| 1. |
- Auer-Grumbach, Michaela, et al.
(författare)
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Rare Variants in MME, Encoding Metalloprotease Neprilysin, Are Linked to Late-Onset Autosomal-Dominant Axonal Polyneuropathies
- 2016
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 99:3, s. 607-623
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Tidskriftsartikel (refereegranskat)abstract
- Axonal polyneuropathies are a frequent cause of progressive disability in the elderly. Common etiologies comprise diabetes mellitus, paraproteinaemia, and inflammatory disorders, but often the underlying causes remain elusive. Late-onset axonal Charcot-Marie-Tooth neuropathy (CMT2) is an autosomal-dominantly inherited condition that manifests in the second half of life and is genetically largely unexplained. We assumed age-dependent penetrance of mutations in a so far unknown gene causing late-onset CMT2. We screened 51 index case subjects with late-onset CMT2 for mutations by whole-exome (WES) and Sanger sequencing and subsequently queried WES repositories for further case subjects carrying mutations in the identified candidate gene. We studied nerve pathology and tissue levels and function of the abnormal protein in order to explore consequences of the mutations. Altogether, we observed heterozygous rare loss-of-function and missense mutations in MME encoding the metalloprotease neprilysin in 19 index case subjects diagnosed with axonal polyneuropathies or neurodegenerative conditions involving the peripheral nervous system. MME mutations segregated in an autosomal-dominant fashion with age-related incomplete penetrance and some affected individuals were isolated case subjects. We also found that MME mutations resulted in strongly decreased tissue availability of neprilysin and impaired enzymatic activity. Although neprilysin is known to degrade beta-amyloid, we observed no increased amyloid deposition or increased incidence of dementia in individuals with MME mutations. Detection of MME mutations is expected to increase the diagnostic yield in late-onset polyneuropathies, and it will be tempting to explore whether substances that can elevate neprilysin activity could be a rational option for treatment.
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| 2. |
- Coffin, Jack, et al.
(författare)
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Crossing wires : short-circuiting marketing theory
- 2022
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Ingår i: Marketing Theory. - : SAGE Publications. - 1470-5931 .- 1741-301X. ; 22:2, s. 275-292
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Tidskriftsartikel (refereegranskat)abstract
- In the popular imagination sex sells. Yet, marketing theory has relatively little to say about sexuality per se. Drawing on Žižek’s metaphor of critical theory as ‘short-circuiting’ the dominant discourse, we conceptualise marketing as a field that theorises sexuality only in a series of ‘closed circuits’. Knowledge becomes hierarchical when some topics, such as sexuality, are denied the theoretical freedom to roam in wider open circuits alongside other ‘mainstream’ marketing topics. We identify four ways in which certain topics are enclosed: theoretical, empirical, institutional and neo-colonial. We then seek to short-circuit this state of affairs by bringing together a heterogeneous group of scholars interested in sexuality. By crossing their critical insights like unexpected connections in a circuit, we create sparks of inspiration that challenge the contents, contexts and concepts that relate to marketing theories of sexuality. Our paper makes a specific theoretical contribution in arguing for sexuality to be treated as a phenomenon worth studying and theorising in its own right. However, it also makes a wider methodological and epistemological contribution in showing how various topics within marketing theory might be short-circuited to help flatten the hierarchies of knowledge created by closed and open circuits.
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| 3. |
- deBejczy, Andrea, et al.
(författare)
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Varenicline for Treatment of Alcohol Dependence: A Randomized, Placebo-Controlled Trial
- 2015
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Ingår i: Alcoholism-Clinical and Experimental Research. - : Wiley. - 0145-6008 .- 1530-0277. ; 39:11, s. 2189-2199
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAlcohol dependence is a devastating illness affecting a large population, and new pharmacological treatments with good efficacy are greatly needed. One potential candidate is varenicline, a smoking cessation agent with partial agonist action at (42) nicotinic acetylcholine receptors. MethodsA total of 160 subjects, 30 to 70years of age, fulfilling DSM-IV criteria for alcohol dependence without any serious physical or mental disorders, were recruited through advertisement at 3 university clinics in Sweden during March 2009 to January 2011. After a 2-week placebo run-in period, subjects received 2mg varenicline daily (titrated from 0.5mg during first week) or placebo for 12weeks in a double-blind manner. ResultsThe primary outcome was the proportion of heavy drinking days, measured by self-reported alcohol consumption. Primary and secondary outcomes were calculated as a mean over the 10-week steady-state active treatment period. In the primary outcome analysis, no effect of varenicline over placebo was found (p=0.73 for the intention to treat [ITT] and 0.92 for per protocol [PP]). Secondary outcome analysis found a significant reduction of specific alcohol marker phosphatidylethanol (PEth) in the blood in the varenicline group compared to placebo (p=0.02 ITT). Craving (p=0.048 PP) and Alcohol Use Disorders Identification Test (AUDIT) scores (p=0.015 ITT) were also reduced in the active treatment group. PEth more strongly correlated with self-reported alcohol consumption than carbohydrate-deficient ttransferrin and -glutamyl transferase, and correlation coefficients were higher in the varenicline group than in the placebo group for all markers. ConclusionsAlthough the results of the main outcome of this study did not support an effect of varenicline in alcohol-dependent individuals, the secondary analyses of PEth, craving and AUDIT score support an effect of varenicline on alcohol consumption. The disclosure of a treatment effect and the lack of a clear placebo effect when using PEth as outcome variable, together with a nonsymmetric bias associated with self-reported data, strongly argue for using the specific biomarker PEth in studies of treatments of alcohol dependence.
