Tobacco and multiple sclerosis susceptibility

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system (CNS) that arises from a combination of a complex genetic predisposition and environmental factors. For northern Europeans, the lifetime risk of MS is 1:400, making it the most common non-traumatic cause of disability in young adults. The strongest genetic associations with MS are located within the human leukocyte antigen (HLA) complex and in recent years, a large number of non-HLA risk loci that influence disease susceptibility have been identified. The contribution of lifestyle and environmental factors is more difficult to study. However, it is important to identify these factors since they are potentially preventable and may also lead to hypotheses on critical pathogenic events. This thesis focuses on the impact of tobacco on MS risk. We replicated the finding of an association between smoking and MS risk and demonstrated that the risk of developing the disease increases with cumulative dose of smoking. However, snuff use, which leads to exposure to high doses of nicotine, was associated with decreased MS risk (paper I). In paper II, we showed an inverse dose-response correlation between cumulative dose of snuff use and disease risk. Nicotine has been shown to be protective in several models of inflammatory diseases, and may thus exert anti-inflammatory and immune-modulating effects in a way that reduces the risk of developing MS. In paper IV, we investigated the association between smoking and MS in more detail. Both duration and intensity of smoking contribute independently to the risk of developing the disease. Smoking affects MS risk regardless of age at exposure, in contrast to many other environmental risk factors which seem to act mainly during adolescence. The detrimental effect of smoking slowly abates after smoking cessation regardless of the timing of smoking and regardless of the cumulative dose of smoking. In paper III, we demonstrated that exposure to passive smoking among never smokers is associated with increased risk of MS. Tobacco smoke, but not tobacco consumption in the form of moist snuff, increases MS risk, suggesting that the critical effects of smoking may be caused by irritation in the lungs. Smoking increases pro-inflammatory cell activation and induces post-translational modifications of proteins in the lungs. In paper V, an interaction was demonstrated between carriage of HLA-DRB1*15, absence of HLA A*02, and smoking in the development of MS. We hypothesize that smoke-induced lung irritation, in the context of MS risk HLA genes, may generate post-translationally modified peptides which are cross-reactive with CNS antigens, promoting a CNS-directed autoaggressive immunity that results in MS. Further studies would be valuable in order to investigate whether other forms of lung irritation contribute to the triggering of MS. Apart from generating data of importance for preventive measures, our finding of an interaction between smoking and HLA genotype emphasizes the need to include data on environmental exposures in genetic analyses of complex diseases and vice versa

Maintenance dept in the cemetery : How it can affect a visitor's grief

Arbetet grundar sig i ett problem med eftersatt underhåll som uppmärksammats på våra kyrkogårdar runt om i landet, något som idag brukar kallas underhållsskuld. Kortfattat innebär det att man skjutit underhållet på framtiden och detta innebär idag ofta att underhållet har vuxit till en underhållsskuld. Det här ger ofta ökade kostnader och större arbetsinsatser. Det bristande underhållet har gett oss miljöer som ibland inte är säkra att vistas i för såväl personalen som besökaren av kyrkogården. Ett bristande underhåll kan även påverka hur besökaren upplever kyrkogården och intrycket av en misskött kyrkogård kan göra att förväntningarna inte motsvaras. Besökaren efterfrågar en lugn, trygg och välskött plats där värdighet och andlighet får utrymme, där det finns möjlighet att minnas och sörja sina anhöriga. Arbetets syfte har varit att undersöka hur ett bristande underhåll skapas och vilka områden på kyrkogården som lätt drabbas av underhållsskuld. Här kan även läsas hur förvaltningen kan arbeta för att motverka en underhållsskuld och skapa en miljö som motsvarar besökarens förväntningar. Att utforma planeringsdokument som styr hur förvaltningen kan arbeta med utveckling, underhåll och skötsel anses vara en bra metod för att skapa kontroll över verksamheten. Att därtill ha personal med rätt kompetens och beslutsfattare med insikt i den gröna verksamheten är också två viktiga punkter för att kunna arbeta framgångsrikt inom förvaltningen. Att arbeta med utveckling av kyrkogården och inte enbart förvaltning är något som återkommer i arbetet när en underhållsskuld skall undvikas. De lagar som berör denna verksamhet tas också upp. En enkätundersökning i slutet av arbetet berättar hur det ser ut på ett antal utvalda förvaltningar i södra Sverige idag. Enkäten visar bland annat att det inom de tillfrågade förvaltningarna idag finns en uppmärksammad underhållsskuld, och att de största bristerna finns på de återlämnade gravarna, i växtmaterial, tekniska lösningar, murar, gångar och andra ytor och även i ytterområden som ofta blir bortprioriterade på grund av tidsbrist. Här kan även läsas vilka områden på kyrkogården där det lätt skapas en underhållskuld

