect sizes.
Findings suggest that PTSD is associated with ANS dysfunction.
In this paper, an orthogonal frequency-division multiplexing (OFDM) waveform radar sensing approach is demonstrated based on field measurements at C-band. We demonstrate a concept that is based on the exploitation of typical wireless communication transmissions to perform passive, distributed radar sensing. Our concept is based on an OFDM radar that operates in the modulation symbol domain and can be well integrated into existing OFDM receivers. The measurement setup and the signal processing steps for the OFDM radar are described. The results show that the passive, distributed radar sensing approach can be used to detect and localize moving cars and even pedestrians in automotive intersection scenarios.
Acquired MDM2 inhibitor resistance is commonly caused by loss-of-function TP53 mutations. In addition to the selection of TP53-mutant cells by MDM2 inhibitors, MDM2 inhibitor-induced DNA damage may promote the formation of TP53 mutations. Here, we cultivated 12 sublines of the intrinsically MDM2 inhibitor-resistant TP53 wild-type acute myeloid leukaemia cell line PL21 for 52 passages in the presence of ineffective concentrations of the MDM2 inhibitor nutlin-3 but did not observe loss-of-function TP53 mutations. This suggests that MDM2 inhibitors select TP53-mutant cells after mutations have occurred, but do not directly promote TP53 mutations. Unexpectedly, many sublines displayed increased sensitivity to the anti-cancer drugs cytarabine, doxorubicin, or gemcitabine. Consequently, therapies can affect the outcome of next-line treatments, even in the absence of a therapy response. This finding is conceptually novel. A better understanding of such processes will inform the design of improved therapy protocols in the future.
B vitamins involved in one-carbon metabolism have been implicated in the development of inflammation- and angiogenesis-related chronic diseases, such as colorectal cancer (CRC). Yet, the role of one-carbon metabolism in inflammation and angiogenesis among CRC patients remains unclear. The objective of this study was to investigate associations of components of one-carbon metabolism with inflammation and angiogenesis biomarkers among newly diagnosed CRC patients (n 238) in the prospective ColoCare Study, Heidelberg. We cross-sectionally analysed associations between twelve B vitamins and one-carbon metabolites and ten inflammation and angiogenesis biomarkers from pre-surgery serum samples using multivariable linear regression models. We further explored associations among novel biomarkers in these pathways with Spearman partial correlation analyses. We hypothesised that pyridoxal-5’-phosphate (PLP) is inversely associated with inflammatory biomarkers. We observed that PLP was inversely associated with C-reactive protein (CRP) (r –0·33, Plinear < 0·0001), serum amyloid A (SAA) (r –0·23, Plinear = 0·003), IL-6 (r –0·39, Plinear < 0·0001), IL-8 (r –0·20, Plinear = 0·02) and TNFα (r –0·12, Plinear = 0·045). Similar findings were observed for 5-methyl-tetrahydrofolate and CRP (r –0·14), SAA (r –0·14) and TNFα (r –0·15) among CRC patients. Folate catabolite acetyl-para-aminobenzoylglutamic acid (pABG) was positively correlated with IL-6 (r 0·27, Plinear < 0·0001), and pABG was positively correlated with IL-8 (r 0·21, Plinear < 0·0001), indicating higher folate utilisation during inflammation. Our data support the hypothesis of inverse associations between PLP and inflammatory biomarkers among CRC patients. A better understanding of the role and inter-relation of PLP and other one-carbon metabolites with inflammatory processes among colorectal carcinogenesis and prognosis could identify targets for future dietary guidance for CRC patients.
The impact of the Singapore Convention might affect both state and companies’ behaviors even more than encouraging mediation. We have had for a long time the phrase “bargaining in the shadow of the law,” and then more recently, in particular when we look at international investment, it is bargaining in the shadow of international arbitration. We know that a dispute could end up in arbitration and therefore impact behaviors before that. I want us to think about what bargaining might look like in the shadow of mediation.
In recent years, the discovery of massive quasars at $z\sim7$ has provided a striking challenge to our understanding of the origin and growth of supermassive black holes in the early Universe. Mounting observational and theoretical evidence indicates the viability of massive seeds, formed by the collapse of supermassive stars, as a progenitor model for such early, massive accreting black holes. Although considerable progress has been made in our theoretical understanding, many questions remain regarding how (and how often) such objects may form, how they live and die, and how next generation observatories may yield new insight into the origin of these primordial titans. This review focusses on our present understanding of this remarkable formation scenario, based on the discussions held at the Monash Prato Centre from November 20 to 24, 2017, during the workshop ‘Titans of the Early Universe: The Origin of the First Supermassive Black Holes’.