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| 4. |
- Forslund, Sofia K., et al.
(författare)
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Combinatorial, additive and dose-dependent drug–microbiome associations
- 2021
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 600:7889, s. 500-505
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Tidskriftsartikel (refereegranskat)abstract
- During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1–5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug–host–microbiome interactions in cardiometabolic disease.
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| 5. |
- Gils, Charlotte, et al.
(författare)
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NT-proBNP on Cobas h 232 in point-of-care testing: Performance in the primary health care versus in the hospital laboratory
- 2015
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Ingår i: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 75:7, s. 602-609
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Tidskriftsartikel (refereegranskat)abstract
- Background. NT-proBNP may be useful for ruling out heart failure in primary health care. In this study we examined the analytical quality of NT-proBNP in primary health care on the Cobas h 232 point-of-care instrument compared with measurements performed in a hospital laboratory. Materials and methods. Blood samples requested for NT-proBNP were collected in primary health care (n = 95) and in a hospital laboratory (n = 107). NT-proBNP was measured on-site on Cobas h 232 instruments both in primary health care centres and at the hospital laboratory and all samples were also analyzed with a comparison method at the hospital. Precision, trueness, accuracy, and lot-variation were determined at different concentration levels and evaluated according to acceptance criteria. Furthermore user-friendliness was assessed by questionnaires. Results. For Cobas h 232 repeatability CV was 8.5-10.7% in the hospital setting and 5.3-10.0% in the primary health care and within the analytical quality specifications, but higher than with the comparison method (<4%). NT-proBNP results obtained in primary health care were significantly higher than by the hospital comparison method (bias ranged from 14.3-23.7%), whereas there was no significant bias when Cobas h 232 was used in the hospital setting (bias ranged from 4.9 to 7.0%). User-friendliness of Cobas h 232 was overall acceptable. Conclusion. Cobas h 232 point-of-care instrument for measurement of NT-proBNP performed satisfactorily with regard to precision, user-friendliness, and lot-variation. A decrease in NT-proBNP levels observed in samples transported to a central laboratory needs further attention and investigation.
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| 6. |
- Isaksson, Anders, et al.
(författare)
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High-Throughput LC-MS/MS Method for Determination of the Alcohol Use Biomarker Phosphatidylethanol in Clinical Samples by Use of a Simple Automated Extraction Procedure-Preanalytical and Analytical Conditions
- 2018
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Ingår i: The Journal of Applied Laboratory Medicine. - : Oxford University Press (OUP). - 2576-9456 .- 2475-7241. ; 2:6, s. 880-892
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Phosphatidylethanol (PEth) is an alcohol use biomarker with higher clinical sensitivity and specificity than commonly used alcohol markers. Since its introduction as a clinical alcohol-marker in 2006, the number of samples sent to our laboratory for the determination of PEth has shown a strong annual increase. This has prompted the need to develop a cost-effective and reliable analytical procedure with high capacity. METHODS: An LC-MS/MS method for the determination of PEth 16:0/18:1 with a short turnaround time (3 min) has been evaluated with respect to accuracy, sensitivity, and precision. We compared this method with a previously used HPLC method, as well as a manual and a simplified automated method for sample workup, and investigated potential causes of analytic and preanalytic errors. RESULTS: The method shows limits of detection and quantification of 0.0075 μmol/L (5.2 ng/mL) and <0.05 μmol/L (<35 ng/mL), respectively. During a 2.1-year period, the method has shown a total CV < 8% for control samples (n = 2808) in the range of 0.10 (70) to 3.5 μmol/L (2461 ng/mL). The simplified automated method for sample preparation works equally well as the manual one. No specific and clinically significant causes of preanalytic errors were found. CONCLUSIONS: This LC-MS/MS method with automated sample workup is well suited for a clinical laboratory with LC-MS/MS experience and has the capability, proven from several years of use, to produce reliable PEth results in a high-volume laboratory (>50000 clinical samples/year).
