Genetic mapping of microbial and host traits reveals production of immunomodulatory lipids by Akkermansia muciniphila in the murine gut.

The molecular bases of how host genetic variation impacts the gut microbiome remain largely unknown. Here we used a genetically diverse mouse population and applied systems genetics strategies to identify interactions between host and microbe phenotypes including microbial functions, using faecal metagenomics, small intestinal transcripts and caecal lipids that influence microbe-host dynamics. Quantitative trait locus (QTL) mapping identified murine genomic regions associated with variations in bacterial taxa; bacterial functions including motility, sporulation and lipopolysaccharide production and levels of bacterial- and host-derived lipids. We found overlapping QTL for the abundance of Akkermansia muciniphila and caecal levels of ornithine lipids. Follow-up in vitro and in vivo studies revealed that A. muciniphila is a major source of these lipids in the gut, provided evidence that ornithine lipids have immunomodulatory effects and identified intestinal transcripts co-regulated with these traits including Atf3, which encodes for a transcription factor that plays vital roles in modulating metabolism and immunity. Collectively, these results suggest that ornithine lipids are potentially important for A. muciniphila-host interactions and support the role of host genetics as a determinant of responses to gut microbes

An integrated Bayesian analysis of LOH and copy number data

Background: Cancer and other disorders are due to genomic lesions. SNP-microarrays are able to measure simultaneously both genotype and copy number (CN) at several Single Nucleotide Polymorphisms (SNPs) along the genome. CN is defined as the number of DNA copies, and the normal is two, since we have two copies of each chromosome. The genotype of a SNP is the status given by the nucleotides (alleles) which are present on the two copies of DNA. It is defined homozygous or heterozygous if the two alleles are the same or if they differ, respectively. Loss of heterozygosity (LOH) is the loss of the heterozygous status due to genomic events. Combining CN and LOH data, it is possible to better identify different types of genomic aberrations. For example, a long sequence of homozygous SNPs might be caused by either the physical loss of one copy or a uniparental disomy event (UPD), i.e. each SNP has two identical nucleotides both derived from only one parent. In this situation, the knowledge of the CN can help in distinguishing between these two events. Results: To better identify genomic aberrations, we propose a method (called gBPCR) which infers the type of aberration occurred, taking into account all the possible influence in the microarray detection of the homozygosity status of the SNPs, resulting from an altered CN level. Namely, we model the distributions of the detected genotype, given a specific genomic alteration and we estimate the parameters involved on public referenc

Infusion fluids contain harmful glucose degradation products

PURPOSE: Glucose degradation products (GDPs) are precursors of advanced glycation end products (AGEs) that cause cellular damage and inflammation. We examined the content of GDPs in commercially available glucose-containing infusion fluids and investigated whether GDPs are found in patients' blood. METHODS: The content of GDPs was examined in infusion fluids by high-performance liquid chromatography (HPLC) analysis. To investigate whether GDPs also are found in patients, we included 11 patients who received glucose fluids (standard group) during and after their surgery and 11 control patients receiving buffered saline (control group). Blood samples were analyzed for GDP content and carboxymethyllysine (CML), as a measure of AGE formation. The influence of heat-sterilized fluids on cell viability and cell function upon infection was investigated. RESULTS: All investigated fluids contained high concentrations of GDPs, such as 3-deoxyglucosone (3-DG). Serum concentration of 3-DG increased rapidly by a factor of eight in patients receiving standard therapy. Serum CML levels increased significantly and showed linear correlation with the amount of infused 3-DG. There was no increase in serum 3-DG or CML concentrations in the control group. The concentration of GDPs in most of the tested fluids damaged neutrophils, reducing their cytokine secretion, and inhibited microbial killing. CONCLUSIONS: These findings indicate that normal standard fluid therapy involves unwanted infusion of GDPs. Reduction of the content of GDPs in commonly used infusion fluids may improve cell function, and possibly also organ function, in intensive-care patients

Формирование эмоциональной культуры как компонента инновационной культуры студентов

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

PRIVACY MATURITY IN SWEDISH MUNICIPALITIES: A Quantitative Survey Based on a Privacy Maturity Framework

Municipalities of Sweden are facing challenges complying with the GDPR. New and changed management processes need to be implemented. We used an inductive quantitative approach applying a privacy maturity framework in a survey in May 2019 where 454 controllers in Swedish municipalities answered. Twenty-three measurable criteria are adopted from the technology-neutral international best-practice standard Generally accepted privacy principles (GAPP) and objective descriptions in the Privacy maturity model (PMM). The results are maturity estimates from level 1 to 5 on the 23 criteria, which we grouped in six attributes. Of the controllers, 52 percent are on level 1, 44 percent on level 2, and only 4 percent are above level 3. The survey also includes four significant findings: (1) Controllers in medium-large municipalities are estimating maturity higher than others. (2) Less than a third of the controllers have defined roles and responsibilities for privacy, except for the data protection officer (DPO). DPOs are estimating maturity even lower. (3) There is a risk for not detecting privacy breaches, due to lack of protection, monitoring and testing of safeguards, lack of controls on third-parties security practices, and treating privacy matters as IT-security queries. Controllers working with sensitive data are rating maturity higher in these areas. (4) Municipalities have prioritised visible processes like a privacy notice, meeting requests from registered and retention practices. There are two strategies found – one ambitious and one cautious. Several of these findings imply further research

