Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.peer-reviewe

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

A study about the significance of typography in the analog format

Abstract (SE) Denna uppsats är den slutliga delen på Medieproducentprogrammet vid Umeå Universitet, inklusive ett påbyggnadsår. Det vill säga att uppsatsen är en kandidatuppsat, även kallad C-uppsats. Syftet med denna var att fördjupa kunskaper och bredda kompetens inom grafisk design, framförallt för tryck och målet var att finna svar på frågeställningar som funnits under utbildningens gång. Framförallt att finna svar på frågan ”vilken betydelse har typografin i analogt format?”. Ett annat mål var även att testa tesen ”det är jobbigare/svårare att läsa text skriven i annan färg än svart på vit/ljus bakgrund”. Den riktar sig till dig som är av olika anledningar intresserad av typografi och dess betydelse, framförallt i tryck. Uppsatsen berör typografins historia, uppbyggnad och basregler. Uppsatsen presenterar även en genomförd undersökning om betydelsen i tryckt format, dock inte en statistisk undersökning, utan en mer empirisk undersökning som fångar upp ett gäng åsikter och värderingar om användandet av typografi. Resultatet av undersökningen presenteras med texter och tabeller och visar på motsättning av vad litteraturen skriver. Undersökningen visar på att människor föredrar att läsa text skriven i sans-seriffer i analogt format, samt att det inte är jobbigare/svårare att läsa text skriven i annan färg än svart på vit/ljus bakgrund. Resutatet av sidoprojektet visas med texter och bilder för att du som läsare ska få en överblick om utseendet och hur resultatet från undersökningen samt teorin implicerats – att man i resultatet valt att skriva med sans-seriffer och utgå från teorins basregler för vad man ska ha i åtanke vid utformning av trycksaker. Uppsatsen har sneglat på vetenskapliga artiklar. Detta kan man läsa om framförallt under diskussionsavsnittet. Där finner man även förslag till fortsatta studier och forskning inom området typografi, samt tankar kring arbetet i sin helhet. Abstract (EN) This paper is the final part of the Media Producer Program at Umeå University, including a supplementary year. This essay is a Bachelor thesis in media technology. The purpose of this was to deepen my knowledge and extend my skills in graphic design, especially for printing. The goal was to find an answer to the question "what is the significance of typography in the analog format?". Another purpose was to test the hypothesis "it is harder to read text written in a different color than black on a white/light background". This thesis are for those who are interested in typography and its importance. The thesis also refer to the history about typography, the structure and basic rules. It also presents a survey of its significance in the analog format. Not a statistical survey, but an empirical study that captures a bunch of opinions and values ​​about the use of typography. The results of the survey are presented with texts and tables, and it shows a disagreement to what the literature says. The result shows that people read text written with sans-serifs rather than text written with serifs. It also shows that people doesn’t thinks it’s harder to read text written with other colors than black on light backgrounds.   The result of the side project appears with texts and pictures, so you  can get an overview about the layout and how the results of the study, and the theory, are implicated. In the essay I have also looked at scientific articles. You can read about that in the discussion section, where you also find suggestions to further studies and research in typography, as well as thoughts on the work in its entirety