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| 7. |
- Isaksson, Anders, et al.
(författare)
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Phosphatidylethanol in blood (B-PEth): A marker for alcohol use and abuse.
- 2011
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Ingår i: Drug Testing and Analysis. - : Wiley. - 1942-7611 .- 1942-7603. ; 3, s. 195-200
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Tidskriftsartikel (refereegranskat)abstract
- Phosphatidylethanol (PEth) represents a group of glycerophospholipid homologues where ethanol by phospholipase D has been bound at the position that normally contains an amino-alcohol. Since the formation of PEth is specifically dependent on ethanol, the diagnostic specificity of PEth as an alcohol biomarker is theoretically 100%. The half-life of PEth in blood is approximately 4 days. The amount of alcohol consumed correlates to blood concentration of PEth and PEth has been shown to be a more sensitive indicator of alcohol consumption than traditional alcohol markers, such as CDT (carbohydrate-deficient transferrin), GGT (γ-glutamyl transferase), and MCV (mean corpuscular volume) or a combination of these. Almost all clinical data so far available are based on a high performance liquid chromatography (HPLC) method with limited analytical sensitivity. With the advent of methods with considerably higher analytical sensitivity (e.g. mass spectrometric methods), clinical sensitivity will increase correspondingly. The possibility of determining very low concentrations of PEth by new sensitive analytical techniques may, however, have both ethical and legal consequences that have to be considered. Copyright © 2011 John Wiley & Sons, Ltd.
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| 8. |
- Jin, Guangfu, et al.
(författare)
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Validation of prostate cancer risk-related loci identified from genome-wide association studies using family-based association analysis : evidence from the International Consortium for Prostate Cancer Genetics (ICPCG)
- 2012
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 131:7, s. 1095-1103
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Tidskriftsartikel (refereegranskat)abstract
- Multiple prostate cancer (PCa) risk-related loci have been discovered by genome-wide association studies (GWAS) based on case-control designs. However, GWAS findings may be confounded by population stratification if cases and controls are inadvertently drawn from different genetic backgrounds. In addition, since these loci were identified in cases with predominantly sporadic disease, little is known about their relationships with hereditary prostate cancer (HPC). The association between seventeen reported PCa susceptibility loci was evaluated with a family-based association test using 1,979 hereditary PCa families of European descent collected by members of the International Consortium for Prostate Cancer Genetics, with a total of 5,730 affected men. The risk alleles for 8 of the 17 loci were significantly over-transmitted from parents to affected offspring, including SNPs residing in 8q24 (regions 1, 2 and 3), 10q11, 11q13, 17q12 (region 1), 17q24 and Xp11. In subgroup analyses, three loci, at 8q24 (regions 1 and 2) plus 17q12, were significantly over-transmitted in hereditary PCa families with five or more affected members, while loci at 3p12, 8q24 (region 2), 11q13, 17q12 (region 1), 17q24 and Xp11 were significantly over-transmitted in HPC families with an average age of diagnosis at 65 years or less. Our results indicate that at least a subset of PCa risk-related loci identified by case-control GWAS are also associated with disease risk in HPC families.
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| 9. |
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| 10. |
- Kollmer, Marius, et al.
(författare)
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Electron tomography reveals the fibril structure and lipid interactions in amyloid deposits
- 2016
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 113:20, s. 5604-5609
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Tidskriftsartikel (refereegranskat)abstract
- Electron tomography is an increasingly powerful method to study the detailed architecture of macromolecular complexes or cellular structures. Applied to amyloid deposits formed in a cell culture model of systemic amyloid A amyloidosis, we could determine the structural morphology of the fibrils directly in the deposit. The deposited fibrils are arranged in different networks, and depending on the relative fibril orientation, we can distinguish between fibril meshworks, fibril bundles, and amyloid stars. These networks are frequently infiltrated by vesicular lipid inclusions that may originate from the death of the amyloid-forming cells. Our data support the role of nonfibril components for constructing fibril deposits and provide structural views of different types of lipid-fibril interactions.
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| 11. |
- Lauridsen, Susanne Vahr, et al.