Nicotinic acetylcholine receptors as mediators of neurotransmitter release

The ability to regulate release of noradrenaline, dopamine and GABA is one of the most important roles of the nicotinic receptors. The release of neurotransmitters following stimulation of nicotinic receptors is addressed in the thesis, with focus on dopamine and noradrenaline. Release of neurotransmitters, mediated through nicotinic receptors, has been researched using various methods, including brain slices, microdialysis and synaptosomes. Research using synaptosomes have provided valuable information regarding nicotinic receptors and their ability to regulate neurotransmitter release. Research using receptor specific antagonists have provided information regarding the stoichiometry of nicotinic receptor in different regions of the brain. The primary focus in the thesis, was the characterization of [3H]dopamine release following stimulation of nicotinic receptors with varenicline and acetylcholine, using synaptosomes from mouse striatum. Using a-conotoxin-MII, the [3H]dopamine release was divided into a-conotoxin- MII-resistant and -sensitive release. [3H]Dopamine release was mediated through a6b2*- and a4b2*-receptors from striatal synaptosomes. The involvement of other receptors could not be ruled out, but based on these results and results from previous studies, the involvement of other nicotinic receptors is supposedly low.Nikotinreceptorernas förmåga att reglera frisättning av noradrenalin, dopamin och GABA hör till deras viktigaste funktioner i det centrala nervsystemet. Frisättning av neurotransmittorer till följd av stimulering av nikotinreceptorer behandlas i denna avhandling. Detta har kunnat undersökas med flera olika metoder, bl.a. hjärnskivor, mikrodialys och synaptosomer. Forskning med synaptosomer har bidragit med värdefull information om nikotinreceptorernas funktion och deras förmåga att förmedla frisättning av olika neurotransmittorer. Dessutom har forskning med nikotinreceptor-antagonister gett information om nikotinreceptorernas stökiometri i olika hjärnområden. I avhandlingen undersöktes nikotinreceptorernas förmåga att reglera dopaminfrisättning från striatala synaptosomer som erhållits från möss. Acetylkolin och vareniklin stimulerade frisättning av [3H]dopamin från de striatala synaptosomerna. Genom att använda den receptorspecifika antagonisten a-conotoxin-MII, undersöktes a-conotoxin-MII-resistent och -känslig frisättning av [3H]dopamin från de striatala synaptosomerna. [3H]Dopaminfrisättningen förmedlades i huvudsak via a6b2*- och a4b2*-receptorerna. Andra nikotinreceptorers roll kunde dock inte helt uteslutas, men baserat på resultat från tidigare forskning antas deras roll i detta vara liten

Sanity Checks Revisited: An Exploration to Repair the Model Parameter Randomisation Test

The Model Parameter Randomisation Test (MPRT) is widely acknowledged in the eXplainable Artificial Intelligence (XAI) community for its well-motivated evaluative principle: that the explanation function should be sensitive to changes in the parameters of the model function. However, recent works have identified several methodological caveats for the empirical interpretation of MPRT. To address these caveats, we introduce two adaptations to the original MPRT -- Smooth MPRT and Efficient MPRT, where the former minimises the impact that noise has on the evaluation results through sampling and the latter circumvents the need for biased similarity measurements by re-interpreting the test through the explanation's rise in complexity, after full parameter randomisation. Our experimental results demonstrate that these proposed variants lead to improved metric reliability, thus enabling a more trustworthy application of XAI methods.Comment: 19 pages, 12 figures, NeurIPS XAIA 202

NoiseGrad: enhancing explanations by introducing stochasticity to model weights

Many efforts have been made for revealing the decision-making process of black-box learning machines such as deep neural networks, resulting in useful local and global explanation methods. For local explanation, stochasticity is known to help: a simple method, called SmoothGrad, has improved the visual quality of gradient-based attribution by adding noise in the input space and taking the average over the noise. In this paper, we extend this idea and propose NoiseGrad that enhances both local and global explanation methods. Specifically, NoiseGrad introduces stochasticity in the weight parameter space, such that the decision boundary is perturbed. NoiseGrad is expected to enhance the local explanation, similarly to SmoothGrad, due to the dual relationship between the input perturbation and the decision boundary perturbation. Furthermore, NoiseGrad can be used to enhance global explanations. We evaluate NoiseGrad and its fusion with SmoothGrad -- FusionGrad -- qualitatively and quantitatively with several evaluation criteria, and show that our novel approach significantly outperforms the baseline methods. Both NoiseGrad and FusionGrad are method-agnostic and as handy as SmoothGrad using simple heuristics for the choice of hyperparameter setting without the need of fine-tuning.Comment: 19 pages, 16 figure

