Norwegian University of Science and Technology

BACKGROUND: Depression is a prevalent and disabling condition in older persons (≥ 60 years) that increases the risk of mortality and negatively influences quality of life (QOL). The relationship between depression, or depressive symptoms, and QOL has been increasingly addressed by research in recent years, but a review that can contribute to a better understanding of this relationship in older persons is lacking. Against this background, we undertook a literature review to assess the relationship between depression and QOL in older persons. SUMMARY: Extensive electronic database searches revealed 953 studies. Of these, 74 studies fulfilled our criteria for inclusion, of which 52 were cross-sectional studies and 22 were longitudinal studies. Thirty-five studies were conducted in a clinical setting, while 39 were community-based epidemiological studies. A clear definition of the QOL concept was described in 25 studies, and 24 different assessment instruments were employed to assess QOL. Depressed older persons had poorer global and generic health-related QOL than nondepressed individuals. An increase in depression severity was associated with a poorer global and generic health-related QOL. The associations appeared to be stable over time and independent of how QOL was assessed. KEY MESSAGES: This review found a significant association between severity of depression and poorer QOL in older persons, and the association was found to be stable over time, regardless which assessment instruments for QOL were applied. The lack of a definition of the multidimensional and multilevel concept QOL was common, and the large variety of QOL instruments in various studies make a direct comparison between the studies difficult.

Eukaryotic cells make many types of primary and processed RNAs that are found either in specific subcellular compartments or throughout the cells. A complete catalogue of these RNAs is not yet available and their characteristic subcellular localizations are also poorly understood. Because RNA represents the direct output of the genetic information encoded by genomes and a significant proportion of a cell’s regulatory capabilities are focused on its synthesis, processing, transport, modification and translation, the generation of such a catalogue is crucial for understanding genome function. Here we report evidence that three-quarters of the human genome is capable of being transcribed, as well as observations about the range and levels of expression, localization, processing fates, regulatory regions and modifications of almost all currently annotated and thousands of previously unannotated RNAs. These observations, taken together, prompt a redefinition of the concept of a gene. A description is given of the ENCODE effort to provide a complete catalogue of primary and processed RNAs found either in specific subcellular compartments or throughout the cell, revealing that three-quarters of the human genome can be transcribed, and providing a wealth of information on the range and levels of expression, localization, processing fates and modifications of known and previously unannotated RNAs. These authors describe the ENCODE (Encyclopedia of DNA Elements) effort to provide a complete catalogue of primary and processed RNAs found either in specific sub-cellular compartments or throughout the cell. They show that three-quarters of the human genome can be transcribed, and provide a wealth of information about the range and levels of expression, localization, processing fates and modifications of both known and previously unannotated RNAs. Collectively, these observations suggest that the current concept of a gene should be revisited.

Summary Structured additive regression models are perhaps the most commonly used class of models in statistical applications. It includes, among others, (generalized) linear models, (generalized) additive models, smoothing spline models, state space models, semiparametric regression, spatial and spatiotemporal models, log-Gaussian Cox processes and geostatistical and geoadditive models. We consider approximate Bayesian inference in a popular subset of structured additive regression models, latent Gaussian models, where the latent field is Gaussian, controlled by a few hyperparameters and with non-Gaussian response variables. The posterior marginals are not available in closed form owing to the non-Gaussian response variables. For such models, Markov chain Monte Carlo methods can be implemented, but they are not without problems, in terms of both convergence and computational time. In some practical applications, the extent of these problems is such that Markov chain Monte Carlo sampling is simply not an appropriate tool for routine analysis. We show that, by using an integrated nested Laplace approximation and its simplified version, we can directly compute very accurate approximations to the posterior marginals. The main benefit of these approximations is computational: where Markov chain Monte Carlo algorithms need hours or days to run, our approximations provide more precise estimates in seconds or minutes. Another advantage with our approach is its generality, which makes it possible to perform Bayesian analysis in an automatic, streamlined way, and to compute model comparison criteria and various predictive measures so that models can be compared and the model under study can be challenged.

Abstract Despite numerous efforts to bring about a clear and unbiased definition of CSR, there is still some confusion as to how CSR should be defined. In this paper five dimensions of CSR are developed through a content analysis of existing CSR definitions. Frequency counts are used to analyse how often these dimensions are invoked. The analysis shows that the existing definitions are to a large degree congruent. Thus it is concluded that the confusion is not so much about how CSR is defined, as about how CSR is socially constructed in a specific context. Copyright © 2006 John Wiley & Sons, Ltd and ERP Environment.