(författare)
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Effect of a Smoking and Alcohol Cessation Intervention Initiated Shortly Before Radical Cystectomy—the STOP-OP Study : A Randomised Clinical Trial
- 2022
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Ingår i: European Urology Focus. - : Elsevier BV. - 2405-4569. ; 8:6, s. 1650-1658
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Tidskriftsartikel (refereegranskat)abstract
- Background: Evidence concerning the reduction of postoperative complications due to smoking and alcohol drinking in patients undergoing radical cystectomy is incomplete. Objective: To evaluate the efficacy of a 6-wk smoking and/or alcohol cessation intervention, initiated shortly before surgery and continued until 4 wk after, in reducing complications. Design, setting, and participants: Between 2014 and 2018, we enrolled 104 patients with high-risk bladder cancer who were daily smokers or consuming at least 3 units of alcohol daily in a multicentre randomised clinical trial. Intervention: Patients were randomised to a 6-wk intensive smoking and/or alcohol cessation intervention or treatment as usual. Outcome measurements and statistical analysis: The primary endpoint was the number of patients developing any postoperative complication, or death, within 30 d after surgery. The secondary endpoints were successful quitters, health-related quality of life, length of stay, time back to habitual activity, and mortality. An intention-to-treat analysis was applied to evaluate treatment effect. Results and limitations: There were some differences in baseline demographic and lifestyle characteristics. Postoperatively, 64% in the intervention group versus 70% in the control group (risk ratio [RR] 0.91, confidence interval [CI] 0.68–1.21, p = 0.51) developed complications. Significantly fewer patients developed three or more complications after 30 d (RR 0.39; CI 0.18–0.84, p = 0.01). The rates of successful quitting were 51% in the intervention group and 27% in the control group (RR 2, CI 1.14–3.51, p = 0.01). The external validity of this trial may be limited because 53% of eligible patients refused participation. Conclusions: Despite a significant effect on the quit rate at completion of the intervention, this multimodal prehabilitation did not show a significant difference regarding our primary outcome postoperative complications. Patient summary: A 6-wk smoking and alcohol cessation intervention in relation to bladder cancer surgery did not reduce postoperative complications, but it was effective in supporting people to quit in the short term.
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| 12. |
- Lengeler, Klaus B, et al.
(författare)
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Analysis of the cell wall integrity pathway of Ashbya gossypii.
- 2013
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Ingår i: Microbiological Research. - : Elsevier BV. - 1618-0623 .- 0944-5013. ; 168:10, s. 607-614
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Tidskriftsartikel (refereegranskat)abstract
- Fungal cells are exposed to rapidly changing environmental conditions, in particular with regard to the osmotic potential. This requires constant remodeling of the cell wall and, therefore, the cell wall integrity (CWI) MAP-kinase pathway plays a major role in shaping the fungal cell wall to protect from adverse external stresses. To provide a comprehensive functional analysis of the Ashbya gossypii CWI pathway we generated a set of ten deletion mutants in conserved components including the cell surface sensors AgWSC1 and AgMID2, a putative Rho1-guanine nucleotide exchange factor, AgTUS1, the protein kinase C, AgPKC1, the MAP-kinases AgBCK1, AgMKK1 and AgMPK1, and transcription factors known to be involved in CWI signaling AgRLM1, AgSWI4 and AgSWI6. Deletion of AgPKC1 shows a severe growth defect with frequent tip cell lysis. Deletion of components of the MAP-kinase module generates a pronounced colony lysis phenotype in older regions of the mycelium. Cytoplasmic leakage was assayed using alkaline phosphatase and β-galactosidase release assays. This indicated that the lysis phenotypes of CWI pathway mutants may be useful to facilitate the isolation of riboflavin from A. gossypii. Remarkably, the Agwsc1 mutant showed a strong (up to 8-fold) increase of riboflavin in the growth medium compared to the parental strain.
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| 13. |
- Lu, Lingyi, et al.
(författare)
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Chromosomes 4 and 8 implicated in a genome wide SNP linkage scan of 762 prostate cancer families collected by the ICPCG
- 2012
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 72:4, s. 410-426
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND In spite of intensive efforts, understanding of the genetic aspects of familial prostate cancer (PC) remains largely incomplete. In a previous microsatellite-based linkage scan of 1,233 PC families, we identified suggestive evidence for linkage (i.e., LOD?=?1.86) at 5q12, 15q11, 17q21, 22q12, and two loci on 8p, with additional regions implicated in subsets of families defined by age at diagnosis, disease aggressiveness, or number of affected members. METHODS. In an attempt to replicate these findings and increase linkage resolution, we used the Illumina 6000 SNP linkage panel to perform a genome-wide linkage scan of an independent set of 762 multiplex PC families, collected by 11 International Consortium for Prostate Cancer Genetics (ICPCG) groups. RESULTS. Of the regions identified previously, modest evidence of replication was observed only on the short arm of chromosome 8, where HLOD scores of 1.63 and 3.60 were observed in the complete set of families and families with young average age at diagnosis, respectively. The most significant linkage signals found in the complete set of families were observed across a broad, 37cM interval on 4q13-25, with LOD scores ranging from 2.02 to 2.62, increasing to 4.50 in families with older average age at diagnosis. In families with multiple cases presenting with more aggressive disease, LOD cores over 3.0 were observed at 8q24 in the vicinity of previously identified common PC risk variants, as well as MYC, an important gene in PC biology. CONCLUSIONS. These results will be useful in prioritizing future susceptibility gene discovery efforts in thiscommon cancer. Prostate 72: 410-426, 2012. (C) 2011 Wiley Periodicals, Inc.