The relationship between nightmares, depression and suicide

Abstract Objective Previous studies investigating the association between nightmares and suicide have yielded different results. We aimed to investigate whether nightmares, directly or indirectly, influence the incidence of suicide. Methods We used a prospective cohort study, based on 40,902 participants with a mean follow-up duration of 19.0 years. Cox proportional hazards models with attained age as time-scale were fitted to estimate hazard ratios (HR) of suicide with 95% confidence intervals (CI) as a function of the presence or absence of depression and nightmares. Mediation analysis was used to asses to what extent the relationship between nightmares and the incidence rate of suicide could be mediated by depression. Results No association was observed between nightmares and the incidence of suicide among participants without depression. Compared with non-depressed participants without nightmares, the incidence of suicide among participants with a diagnosis of depression was similar among those with and without nightmares (HR 12.3, 95% CI 5.55–27.2 versus HR 13.2, 95% CI 7.25–24.1). The mediation analysis revealed no significant effects of nightmares on suicide incidence. However, the incidence of depression during follow-up was higher among those who suffered from nightmares than among those who did not (p Conclusions Our findings indicate that nightmares have no influence on the incidence rate of suicide, but may reflect pre-existing depression. This is supported by a recent discovery of a strong genetic correlation of nightmares with depressive disorders, with no evidence that nightmares would predispose to psychiatric illness or psychological problems. Interventions targeting both depression and nightmares, when these conditions co-occur, may provide additional therapeutic benefit

The Meta-Evaluation Problem in Explainable AI: Identifying Reliable Estimators with MetaQuantus

Explainable AI (XAI) is a rapidly evolving field that aims to improve transparency and trustworthiness of AI systems to humans. One of the unsolved challenges in XAI is estimating the performance of these explanation methods for neural networks, which has resulted in numerous competing metrics with little to no indication of which one is to be preferred. In this paper, to identify the most reliable evaluation method in a given explainability context, we propose MetaQuantus -- a simple yet powerful framework that meta-evaluates two complementary performance characteristics of an evaluation method: its resilience to noise and reactivity to randomness. We demonstrate the effectiveness of our framework through a series of experiments, targeting various open questions in XAI, such as the selection of explanation methods and optimisation of hyperparameters of a given metric. We release our work under an open-source license to serve as a development tool for XAI researchers and Machine Learning (ML) practitioners to verify and benchmark newly constructed metrics (i.e., ``estimators'' of explanation quality). With this work, we provide clear and theoretically-grounded guidance for building reliable evaluation methods, thus facilitating standardisation and reproducibility in the field of XAI.Comment: 30 pages, 12 figures, 3 table

Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk.

ObjectiveWe sought to estimate the causal effect of low serum 25(OH)D on multiple sclerosis (MS) susceptibility that is not confounded by environmental or lifestyle factors or subject to reverse causality.MethodsWe conducted mendelian randomization (MR) analyses using an instrumental variable (IV) comprising 3 single nucleotide polymorphisms found to be associated with serum 25(OH)D levels at genome-wide significance. We analyzed the effect of the IV on MS risk and both age at onset and disease severity in 2 separate populations using logistic regression models that controlled for sex, year of birth, smoking, education, genetic ancestry, body mass index at age 18-20 years or in 20s, a weighted genetic risk score for 110 known MS-associated variants, and the presence of one or more HLA-DRB1*15:01 alleles.ResultsFindings from MR analyses using the IV showed increasing levels of 25(OH)D are associated with a decreased risk of MS in both populations. In white, non-Hispanic members of Kaiser Permanente Northern California (1,056 MS cases and 9,015 controls), the odds ratio (OR) was 0.79 (p = 0.04, 95% confidence interval (CI): 0.64-0.99). In members of a Swedish population from the Epidemiological Investigation of Multiple Sclerosis and Genes and Environment in Multiple Sclerosis MS case-control studies (6,335 cases and 5,762 controls), the OR was 0.86 (p = 0.03, 95% CI: 0.76-0.98). A meta-analysis of the 2 populations gave a combined OR of 0.85 (p = 0.003, 95% CI: 0.76-0.94). No association was observed for age at onset or disease severity.ConclusionsThese results provide strong evidence that low serum 25(OH)D concentration is a cause of MS, independent of established risk factors