| 1811. |
- Lindstrand, Anna, et al.
(author)
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From cytogenetics to cytogenomics : whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability
- 2019
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In: Genome Medicine. - : BMC. - 1756-994X. ; 11:1
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Journal article (peer-reviewed)abstract
- BackgroundSince different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements, underlie intellectual disability, we evaluated the use of whole-genome sequencing (WGS) rather than chromosomal microarray analysis (CMA) as a first-line genetic diagnostic test.MethodsWe analyzed three cohorts with short-read WGS: (i) a retrospective cohort with validated copy number variants (CNVs) (cohort 1, n=68), (ii) individuals referred for monogenic multi-gene panels (cohort 2, n=156), and (iii) 100 prospective, consecutive cases referred to our center for CMA (cohort 3). Bioinformatic tools developed include FindSV, SVDB, Rhocall, Rhoviz, and vcf2cytosure.ResultsFirst, we validated our structural variant (SV)-calling pipeline on cohort 1, consisting of three trisomies and 79 deletions and duplications with a median size of 850kb (min 500bp, max 155Mb). All variants were detected. Second, we utilized the same pipeline in cohort 2 and analyzed with monogenic WGS panels, increasing the diagnostic yield to 8%. Next, cohort 3 was analyzed by both CMA and WGS. The WGS data was processed for large (>10kb) SVs genome-wide and for exonic SVs and SNVs in a panel of 887 genes linked to intellectual disability as well as genes matched to patient-specific Human Phenotype Ontology (HPO) phenotypes. This yielded a total of 25 pathogenic variants (SNVs or SVs), of which 12 were detected by CMA as well. We also applied short tandem repeat (STR) expansion detection and discovered one pathologic expansion in ATXN7. Finally, a case of Prader-Willi syndrome with uniparental disomy (UPD) was validated in the WGS data.Important positional information was obtained in all cohorts. Remarkably, 7% of the analyzed cases harbored complex structural variants, as exemplified by a ring chromosome and two duplications found to be an insertional translocation and part of a cryptic unbalanced translocation, respectively.ConclusionThe overall diagnostic rate of 27% was more than doubled compared to clinical microarray (12%). Using WGS, we detected a wide range of SVs with high accuracy. Since the WGS data also allowed for analysis of SNVs, UPD, and STRs, it represents a powerful comprehensive genetic test in a clinical diagnostic laboratory setting.
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| 1812. |
- Lindstrand, Anna, et al.
(author)
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Genome sequencing is a sensitive first-line test to diagnose individuals with intellectual disability
- 2022
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In: Genetics in Medicine. - : ELSEVIER SCIENCE INC. - 1098-3600 .- 1530-0366. ; 24:11, s. 2296-2307
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Journal article (peer-reviewed)abstract
- Purpose: Individuals with intellectual disability (ID) and/or neurodevelopment disorders (NDDs) are currently investigated with several different approaches in clinical genetic diagnostics. Methods: We compared the results from 3 diagnostic pipelines in patients with ID/NDD: genome sequencing (GS) first (N = 100), GS as a secondary test (N = 129), or chromosomal microarray (CMA) with or without FMR1 analysis (N = 421). Results: The diagnostic yield was 35% (GS -first), 26% (GS as a secondary test), and 11% (CMA/FMR1). Notably, the age of diagnosis was delayed by 1 year when GS was performed as a secondary test and the cost per diagnosed individual was 36% lower with GS first than with CMA/FMR1. Furthermore, 91% of those with a negative result after CMA/FMR1 analysis (338 individuals) have not yet been referred for additional genetic testing and remain undiagnosed. Conclusion: Our findings strongly suggest that genome analysis outperforms other testing strategies and should replace traditional CMA and FMR1 analysis as a first-line genetic test in individuals with ID/NDD. GS is a sensitive, time-and cost-effective method that results in a confirmed molecular diagnosis in 35% of all referred patients. (c) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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| 1813. |
- Lindström, Sandra, et al.