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| 14. |
- Marques, Paul, et al.
(författare)
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Detection of Phosphatidylethanol (PEth) in the Blood of Drivers in an Alcohol Ignition Interlock Program
- 2011
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Ingår i: Traffic Injury Prevention. - : Informa UK Limited. - 1538-9588 .- 1538-957X. ; 12:2, s. 136-141
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The rate of failed interlock blood alcohol content (BAC) tests is a strong predictor of recidivism post-interlock and a partial proxy for alcohol use. Alcohol biomarkers measured at the start of an interlock program are known to correlate well with rates of failed BAC tests over months of interlock use. This study evaluates 2 methods of measuring low blood levels of the biomarker phosphatidylethanol (PEth). PEth is a 100 percent alcohol-specific biomarker and strongly intercorrelated with several independent indicators of drinking driving risk, including 8 other biomarkers, 3 psychometric assessments, and the rate of failed interlock BAC tests during many months of interlock use. Does a more sensitive method of measuring PEth at program entry detect drinking even among those who subsequently log no failed interlock tests? Methods: In a sample of 281 driver blood samples, PEth was measured by both high-performance liquid chromatography (HPLC) and liquid chromatography tandem mass spectrometry (LCMSMS) in order to compare sensitivity and accuracy. The average rate of failed interlock BAC tests was the criterion measure for marker sensitivity. LCMSMS, calibrated to detect low levels of drinking as a possible measure of abstinence violation, was judged relative to the standard HPLC assay for PEth measured up to 4 mol/L. Results: The 2 methods showed a good quantitative relationship (r2 .86). LCMSMS detected positive PEth levels in samples that were below the limit of detection of the HPLC method. PEth measured by LCMSMS was positive for a higher proportion of driving under the influence (DUI) offenders who logged zero failed interlock BAC tests than were detected by HPLC. Conclusion: Although HPLC is the widely used standard for measuring PEth in clinical alcoholism samples, the LCMSMS method, when calibrated to detect trace amounts of the major component of PEth, can detect abstinence levels of alcohol near zero intake and still correlate strongly with other indicators related to alcohol use and road safety.
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| 15. |
- Nilsson, Sara, et al.
(författare)
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Analysis of binding sites on complement factor I that are required for its activity.
- 2010
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 285, s. 6235-6245
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Tidskriftsartikel (refereegranskat)abstract
- The central complement inhibitor factor I (FI) degrades activated complement factors C4b and C3b in the presence of cofactors such as C4b-binding protein, factor H, complement receptor 1 and membrane cofactor protein. FI is a serine protease composed of two chains; the light chain comprises the serine protease domain, while the heavy chain contains several domains: the FI and membrane attack complex domain (FIMAC), CD5, low density lipoprotein receptor 1 (LDLr1) and LDLr2 domains. In order to understand better how FI acts as a complement inhibitor, we used homology-based models of FI domains to predict potential binding sites. Specific amino acids were then mutated to yield 16 well-expressed mutants, which were then purified from media of eukaryotic cells for functional analyses. The Michaelis constant (Km) of all FI mutants towards a small substrate was not altered while some mutants showed increased maximum initial velocity (Vmax). All the mutations in the FIMAC domain affected the ability of FI to degrade C4b and C3b irrespective of the cofactor used whereas only some mutations in the CD5 and LDLr1/2 domains had similar effect. These same mutants also showed impaired binding to C3met. In conclusion, the FIMAC domain appears to harbor the main binding sites important for the ability of FI to degrade C4b and C3b.