A lasting legacy of the International Polar Year (IPY) 2007–2008 was the promotion of the Permafrost Young Researchers Network (PYRN), initially an IPY outreach and education activity by the International Permafrost Association (IPA). With the momentum of IPY, PYRN developed into a thriving network that still connects young permafrost scientists, engineers, and researchers from other disciplines. This research note summarises (1) PYRN’s development since 2005 and the IPY’s role, (2) the first 2015 PYRN census and survey results, and (3) PYRN’s future plans to improve international and interdisciplinary exchange between young researchers. The review concludes that PYRN is an established network within the polar research community that has continually developed since 2005. PYRN’s successful activities were largely fostered by IPY. With >200 of the 1200 registered members active and engaged, PYRN is capitalising on the availability of social media tools and rising to meet environmental challenges while maintaining its role as a successful network honouring the legacy of IPY.
Physical activity (PA) may be therapeutic for people with severe mental illness (SMI) who generally have low PA and experience numerous life style-related medical complications. We conducted a meta-review of PA interventions and their impact on health outcomes for people with SMI, including schizophrenia-spectrum disorders, major depressive disorder (MDD) and bipolar disorder. We searched major electronic databases until January 2018 for systematic reviews with/without meta-analysis that investigated PA for any SMI. We rated the quality of studies with the AMSTAR tool, grading the quality of evidence, and identifying gaps, future research needs and clinical practice recommendations. For MDD, consistent evidence indicated that PA can improve depressive symptoms versus control conditions, with effects comparable to those of antidepressants and psychotherapy. PA can also improve cardiorespiratory fitness and quality of life in people with MDD, although the impact on physical health outcomes was limited. There were no differences in adverse events versus control conditions. For MDD, larger effect sizes were seen when PA was delivered at moderate-vigorous intensity and supervised by an exercise specialist. For schizophrenia-spectrum disorders, evidence indicates that aerobic PA can reduce psychiatric symptoms, improves cognition and various subdomains, cardiorespiratory fitness, whilst evidence for the impact on anthropometric measures was inconsistent. There was a paucity of studies investigating PA in bipolar disorder, precluding any definitive recommendations. No cost effectiveness analyses in any SMI condition were identified. We make multiple recommendations to fill existing research gaps and increase the use of PA in routine clinical care aimed at improving psychiatric and medical outcomes.
We extend Følner’s amenability criterion to the realm of general topological groups. Building on this, we show that a topological group $G$ is amenable if and only if its left-translation action can be approximated in a uniform manner by amenable actions on the set $G$. As applications we obtain a topological version of Whyte’s geometric solution to the von Neumann problem and give an affirmative answer to a question posed by Rosendal.
Empathy is a basic human ability, and patients with schizophrenia show
dysfunctional empathic abilities on the behavioural and neural level.
These dysfunctions may precede the onset of illness; thus, it seems
mandatory to examine the empathic abilities in individuals at clinical
high risk for psychosis.
Using functional magnetic resonance imaging, we measured 15 individuals
at clinical high risk of psychosis (CHR group) and compared their empathy
performance with 15 healthy volunteers and 15 patients with
Behavioural data analysis indicated no significant deficit in the CHR
group. Functional data analysis revealed hyperactivation in a
frontotemporoparietal network including the amygdala in the CHR group
compared with the other two groups.