Life cycle impact assessment (LCIA) translates emissions and resource extractions into a limited number of environmental impact scores by means of so-called characterisation factors. There are two mainstream ways to derive characterisation factors, i.e. at midpoint level and at endpoint level. To further progress LCIA method development, we updated the ReCiPe2008 method to its version of 2016. This paper provides an overview of the key elements of the ReCiPe2016 method. We implemented human health, ecosystem quality and resource scarcity as three areas of protection. Endpoint characterisation factors, directly related to the areas of protection, were derived from midpoint characterisation factors with a constant mid-to-endpoint factor per impact category. We included 17 midpoint impact categories. The update of ReCiPe provides characterisation factors that are representative for the global scale instead of the European scale, while maintaining the possibility for a number of impact categories to implement characterisation factors at a country and continental scale. We also expanded the number of environmental interventions and added impacts of water use on human health, impacts of water use and climate change on freshwater ecosystems and impacts of water use and tropospheric ozone formation on terrestrial ecosystems as novel damage pathways. Although significant effort has been put into the update of ReCiPe, there is still major improvement potential in the way impact pathways are modelled. Further improvements relate to a regionalisation of more impact categories, moving from local to global species extinction and adding more impact pathways. Life cycle impact assessment is a fast evolving field of research. ReCiPe2016 provides a state-of-the-art method to convert life cycle inventories to a limited number of life cycle impact scores on midpoint and endpoint level.

Importance: Mendelian randomization (MR) studies use genetic variation associated with modifiable exposures to assess their possible causal relationship with outcomes and aim to reduce potential bias from confounding and reverse causation. Objective: To develop the STROBE-MR Statement as a stand-alone extension to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guideline for the reporting of MR studies. Design, Setting, and Participants: The development of the STROBE-MR Statement followed the Enhancing the Quality and Transparency of Health Research (EQUATOR) framework guidance and used the STROBE Statement as a starting point to draft a checklist tailored to MR studies. The project was initiated in 2018 by reviewing the literature on the reporting of instrumental variable and MR studies. A group of 17 experts, including MR methodologists, MR study design users, developers of previous reporting guidelines, and journal editors, participated in a workshop in May 2019 to define the scope of the Statement and draft the checklist. The draft checklist was published as a preprint in July 2019 and discussed on the preprint platform, in social media, and at the 4th Mendelian Randomization Conference. The checklist was then revised based on comments, further refined through 2020, and finalized in July 2021. Findings: The STROBE-MR checklist is organized into 6 sections (Title and Abstract, Introduction, Methods, Results, Discussion, and Other Information) and includes 20 main items and 30 subitems. It covers both 1-sample and 2-sample MR studies that assess 1 or multiple exposures and outcomes, and addresses MR studies that follow a genome-wide association study and are reported in the same article. The checklist asks authors to justify why MR is a helpful method to address the study question and state prespecified causal hypotheses. The measurement, quality, and selection of genetic variants must be described and attempts to assess validity of MR-specific assumptions should be well reported. An item on data sharing includes reporting when the data and statistical code required to replicate the analyses can be accessed. Conclusions and Relevance: STROBE-MR provides guidelines for reporting MR studies. Improved reporting of these studies could facilitate their evaluation by editors, peer reviewers, researchers, clinicians, and other readers, and enhance the interpretation of their results.

Abstract In the period 1946-2001, there were 225 armed conflicts and 34 of them were active in all of or part of 2001. Armed conflict remains a serious problem in the post-Cold War period. For three decades, the Correlates of War project has served as the main supplier of reliable data used in longitudinal studies of external and internal armed conflict. The COW datasets on war use the relatively high threshold of 1,000 battle-deaths. The Uppsala dataset on armed conflict has a lower threshold, 25 annual battle-deaths, but has so far been available for only the post-Cold War period. This dataset has now been backdated to the end of World War II. This article presents a report on armed conflict based on this backdate as well as another annual update. It presents the procedures for the backdating, as well as trends over time and breakdowns for the type of conflict. It assesses the criteria for measuring armed conflict and discusses some directions for future data collection in this area.

Abstract Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature 1 . Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses 3–15 , enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated—but distinct—DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.

Abstract Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter 4 ; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation 5,6 ; analyses timings and patterns of tumour evolution 7 ; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity 8,9 ; and evaluates a range of more-specialized features of cancer genomes 8,10–18 .

Molecular networks guide the biochemistry of a living cell on multiple levels: Its metabolic and signaling pathways are shaped by the network of interacting proteins, whose production, in turn, is controlled by the genetic regulatory network. To address topological properties of these two networks, we quantified correlations between connectivities of interacting nodes and compared them to a null model of a network, in which all links were randomly rewired. We found that for both interaction and regulatory networks, links between highly connected proteins are systematically suppressed, whereas those between a highly connected and low-connected pairs of proteins are favored. This effect decreases the likelihood of cross talk between different functional modules of the cell and increases the overall robustness of a network by localizing effects of deleterious perturbations.

1We are grateful to two anonymous referees and editor Andrew Scott for their constructive suggestions. We also want to thank Jens Chr. Andvig, Carl-Johan Lars Dalgaard, and James A. Robinson and a number of seminar participants for valuable comments.