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| 16. |
- Steins, Krisjanis, 1971-
(författare)
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Discrete-Event Simulation for Hospital Resource Planning : Possibilities and Requirements
- 2010
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The delivery of health care services has been under pressure due to limited funding and increasing demand. This has highlighted the need to increase not only the effectiveness but also the efficiency of health care delivery. Discrete-event simulation has been suggested as an analysis tool in health care management to support the planning of health care resources.The overall purpose of this thesis is to investigate the possibilities and requirements for using discrete-event simulation in analyzing and planning the use of hospital resources. This is achieved by three case studies that focus on improvements in patient flow of emergency patients that require a radiology examination, intensive care unit capacity planning and operating room allocation strategies, respectively.The first case investigates the current stage of digitization and process orientation in hospital care as a prerequisite for efficient process simulation and analysis. The study reveals an emergency-radiology patient flow process that is not very well measured and uncovers disparate information systems storing incompatible and fragmented data. These results indicate that the current degree of process orientation and the current IT infrastructure does not enable efficient use of quantitative process analysis and management tools like simulation.In the second case the possibilities to develop generic hospital unit simulation models by building and validating a generic intensive care unit (ICU) model are explored. The results show that some of the modeling approaches described in literature cannot replicate the actual behavior observed in all studied ICUs. It is important to identify patient groups for different admission priorities, to account for over-utilizations in the model logic, and to discover and properly model dependencies in the input data. The research shows that it is possible to develop a generic ICU simulation model that could realistically describe the performance of different real ICUs in terms of occupancy, coverage and transfers.The value of simulation modeling in health care management is examined in the third case through the development and use of a simulation model for optimal resource allocation and patient flow in a hospital operating department. The goal of the simulation modeling in this case was to identify bottlenecks in the patient flow and to try different alternatives for allocation of operating room capacity in order to increase the utilization of operating room resources. The final model was used to evaluate four different proposed changes to operating room time allocation.
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| 17. |
- Stenton, Joanna, et al.
(författare)
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Inter Individual Variation and Factors Regulating the Formation of Phosphatidylethanol
- 2019
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Ingår i: Alcoholism: Clinical and Experimental Research. - : Wiley. - 0145-6008 .- 1530-0277. ; 43:11, s. 2322-2331
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alcohol use disorders are a major but often unrecognized health problem. Alcohol markers can therefore be of great value for diagnosis, follow-up, and treatment evaluation. Phosphatidylethanol in blood (B-PEth) is an alcohol biomarker with higher clinical sensitivity and specificity than commonly used alcohol markers but has shown a considerable interindividual variation in relation to reported consumption. Methods: An in vitro system was used to investigate factors, which may affect the formation rate of PEth or which may give rise to interindividual variation in the rate of formation. In this system, isolated erythrocytes from 31 individuals were incubated in the presence of various concentrations of ethanol (EtOH). The concentration of PEth and phosphatidylcholine (PC), the parent molecule of PEth, was determined by chromatographic methods. Results: Time, EtOH, and PC concentration were major factors determining the amount of PEth formed. The interindividual variation in PEth formation rate, calculated at an EtOH concentration of 50 mmol/l, showed a coefficient of variation (CV) from 23 to 31% for the different PEth forms studied (PEth 16:0/18:2, total PEth and PEth 16:0/18:1). The concentration of PC was found to be an important determinant of this variation. The formation rate for PEth 16:0/18:2 was somewhat higher than for PEth 16:0/18:1. The formation of PEth 16:0/18:1 but not PEth 16:0/18:2 showed a positive correlation to the concentration of PEth at baseline (endogenous PEth). Calculation of enzyme kinetics for the reaction resulting in the formation of PEth 16:0/18:1 or PEth 16:0/18:2 showed an apparent Km (Michaelis constant) of approximately 160 to 170 mmol/l. Conclusions: Interindividual variation in the formation rate of PEth appears to be a significant but relatively modest source of variation in the relation between B-PEth and reported consumption. Correction for interindividual variation in PC concentrations might substantially reduce the interindividual variability in PEth formation and consequently in B-PEth.
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| 18. |
- Szulkin, Robert, et al.
(författare)
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Prediction of individual genetic risk to prostate cancer using a polygenic score.
- 2015
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 75:13, s. 1467-74
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction.METHODS: We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls.RESULTS: The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk.CONCLUSIONS: Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction.
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| 19. |
- Teerlink, Craig C., et al.
(författare)
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Association analysis of 9,560 prostate cancer cases from the International Consortium of Prostate Cancer Genetics confirms the role of reported prostate cancer associated SNPs for familial disease
- 2014
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Ingår i: Human Genetics. - : Springer. - 0340-6717 .- 1432-1203. ; 133:3, s. 347-356
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Tidskriftsartikel (refereegranskat)abstract
- Previous GWAS studies have reported significant associations between various common SNPs and prostate cancer risk using cases unselected for family history. How these variants influence risk in familial prostate cancer is not well studied. Here, we analyzed 25 previously reported SNPs across 14 loci from prior prostate cancer GWAS. The International Consortium for Prostate Cancer Genetics (ICPCG) previously validated some of these using a family-based association method (FBAT). However, this approach suffered reduced power due to the conditional statistics implemented in FBAT. Here, we use a case-control design with an empirical analysis strategy to analyze the ICPCG resource for association between these 25 SNPs and familial prostate cancer risk. Fourteen sites contributed 12,506 samples (9,560 prostate cancer cases, 3,368 with aggressive disease, and 2,946 controls from 2,283 pedigrees). We performed association analysis with Genie software which accounts for relationships. We analyzed all familial prostate cancer cases and the subset of aggressive cases. For the familial prostate cancer phenotype, 20 of the 25 SNPs were at least nominally associated with prostate cancer and 16 remained significant after multiple testing correction (p a parts per thousand currency sign 1E (-3)) occurring on chromosomal bands 6q25, 7p15, 8q24, 10q11, 11q13, 17q12, 17q24, and Xp11. For aggressive disease, 16 of the SNPs had at least nominal evidence and 8 were statistically significant including 2p15. The results indicate that the majority of common, low-risk alleles identified in GWAS studies for all prostate cancer also contribute risk for familial prostate cancer, and that some may contribute risk to aggressive disease.