Anaesthesia and Genetics of the Ryanodine 1 Receptor

The only validated method to characterize the phenotype and to reach a definitive diagnosis of Malignant Hyperthermia Susceptibility (MHS; OMIM *145600), a pharmacogenetic disease linked to the Ryanodine 1 receptor gene (RYR1; OMIM *180901), is an invasive muscle contraction test requiring a muscle biopsy, according to the European (IVCT) protocol or to the North American (CHCT) protocol. The series of scientific papers in this thesis tries to reach as far as possible in diagnosing MHS from peripheral venous blood samples collected at the patients’ local primary care provider and sent to the laboratory over significant transportation time and distance. Study I uses a traditional method of direct sequencing of a limited number of central exons of the RYR1 gene in the Swedish population with an outcome of only one fifth of the tested probands positive for a known MH causative mutation. Study II tries to bypass the laborious direct sequencing method of the very large RYR1 gene by using a method of stabilizing RNA in test tubes for transportation and synthesizing of RYR1cDNA for direct sequencing. Study IV implies a recent method based on establishing and analysing High Resolution Melting (HRM) DNA curves of 131 amplicons of the RYR1 on stable genomic DNA with an encouraging finding of a sequence variant in 81 % of the tested patients and similarly reducing the sequencing work by 79 %. By analysing all the found sequence variants in studies I, II and IV leading to amino acid changes in the final RYR1 receptor, it seems that the formerly known hotspot (N-terminal, central and C-terminal) distribution pattern can be seen, but sequence variants appear also outside of these traditional hotspots. Therefore coverage of the total coding region of the gene remains necessary. Another fact is that about half of the found sequence variants leading to amino acid changes are previously unknown and therefore uncharacterized at functional level. Study III presents a method of measuring the [Ca2+]i resting level and the increase in cytoplasmic [Ca2+]i level in prepared B lymphoblastic cell clones from patients carrying the actual candidate mutations, after influence of a RYR1 agonist. And of combining the outcome data on cellular level with clinical data. The series of studies I-IV presented in this thesis cannot give a definitive method to reach the diagnosis MHS, or even more important; to reach the definitive diagnosis of MHN, without an IVCT. But it can present advanced techniques to describe the genetical status of the patients and the impact of new previously unknown candidate mutations at functional level, and to combine this data with clinical data, based on only a simple venous blood sample. Once a MH causative mutation is found in a pedigree this allows for predictive testing in the family members and the individuals positive for the actual mutation can be assigned MHS without an IVCT, whereas the individuals negative for the mutation must go through IVC testing in order to confirm the MHN status

ROS- Relationer och Sexualitet : En granskning av ROS- policyn på uppdrag av Örebro kommun

Relationer och sexualitet utgör grundläggande behov för alla människor men detta är något som ofta förbises av omgivningen när det gäller funktionsnedsatta personer. Studiens syfte var att undersöka hur Örebro kommuns ROS- policy för bemötande av brukares känslor, relationer och sexualitet tillämpas i dagliga arbetet på boenden med särskild service inom förvaltningen för funktionshindrade. Studien har haft följande frågeställningar: hur följer medarbetarna ROS- policyn, på vilket sätt kan medarbetarnas förhållningssätt påverka brukarnas möjligheter till relationer och privatliv. För att få svar på forskningsfrågorna användes kvalitativa intervjuer, för att generera uttömmande och detaljerade svar. Intervjuer genomfördes med elva enskilda medarbetare, vilka valts ut genom målinriktat urval via en pedagogisk verksamhetsutvecklare. Av resultatet tolkades att Örebro kommun behöver informera, utbilda samt stötta sina medarbetare ytterligare för att ROS – policyn skall få ökad inverkan i de olika verksamheterna för att i förlängningen öka möjligheterna för brukare att få leva som alla andra.Relationships and sexuality are among the basic needs of all human beings but this is something that is often overlooked by the social environment concerning for disabled people. The aim of the study was to examine how Örebro (Relations and sexuality) ROS-policy for treatment of the disabled people’s emotions, relationships and sexuality, applied in daily work at accommodation with special services within the administration for the disabled. The research questions in the essay were; how employees follow the ROS-policy, how can employees 'attitudes affect the disabled people’s opportunities for relationships and personal life. In order to obtain answers to the research questions qualitative interview were used to prevail exhaustive and detailed answers. Interviews were conducted with 11 individual respondents, selected through a purposive sampling through an educational activity developer. The result was interpreted and showed that Örebro municipality needs to inform, educate and support their employees furthermore before the ROS-policy could be more influential in the residential caring homes in order to ultimately increase the opportunities for disabled to live like everyone else