Use of multiple methods for genotyping Fusarium during an outbreak of contact lens associated fungal keratitis in Singapore

<p>Abstract</p> <p>Background</p> <p>In Singapore, an outbreak of fungal keratitis caused by members of the <it>Fusarium solani </it>species complex (FSSC) was identified in March 2005 to May 2006 involving 66 patients. Epidemiological investigations have indicated that improper contact lens wear and the use of specific contact lens solutions were risk factors.</p> <p>Methods</p> <p>We assessed the genetic diversity of the isolates using AFLP, Rep-PCR, and ERIC-PCR and compared the usefulness of these typing schemes to characterize the isolates.</p> <p>Results</p> <p>AFLP was the most discriminative typing scheme and appears to group FSSC from eye infections and from other infections differently.</p> <p>Conclusion</p> <p>There was a high genomic heterogeneity among the isolates confirming that this was not a point source outbreak.</p

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Publisher Copyright: © 2022, The Author(s).Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Peer reviewe

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Funding GMP, PN, and CW are supported by NHLBI R01HL127564. GMP and PN are supported by R01HL142711. AG acknowledge support from the Wellcome Trust (201543/B/16/Z), European Union Seventh Framework Programme FP7/2007–2013 under grant agreement no. HEALTH-F2-2013–601456 (CVGenes@Target) & the TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation’s Grant number NNF15CC0018486. JMM is supported by American Diabetes Association Innovative and Clinical Translational Award 1–19-ICTS-068. SR was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant No 312062), the Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, and University of Helsinki HiLIFE Fellow and Grand Challenge grants. EW was supported by the Finnish innovation fund Sitra (EW) and Finska Läkaresällskapet. CNS was supported by American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016. Charles N Rotimi is supported by Z01HG200362. Zhe Wang, Michael H Preuss, and Ruth JF Loos are supported by R01HL142302. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215–2001) and the MRC Integrative Epidemiology Unit (MC_UU_00011), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). Ruth E Mitchell is a member of the MRC Integrative Epidemiology Unit at the University of Bristol funded by the MRC (MC_UU_00011/1). Simon Haworth is supported by the UK National Institute for Health Research Academic Clinical Fellowship. Paul S. de Vries was supported by American Heart Association grant number 18CDA34110116. Julia Ramierz acknowledges support by the People Programme of the European Union’s Seventh Framework Programme grant n° 608765 and Marie Sklodowska-Curie grant n° 786833. Maria Sabater-Lleal is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and co-financed by the European Social Fund. Jian Yang is funded by the Westlake Education Foundation. Olga Giannakopoulou has received funding from the British Heart Foundation (BHF) (FS/14/66/3129). CHARGE Consortium cohorts were supported by R01HL105756. Study-specific acknowledgements are available in the Additional file 32: Supplementary Note. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.Peer reviewedPublisher PD

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk

A Mortality Prediction Rule for Hematology Patients with Invasive Aspergillosis Based on Serum Galactomannan Kinetics

In invasive aspergillosis (IA), an early and adequate assessment of the response to the initial antifungal therapy remains problematic. We retrospectively analyzed 206 hematology patients with proven or probable IA, and collected serial serum galactomannan (sGM) values and survival status through week 6 and week 12. We created a model for survival at week 6 based on the sGM taken at baseline and on early sGM kinetics. This resulted in a rule predicting that patients with a baseline sGM index >1.4, who failed to lower that index to <0.5 after one week, had a mortality rate of 48.1% at week 6. Conversely, patients presenting with a baseline sGM index ≤1.4 that obtained a negative sGM (<0.5) after one week, had a mortality that was almost five times lower at only 10.1% by week 6. These findings were confirmed in an external cohort from an independent prospective study. In conclusion, sGM kinetics correlate well with treatment outcomes in hematology patients with IA. We present a rule which is easy to use at the bedside and has good accuracy in predicting week 6 survival.status: publishe

Thirteen AFLP groups comprising at least two isolates were formed at 90% similarity

Distribution of the isolates according to species complex, location, sample, AFLP group, Rep-PCR group, ERIC-PCR group (only groups with two or more isolates are given). MLST results are from reference 3. N/A = no data. CGH = Changi General Hospital, NHC = National Heart Centre, NUH = National University Hospital, SGH = Singapore General Hospital, SNEC = Singapore National Eye Centre, TTSH = Tan Tock Seng Hospital. Fallax refers to .<p><b>Copyright information:</b></p><p>Taken from "Use of multiple methods for genotyping during an outbreak of contact lens associated fungal keratitis in Singapore"</p><p>http://www.biomedcentral.com/1471-2334/8/92</p><p>BMC Infectious Diseases 2008;8():92-92.</p><p>Published online 15 Jul 2008</p><p>PMCID:PMC2483985.</p><p></p

Associations of autozygosity with a broad range of human phenotypes

Abstract: In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding

Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial

10.1016/s0140-6736(22)02324-8The Lancet4011037049-5

The power of genetic diversity in genome-wide association studies of lipids

Elevated blood lipid levels are heritable risk factors of cardiovascular disease with varying prevalence worldwide due to differing dietary patterns and medication use(1). Despite advances in prevention and treatment, particularly through the lowering of low-density lipoprotein cholesterol levels(2), heart disease remains the leading cause of death worldwide(3). Genome-wide association studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS(4–23) have been conducted in European ancestry populations and may have missed genetic variants contributing to lipid level variation in other ancestry groups due to differences in allele frequencies, effect sizes, and linkage-disequilibrium (LD) patterns(24). Here we conduct a multi-ancestry genome-wide genetic discovery meta-analysis of lipid levels in ~1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support expanding recruitment into new ancestries even with relatively smaller sample sizes. We find that increasing diversity rather than studying additional European ancestry individuals results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in N~295,000 from 6 ancestries), with modest gains in the number of discovered loci and ancestry-specific variants. As GWAS expands its emphasis beyond identifying genes and fundamental biology towards using genetic variants for preventive and precision medicine(25), we anticipate that increased participant diversity will lead to more accurate and equitable(26) application of polygenic scores in clinical practice