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| 20. |
- Walther, Lisa, et al.
(författare)
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Alcohol Consumption in Obese Patients Before and After Gastric Bypass as Assessed with the Alcohol Marker Phosphatidylethanol (PEth)
- 2018
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Ingår i: Obesity Surgery. - : Springer Science and Business Media LLC. - 0960-8923 .- 1708-0428. ; 28:8, s. 2354-2360
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Roux-en-Y gastric bypass (RYGB) causes more rapid and enhanced absorption of alcohol. RYGB patients have also been reported to use more inpatient care for alcohol-related disease than do patients after other bariatric procedures. The present study was designed to evaluate alcohol consumption level before and after gastric bypass using a sensitive and specific alcohol biomarker. Materials and Methods: Two separate consecutive groups of patients and a group of healthy blood donors, as reference group, were included in the study. Alcohol intake was assessed using the alcohol marker phosphatidylethanol (PEth) at preoperative baseline and at 1 and 2 years postoperatively. In the first patient group (n = 133), neither surgeon nor patient was informed about the results of PEth testing. In the second group (n = 214), PEth results above 0.30 μmol/L were considered to indicate excessive alcohol consumption and led to preoperative alcohol counseling. The groups were followed for 2 and 1 year, respectively. Results: PEth results were significantly lower in both patient groups at baseline as well as postoperatively compared with the reference group. In both patient groups, there was a significant increase in PEth values at postoperative follow-up compared to baseline. Conclusions: Several physiological changes postoperatively have to be considered when interpreting PEth results in obese patients with dramatic weight reductions. According to results for PEth, obese patients treated with bariatric surgery would seem to have lower alcohol consumption compared with the reference group. Although slightly increasing their PEth values postoperatively, the RYGB patients did not reach the PEth values of the reference group.
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| 21. |
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| 22. |
- Walther, Lisa, et al.
(författare)
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Phosphatidylethanol is Superior to Carbohydrate-Deficient Transferrin and -Glutamyltransferase as an Alcohol Marker and is a Reliable Estimate of Alcohol Consumption Level
- 2015
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Ingår i: Alcoholism-Clinical and Experimental Research. - : Wiley. - 0145-6008 .- 1530-0277. ; 39:11, s. 2200-2208
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIn clinical practice as well as research situations, it is of great importance to get reliable information about a patient's alcohol consumption. The aim of the study was to investigate the correlation of alcohol biomarkers (phosphatidylethanol [PEth], carbohydrate-deficient transferrin [CDT], -glutamyltransferase, aspartate aminotransferase, and alanine aminotransferase) to retrospective as well as diary-based alcohol self-reports and to examine whether it is possible to correlate a biomarker result to a more precise level of alcohol consumption. MethodsOne hundred and sixty alcohol-dependent patients were included in a randomized, placebo-controlled clinical trial of pharmacotherapy for alcohol dependence, of which 115 (76 men and 39 women) completed the study. Retrospective alcohol consumption data were collected at baseline, and alcohol diaries were used during the study. Blood samples for determination of alcohol biomarkers were collected on 5 occasions during the study. ResultsPEth and CDT showed a better correlation with alcohol consumption documented in the diary (PEth r(s)=0.56 and CDT r(s)=0.35) than with retrospective consumption data (PEth r(s)=0.23 and CDT r(s)=0.22). An even higher correlation (r(s)=0.63) was seen between the 2 alcohol biomarkers PEth and CDT. At all consumption levels, PEth had the highest sensitivity of all biomarkers studied. ConclusionsPEth was the biomarker with the best correlation to self-reported alcohol consumption. PEth was superior to CDT owing to its substantially higher sensitivity but also due to its closer correlation to self-report. PEth values can be translated into an approximate level of alcohol consumption and PEth appears to be a more reliable measure of alcohol consumption than self-reports.
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| 23. |
- Wasserstrom, Lisa, et al.
(författare)
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Developmental Growth Control Exerted via the Protein A Kinase Tpk2 in Ashbya gossypii.