Despite normal behavioural performance, the CHR group activated the
neural empathy network differently and specifically showed
hyperactivation in regions critical for emotion processing. This could
suggest a compensatory mechanism reflecting emotional hypersensitivity or
dysfunctional emotion regulation. Further investigations should clarify
the role of these neural alterations for development and exacerbation of
The aim of the present study was to examine the association between intake of five common antioxidative nutrients from supplements and medications (vitamin E, vitamin C, carotenoids, Se, and Zn) and levels of high-sensitivity C-reactive protein (hs-CRP) in the general population. For this purpose, a total of 2924 participants of the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 study (2006–8) were investigated cross-sectionally. Intake of dietary supplements and medication during the last 7 d was recorded in a personal interview, when participants were asked to show product packages of ingested preparations. Linear regression models were calculated; first, the exposure to regular nutrient intake was treated with a binary response (yes/no); then regularly ingested amounts were divided into quartiles to examine dose–response relationships. Effect of single v. combined supplementation of antioxidants was assessed through the inclusion of interaction terms into the models. Regular intake of any of the five investigated antioxidants per se was not associated with hs-CRP levels. However, dose–response analyses revealed that participants who regularly ingested more than 78 mg vitamin E/d, which corresponds to the upper quartile, had 22 % lower hs-CRP levels (95 % CI 0·63, 0·97) compared to those of persons who were not exposed to any vitamin E supplementation. Stratified analyses showed that this association was found only in persons who took vitamin E in combination with other antioxidants. The combined supplementation of vitamin E with other antioxidants could thus be a promising strategy for the prevention of inflammation-related diseases in the general population, if further studies could confirm that the proposed association is causal.
In this study, Vickers indentation was used to investigate the two-way shape-memory effect (TWSME) in an austenitic Ti-50.9 at.% Ni alloy, exposed to different heat treatments. Three aging treatments were used to manipulate the size of Ti3Ni4 precipitates. All samples were Vickers indented, and the indent depth was investigated as function of thermal cycling. The TWSME was found only in the material aged at 400 °C, which contained coherent precipitates. Thermal cycling shows stable TWSME, however, heating well above the austenite finish temperature lead to permanent austenitic protrusions. The results indicate that stabilized martensite plays a critical role in creating TWSME surfaces.
The objectives were to conduct a meta-analysis in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards to determine effect sizes (Cohen's d) for cognitive dysfunction in adults with type 2 diabetes, relative to nondiabetic controls, and to obtain effect sizes for the most commonly reported neuropsychological tests within domains. Twenty-four studies, totaling 26,137 patients (n = 3351 with diabetes), met study inclusion criteria. Small to moderate effect sizes were obtained for five of six domains: motor function (3 studies, n = 2374; d = −0.36), executive function (12 studies, n = 1784; d = −0.33), processing speed (16 studies, n = 3076; d = −0.33), verbal memory (15 studies, n = 4,608; d = −0.28), and visual memory (6 studies, n = 1754; d = −0.26). Effect size was smallest for attention/concentration (14 studies, n = 23,143; d = −0.19). The following tests demonstrated the most notable performance decrements in diabetes samples: Grooved Pegboard (dominant hand) (d = −0.60), Rey Auditory Verbal Learning Test (immediate) (d = −0.40), Trails B (d = −0.39), Rey-Osterreith Complex Figure (delayed) (d = −0.38), Trails A (d = −0.34), and Stroop Part I (d = −0.28). This study provides effect sizes to power future epidemiological and clinical diabetes research studies examining cognitive function and to help inform the selection of neuropsychological tests. (JINS, 2014, 20, 1–14)
Now that most countries have harmonized intellectual property right (IPR) legislation as a consequence of signing the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPs), the dispute about the optimal level of IPR protection has shifted toward IPR enforcement. This paper develops an endogenous growth framework with two open economies satisfying the classical North–South assumptions to study (a) the regions' incentives to enforce IPRs in a decentralized game, (b) the desired IPR enforcement of the two regions in negotiation rounds on global harmonization, and (c) the constrained efficient enforcement level. We show how the different solutions relate to each other and how the results depend on the research productivity in the North and the regions' relative market sizes. Although growth rates increase substantially when IPR enforcement is harmonized at the North's desired level, our numerical simulation suggests that the South may also benefit in terms of long-run welfare.
A layered composite coating material with favorable properties for application as a transparent conductor is presented. It is composed of layers of three nanoscopic materials, namely zinc oxide nanoparticles, single wall nanotubes, and graphene oxide nanosheets. The electrically conducting layer consists of single wall nanotubes (SWNTs). The layer of zinc oxide nanoparticles acts as a primer. It increases the adhesion and the stability of the films against mechanical stresses. The top layer of graphene oxide enhances the conductivity of such coatings. Such three-layer composite coatings show better conductivity (without compromising transparency) and improved mechanical stability compared to pure SWNT films. The processes used in the preparation of such coatings are easily scalable.