(author)
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PM 2/21 : Methods for assessing the effects of plant protection products on biodiversity
- 2021
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Reports (other academic/artistic)abstract
- Lund University was commissioned by the Swedish Chemicals Agency to map and describe emerging methodologies that assess the indirect impact of plant protection products on nontarget organism individuals and populations, and studies that evaluates if current risk assessment methodologies are sufficient to assess direct effects of plant protection products on biodiversity. The commission was performed in two parts. First, we made an inventory ofemerging methods to assess indirect effects of plant protection products on non-target organisms among risk assessment authorities in nine countries. Second, we reviewed the scientific literature by performing a systematic search of scientific databases and mapped research discussing method development to assess indirect effects of plant protection products on non-target individuals and populations, and direct effects of plant protection products on biodiversity.The inventory shows that there are few ongoing attempts to assess indirect effects of plant protection products in the light of environmental risk assessment schemes among the countries we asked. In Germany, requirements were introduced in 2018 to assess the indirect effects of plant protection products via trophic interactions when registering new plant protection products, but these requirements were withdrawn in the autumn of 2019 due to lack of legal basis for their implementation.Our literature review showed that approaches to assess indirect effects on individuals or populations of plant protection products in a risk assessment context involves both model ecosystems (cosms), field studies, and mathematical, mainly mechanistic effects models. Knowledge of species interactions is a key to understand the underlying mechanisms thatshape how plant protection products impact biodiversity.While plenty of papers suggest that current risk assessment methodologies are insufficient to safeguard biodiversity, few papers have actually compared how well different environmental risk methodologies protect biodiversity. The current risk assessment methods are based shortterm laboratory studies on single test species, or on simplified communities in mesocosm experiments, which provide information on acute toxicity. The validity and usefulness of such laboratory studies have been criticized for not including variation in space and time,interactions with other stressors and indirect effects caused by competition and trophic interactions between populations. This hampers the possibility of using them to assess effects on biodiversity in field situations. Furthermore, it is proposed that the current risk assessment of plant protection products can be improved by increasing the representation of test species, including previously neglected taxonomic groups, such as microorganisms and fungi.According to several studies, future environmental risk assessment methods should to a larger extent than today combine laboratory, field and semi-field studies and mathematical models to capture indirect effects and direct effects on biodiversity. Other proposals are to complement and combine the bottom-up approaches of the current environmental risk assessment, that largely relies on extrapolation of effects on individuals assessed in standard laboratory tests to communities, with top-down approaches such as monitoring of landscape and communities, as well as combine bottom-up and top-down methods, to make accurate assessments of the risks plant protection products poses to biodiversity.
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| 1814. |
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| 1815. |
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| 1816. |
- Ling, Charlotte, et al.
(author)
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Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins.
- 2004
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In: Journal of Clinical Investigation. - 0021-9738. ; 114:10, s. 1518-1526
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Journal article (peer-reviewed)abstract
- Genetic and environmental factors contribute to age-dependent susceptibility to type 2 diabetes. Recent studies have reported reduced expression of PPAR{gamma} coactivator 1{alpha} (PGC-1{alpha}) and PGC-1ß genes in skeletal muscle from type 2 diabetic patients, but it is not known whether this is an inherited or acquired defect. To address this question we studied expression of these genes in muscle biopsies obtained from young and elderly dizygotic and monozygotic twins without known diabetes before and after insulin stimulation and related the expression to a Gly482Ser variant in the PGC-1{alpha} gene. Insulin increased and aging reduced skeletal muscle PGC-1{alpha} and PGC-1ß mRNA levels. This age-dependent decrease in muscle gene expression was partially heritable and influenced by the PGC-1{alpha} Gly482Ser polymorphism. In addition, sex, birth weight, and aerobic capacity influenced expression of PGC-1{alpha} in a complex fashion. Whereas expression of PGC-1{alpha} in muscle was positively related to insulin-stimulated glucose uptake and oxidation, PGC-1ß expression was positively related to fat oxidation and nonoxidative glucose metabolism. We conclude that skeletal muscle PGC-1{alpha} and PGC-1ß expression are stimulated by insulin and reduced by aging. The data also suggest different regulatory functions for PGC-1{alpha} and PGC-1ß on glucose and fat oxidation in muscle cells. The finding that the age-dependent decrease in the expression of these key genes regulating oxidative phosphorylation is under genetic control could provide an explanation by which an environmental trigger (age) modifies genetic susceptibility to type 2 diabetes.
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| 1817. |
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| 1818. |
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Linköpingsbygden : Hembygdsföreningar berättar
- 2004
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Editorial collection (other academic/artistic)abstract
- I Linköpingsområdet finns ett 25-tal hembygdsföreningar. Av dessa medverkar ungefär hälften i denna gemensamma bok. Vi har valt att kalla boken för Linköpingsbygden, ett namn som visserligen använts tidigare, men som ger en bild av vad som avhandlas i boken. I det här sammanhanget har vi kompletterat med en undertitel: Hembygdsföreningar berättar. En titt i innehållsförteckningen vias på det breda område hembygdsföreningarna verkar inom. De medverkande föreningarna representerar några av de miljöer som finns i Linköpings kommun, skogsbygd, slättbygd och stadsmiljö.