- 2015
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Ingår i: Eukaryotic Cell. - 1535-9778. ; 14:6, s. 593-601
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Tidskriftsartikel (refereegranskat)abstract
- Sporulation in Ashbya gossypii is induced by nutrient-limited conditions and leads to the formation of haploid spores. Using RNA-seq, we have determined a gene set induced upon sporulation, which bears considerable overlap with that of Saccharomyces cerevisiae but also contains A. gossypii-specific genes. Addition of cyclic AMP (cAMP) to nutrient-limited media blocks sporulation and represses the induction of sporulation specific genes. Deletion of the protein kinase A (PKA) catalytic subunits encoded by TPK1 and TPK2 showed reduced growth in tpk1 but enhanced growth in the tpk2 strain; however, both mutants sporulated well. Sporulation can be blocked by cAMP in tpk1 but not in tpk2 strains. Similarly, TPK2 acts at a second developmental switch promoting the break in spore dormancy. In S. cerevisiae, PKA phosphorylates and inhibits Msn2/4. The transcript profiles of the tpk1 and msn2/4 mutants were very similar to that of the wild type under sporulation conditions. However, deletion of the single A. gossypii MSN2/4 homolog generated a specific sporulation defect. We identified a set of genes involved in spore wall assembly that was downregulated in the msn2/4 mutant, particularly DIT2, suggesting that poor spore viability may be due to lysis of spores. Our results reveal specific functional differences between the two catalytic PKA subunits in A. gossypii and identified Tpk2 as the key A kinase that transduces developmental decisions of growth. Our data also suggest that Msn2/4 is involved only at a late step of sporulation in A. gossypii and is not a major regulator of IME1.
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| 24. |
- Wasserstrom, Lisa, et al.
(författare)
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Fungal model systems and the elucidation of pathogenicity determinants
- 2014
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Ingår i: Fungal Genetics and Biology. - : Elsevier BV. - 1087-1845. ; 70, s. 42-67
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Tidskriftsartikel (refereegranskat)abstract
- Fungi have the capacity to cause devastating diseases of both plants and animals, causing significant harvest losses that threaten food security and human mycoses with high mortality rates. As a consequence, there is a critical need to promote development of new antifungal drugs, which requires a comprehensive molecular knowledge of fungal pathogenesis. In this review, we critically evaluate current knowledge of seven fungal organisms used as major research models for fungal pathogenesis. These include pathogens of both animals and plants; Ashbya gossypii, Aspergillus fumigatus, Candida albicans, Fusarium oxysporum, Magnaporthe oryzae, Ustilago maydis and Zymoseptoria tritici. We present key insights into the virulence mechanisms deployed by each species and a comparative overview of key insights obtained from genomic analysis. We then consider current trends and future challenges associated with the study of fungal pathogenicity.
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| 25. |
- Wasserstrom, Lisa, et al.
(författare)
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Molecular determinants of sporulation in Ashbya gossypii.
- 2013
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Ingår i: Genetics. - : Oxford University Press (OUP). - 0016-6731 .- 1943-2631. ; 195:1, s. 87-99
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Tidskriftsartikel (refereegranskat)abstract
- Regulation of development and entry into sporulation is critical for fungi to ensure survival of unfavorable environmental conditions. Here we present an analysis of gene sets regulating sporulation in the homothallic ascomycete Ashbya gossypii. Deletion of components of the conserved pheromone/starvation MAP kinase cascades, e.g., STE11 and STE7, results in increased sporulation. In kar3 mutants sporulation is severely reduced, while deletion of KAR4 as well as of homologs of central Saccharomyces cerevisiae regulators of sporulation, IME1, IME2, IME4, and NDT80, abolishes sporulation in A. gossypii. Comparison of RNAseq transcript profiles of sporulation-deficient mutants identified a set of 67 down-regulated genes, most of which were up-regulated in the oversporulating ste12 mutant. One of these differentially expressed genes is an endoglucanase encoded by ENG2. We found that Eng2p promotes hyphal fragmentation as part of the developmental program of sporulation, which generates single-celled sporangia. Sporulation-deficient strains are arrested in their development but form sporangia. Supply of new nutrients enabled sporangia to return to hyphal growth, indicating that these cells are not locked in meiosis. Double-strand break (DSB) formation by Spo11 is apparently not required for sporulation; however, the absence of DMC1, which repairs DSBs in S. cerevisiae, results in very poor sporulation in A. gossypii. We present a comprehensive analysis of the gene repertoire governing sporulation in A. gossypii and suggest an altered regulation of IME1 expression compared to S. cerevisiae.
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| 26. |
- Önning, Gunilla, et al.
(författare)
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Selenium and selenoproteins in food
- 2004
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Ingår i: Metal Ions in Biology and Medicine, vol 8. - 1257-2535. - 9782742005222 ; 8, s. 79-81
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Konferensbidrag (refereegranskat)
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