Genetiska och funktionella studier av hereditär myopati med laktacidos

Hereditary myopathy with lactic acidosis (HML, OMIM#255125) is an autosomal recessive disorder which originates from Västerbotten and Ångermanland in the Northern part of Sweden. HML is characterized by severe exercise intolerance which manifests with tachycardia, dyspnea, muscle pain, cramps, elevated lactate and pyruvate levels, weakness and myoglobinuria. The symptoms arise from malfunction of the energy metabolism in skeletal muscles with defects in several important enzymes involved in the TCA cycle and the electron transport chain. All affected proteins contain iron-sulfur (Fe-S) clusters, which led to the suggestion that the disease was caused by malfunctions in either the transportation, assembly or processing of Fe-S clusters. The aim of my thesis was to identify the disease causing gene of HML and to investigate the underlying disease-mechanisms. In paper I we identified a disease-critical region on chromosome 12; a region containing 16 genes. One of the genes coded for the Fe-S cluster assembly protein ISCU and an intronic base pair substitution (g.7044G>C) was identified in the last intron of this gene. The mutation gave rise to the insertion of intron sequence into the mRNA, leading to a protein containing 15 abberant amino acids and a premature stop. In paper II we investigated why a mutation in an evolutionary well conserved protein with a very important cellular role, which in addition is expressed in almost all tissues, gives rise to a muscle-restricted phenotype. Semi-quantitative RT-PCR analysis showed that the mutant transcript constituted almost 80% of total ISCU mRNA in muscle, while in both heart and liver the normal splice form was dominant. We could also show that, in mice, complete absence of Iscu protein was coupled with early embryonic death, further emphasizing the importance of the protein in all tissues. These data strongly suggested that tissue-specific splicing was the main mechanism responsible for the muscle-specific phenotype of HML. In paper III the splicing mechanisms that give rise to the mutant ISCU transcript was further investigated. We identified three proteins; PTBP1, IGF2BP1 and RBM39, that could bind to the region containing the mutation and could affect the splicing pattern of ISCU in an in vitro system. PTBP1 repressed the inclusion of the intronic sequence, while IGF2BP1 and RBM39 repressed the total ISCU mRNA level though the effect was more pronounced for the normal transcript. Moreover, IGF2BP1 and RBM39 were also able to reverse the effect of PTBP1. IGF2BP1, though not a splicing factor, had higher affinity for the mutant sequence. This suggested that the mutation enables IGF2BP1 binding, thereby preventing the PTBP1 induced repression seen in the normal case. In conclusion, we have determined the genetic cause of HML, identifying a base pair substitution in the last intron of the ISCU gene that gives rise to abnormally spliced transcript. The muscle-specific phenotype was also analyzed and tissue-specific splicing was identified as the main disease-mechanism. Furthermore, nuclear factors with ability to affect the splicing pattern of the mutant ISCU gene were identified. This work has thoroughly investigated the fundamental disease mechanisms, thus providing deeper understanding for this hereditary myopathy

The art of using the Dramaturgical curve in an information film

This report is the final part of my studies at the Media Producer Programme at Umeå University. This report is about a project to the Church of Sweden Youth, which has been to direct an information film to on the topic annual meeting.   To implement this project in a good way, a literature review on the Dramaturgical curve has been done. The literature review focus on what the differences and similarities between the dramaturgical curve for television and film productions is, how to capture the audience's interest in general and also how to structure a good information film, as well as things that may be helpful to think about. This is presented in the theory section along with references.   The report also present specifically about what has been done, how and why. In the report you can also read my thoughts concerning the project and the thesis as a whole. This is presented in the later part of the report - implementation, results and discussion

En klick kreativitet, en droppe fantasi och en inspirerande pedagog

Uppsatsens syfte har varit att se hur två olika förskolor arbetar med bildskapande. I denna forskning ville vi även betrakta och belysa pedagogens roll i den bildskapande processen. Detta har gjorts genom observationer av en bildskapandeaktivitet på de två förskolorna samt intervjuer av två pedagoger som arbetar där. Uppsatsen är även utförd med fortlöpande litteraturstudier kopplade till vårt ämne. Arbetet visar att pedagogens roll är avgörande för hur kvaliteten och utformningen vid en bildskapandesituation ser ut. Det framkommer även att bildskapande är en viktig del av ett barns vardag, att det främjar barns fantasi och kreativitet, och att man i förskolan bör arbeta aktivt med detta. En inspirerande pedagog lägger grunden för barns lust att skapa!The purpose of this essay is to se how two different pre- schools work with art creating. In our research we also wanted to se the pedagogues roll in the process

Moral Distress, Health and Intention to Leave : Critical Care Nurses’ Perceptions During COVID-19 Pandemic

Introduction: Moral distress increases the risk that critical care nurses will lose the ability to provide quality nursing care. Aims: To describe person-related conditions and perceptions of moral distress, health and intention to leave among critical care nurses in intensive care units, and to examine the relationship between person-related conditions, moral distress, health and intention to leave. Method: Cross-sectional, with 220 critical care nurses in 15 Swedish ICUs, and data gathered via a self-reported questionnaire. Results: Highest moral distress scores were reported in futile care and poor teamwork and 21% reported entertaining an intention to leave. Self-reported health was lower than before the COVID-19 pandemic and 4.1% reported pronounced exhaustion disorder. Self-reported health, reduced capacity to tolerate demands under time pressure, emotional instability or irritability, physical weakness, or being more easily fatigued and with decreased well-being were factors that had a relationship with futile care. Sleeping problems and intention to leave had a relationship with poor teamwork. Conclusions: Different strategies are needed to reduce moral distress and the leadership is crucial for managing crises such as the COVID-19 pandemic.