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| 1819. |
- Linnros, Evelina, 1990-
(author)
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Essays on Fertility and Health
- 2024
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Doctoral thesis (other academic/artistic)abstract
- Infertility Risk and Child MarriageThe high infertility rates observed in some developing countries may have broad societal impacts, for example by people marrying and having children at a young age to increase their chances of reaching their fertility target. I study the link between infertility risk and marriage timing using data from Madagascar. Specifically, I focus on how infertility risk affects the probability of child marriage, a practice associated with adverse outcomes for young brides and their children. I use spatial variation in exposure to the parasite schistosomiasis. The empirical strategy compares two strains of this parasite, similar in their transmission mechanisms and health impacts, except that one of the two strains causes infertility. In my data, exposure to this strain increases the probability that a woman is infertile by 40%. I find that exposure to the infertility-causing strain increases the probability of child marriage and early fertility by 22%.Maternal Health and Labor Market OutcomesWe study how severe injuries related to childbirth affect mothers' labor market outcomes. 1 in 20 first-time mothers who have a vaginal delivery suffer a severe birth tear, which can have long-lasting adverse impacts on their health and quality of life. Using a difference-in-differences design with a matched control group, we find that severe birth tears lead to a 6% higher earnings loss in the first five years after childbirth compared to the control group. The effect is larger for mothers from low SES backgrounds, while high SES mothers are found to seek more healthcare following their injury.Alcohol Availability, Prenatal Conditions and Midlife Mental Health We examine the long-term mental health effects of an 8.5-month policy experiment that led to a sharp and unexpected increase in alcohol availability, focusing on individuals exposed to the policy in utero. We use administrative healthcare and drug prescription records to identify individuals who have received treatment for a mental health disorder. Prenatal exposure to the policy had a large and persistent effect on mental health: the exposed cohort is 16% more likely to be treated for a mental disorder in midlife. The effect is largest for those exposed from the second trimester and is only partly explained by the lower earnings observed among exposed individuals.The Value of Monitoring for Disaster Prevention: The Desert LocustMonitoring systems are meant to detect early signs of potentially disastrous outbreaks of diseases and pests, in time for preventative action. These monitoring systems are costly, and identifying their economic value requires estimating damages from outbreaks in empirical settings where monitoring is neither uniform nor exogenous. We estimate the value of monitoring systems for desert locusts, known to devour entire agricultural fields. We leverage conflict and weather events in breeding areas to detect the effects of monitoring interruptions on swarm outbreaks. We then reconstruct the spatial patterns of locust migrations to propagate these effects on swarm outbreaks beyond breeding areas. Finally, we show that in-utero exposure to a swarm increases the probability of stunting by 16%. These estimates allow us to quantify the effects of a change in monitoring efforts on subsequent locust swarms and on human health.
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| 1820. |
- Liss, Per, et al.
(author)
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Renal effects of CO2 and iodinated contrast media in patients undergoing renovascular intervention : a prospective, randomized study
- 2005
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In: Journal of Vascular and Interventional Radiology. - 1051-0443 .- 1535-7732. ; 16:1, s. 57-65
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Journal article (peer-reviewed)abstract
- PURPOSE: CO2 gas has been proposed for use instead of iodinated contrast media in angiographic examinations in patients at risk of developing renal failure from contrast media. The influence of intraarterial injection of CO2 with small added amounts of ioxaglate (200 mgI/mL) or ioxaglate alone on renal function in patients with suspected renal artery stenosis was studied in a prospective, randomized study. MATERIALS AND METHODS: One hundred twenty-three patients underwent renovascular intervention (n = 83) and/or renal angiography (n = 40) for suspected renal artery stenosis. Patients with a serum creatinine concentration less than 200 micromol/L (n = 82) were randomized prospectively to receive CO2 with small added amounts of ioxaglate (n = 37) or only ioxaglate (n = 45). Patients with serum creatinine levels greater than 200 micromol/L (n = 41) were not randomized and initially received CO2. Serum creatinine concentrations were measured within 1 day before and 1 day, 2 days, and 2-3 weeks after the procedure. RESULTS: The amount of injected CO2 did not relate to an increase in serum creatinine level. In the randomized groups, and also when the whole patient sample was considered, the amount of injected iodine was significantly correlated (P = .011) with an increase in serum creatinine level and a decrease in estimated creatinine clearance after 2 days. Among the randomized patients, one in the CO2 group and three in the ioxaglate group had a more than 25% increase in serum creatinine level within the first 2 days after the intervention. CONCLUSION: The risk of impairment of renal function is lower after injection of CO2 with small amounts of added ioxaglate compared with injection of a larger amount of ioxaglate alone. The larger the amount of administered iodinated contrast medium, the greater the risk of development of renal failure.
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