Summary Continuously indexed Gaussian fields (GFs) are the most important ingredient in spatial statistical modelling and geostatistics. The specification through the covariance function gives an intuitive interpretation of the field properties. On the computational side, GFs are hampered with the big n problem, since the cost of factorizing dense matrices is cubic in the dimension. Although computational power today is at an all time high, this fact seems still to be a computational bottleneck in many applications. Along with GFs, there is the class of Gaussian Markov random fields (GMRFs) which are discretely indexed. The Markov property makes the precision matrix involved sparse, which enables the use of numerical algorithms for sparse matrices, that for fields in ℝ2 only use the square root of the time required by general algorithms. The specification of a GMRF is through its full conditional distributions but its marginal properties are not transparent in such a parameterization. We show that, using an approximate stochastic weak solution to (linear) stochastic partial differential equations, we can, for some GFs in the Matérn class, provide an explicit link, for any triangulation of ℝd, between GFs and GMRFs, formulated as a basis function representation. The consequence is that we can take the best from the two worlds and do the modelling by using GFs but do the computations by using GMRFs. Perhaps more importantly, our approach generalizes to other covariance functions generated by SPDEs, including oscillating and non-stationary GFs, as well as GFs on manifolds. We illustrate our approach by analysing global temperature data with a non-stationary model defined on a sphere.

, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

The accumulation of plastic litter in natural environments is a global issue. Concerns over potential negative impacts on the economy, wildlife, and human health provide strong incentives for improving the sustainable use of plastics. Despite the many voices raised on the issue, we lack a consensus on how to define and categorize plastic debris. This is evident for microplastics, where inconsistent size classes are used and where the materials to be included are under debate. While this is inherent in an emerging research field, an ambiguous terminology results in confusion and miscommunication that may compromise progress in research and mitigation measures. Therefore, we need to be explicit on what exactly we consider plastic debris. Thus, we critically discuss the advantages and disadvantages of a unified terminology, propose a definition and categorization framework, and highlight areas of uncertainty. Going beyond size classes, our framework includes physicochemical properties (polymer composition, solid state, solubility) as defining criteria and size, shape, color, and origin as classifiers for categorization. Acknowledging the rapid evolution of our knowledge on plastic pollution, our framework will promote consensus building within the scientific and regulatory community based on a solid scientific foundation.

Plastic pollution accumulating in an area of the environment is considered "poorly reversible" if natural mineralization processes occurring there are slow and engineered remediation solutions are improbable. Should negative outcomes in these areas arise as a consequence of plastic pollution, they will be practically irreversible. Potential impacts from poorly reversible plastic pollution include changes to carbon and nutrient cycles; habitat changes within soils, sediments, and aquatic ecosystems; co-occurring biological impacts on endangered or keystone species; ecotoxicity; and related societal impacts. The rational response to the global threat posed by accumulating and poorly reversible plastic pollution is to rapidly reduce plastic emissions through reductions in consumption of virgin plastic materials, along with internationally coordinated strategies for waste management.

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

The metaverse has the potential to extend the physical world using augmented and virtual reality technologies allowing users to seamlessly interact within real and simulated environments using avatars and holograms. Virtual environments and immersive games (such as, Second Life, Fortnite, Roblox and VRChat) have been described as antecedents of the metaverse and offer some insight to the potential socio-economic impact of a fully functional persistent cross platform metaverse. Separating the hype and “meta…” rebranding from current reality is difficult, as “big tech” paints a picture of the transformative nature of the metaverse and how it will positively impact people in their work, leisure, and social interaction. The potential impact on the way we conduct business, interact with brands and others, and develop shared experiences is likely to be transformational as the distinct lines between physical and digital are likely to be somewhat blurred from current perceptions. However, although the technology and infrastructure does not yet exist to allow the development of new immersive virtual worlds at scale - one that our avatars could transcend across platforms, researchers are increasingly examining the transformative impact of the metaverse. Impacted sectors include marketing, education, healthcare as well as societal effects relating to social interaction factors from widespread adoption, and issues relating to trust, privacy, bias, disinformation, application of law as well as psychological aspects linked to addiction and impact on vulnerable people. This study examines these topics in detail by combining the informed narrative and multi-perspective approach from experts with varied disciplinary backgrounds on many aspects of the metaverse and its transformational impact. The paper concludes by proposing a future research agenda that is valuable for researchers, professionals and policy makers alike.

This study, which is a part of the initiative 'Lifting The Burden: The Global Campaign to Reduce the Burden of Headache Worldwide', assesses and presents all existing evidence of the world prevalence and burden of headache disorders. Population-based studies applying International Headache Society criteria for migraine and tension-type headache, and also studies on headache in general and 'chronic daily headache', have been included. Globally, the percentages of the adult population with an active headache disorder are 46% for headache in general, 11% for migraine, 42% for tension-type headache and 3% for chronic daily headache. Our calculations indicate that the disability attributable to tension-type headache is larger worldwide than that due to migraine. On the World Health Organization's ranking of causes of disability, this would bring headache disorders into the 10 most disabling conditions for the two genders, and into the five most disabling for women.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

Quality of Life, Cancer