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| 2. |
- Gallagher, Michael D., et al.
(author)
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TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions
- 2014
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In: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 127:3, s. 407-418
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Journal article (peer-reviewed)abstract
- Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.
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| 3. |
- Kanoni, Stavroula, et al.
(author)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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In: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Journal article (peer-reviewed)abstract
- 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.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.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 4. |
- Mansoor, Rashid, et al.
(author)
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Haematological consequences of acute uncomplicated falciparum malaria : a WorldWide Antimalarial Resistance Network pooled analysis of individual patient data
- 2022
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In: BMC Medicine. - : Springer Nature. - 1741-7015. ; 20:1
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Journal article (peer-reviewed)abstract
- BackgroundPlasmodium falciparum malaria is associated with anaemia-related morbidity, attributable to host, parasite and drug factors. We quantified the haematological response following treatment of uncomplicated P. falciparum malaria to identify the factors associated with malarial anaemia.MethodsIndividual patient data from eligible antimalarial efficacy studies of uncomplicated P. falciparum malaria, available through the WorldWide Antimalarial Resistance Network data repository prior to August 2015, were pooled using standardised methodology. The haematological response over time was quantified using a multivariable linear mixed effects model with nonlinear terms for time, and the model was then used to estimate the mean haemoglobin at day of nadir and day 7. Multivariable logistic regression quantified risk factors for moderately severe anaemia (haemoglobin < 7 g/dL) at day 0, day 3 and day 7 as well as a fractional fall >= 25% at day 3 and day 7.ResultsA total of 70,226 patients, recruited into 200 studies between 1991 and 2013, were included in the analysis: 50,859 (72.4%) enrolled in Africa, 18,451 (26.3%) in Asia and 916 (1.3%) in South America. The median haemoglobin concentration at presentation was 9.9 g/dL (range 5.0-19.7 g/dL) in Africa, 11.6 g/dL (range 5.0-20.0 g/dL) in Asia and 12.3 g/dL (range 6.9-17.9 g/dL) in South America. Moderately severe anaemia (Hb < 7g/dl) was present in 8.4% (4284/50,859) of patients from Africa, 3.3% (606/18,451) from Asia and 0.1% (1/916) from South America. The nadir haemoglobin occurred on day 2 post treatment with a mean fall from baseline of 0.57 g/dL in Africa and 1.13 g/dL in Asia. Independent risk factors for moderately severe anaemia on day 7, in both Africa and Asia, included moderately severe anaemia at baseline (adjusted odds ratio (AOR) = 16.10 and AOR = 23.00, respectively), young age (age < 1 compared to >= 12 years AOR = 12.81 and AOR = 6.79, respectively), high parasitaemia (AOR = 1.78 and AOR = 1.58, respectively) and delayed parasite clearance (AOR = 2.44 and AOR = 2.59, respectively). In Asia, patients treated with an artemisinin-based regimen were at significantly greater risk of moderately severe anaemia on day 7 compared to those treated with a non-artemisinin-based regimen (AOR = 2.06 [95%CI 1.39-3.05], p < 0.001).ConclusionsIn patients with uncomplicated P. falciparum malaria, the nadir haemoglobin occurs 2 days after starting treatment. Although artemisinin-based treatments increase the rate of parasite clearance, in Asia they are associated with a greater risk of anaemia during recovery.
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| 5. |
- Van Deerlin, Vivian M, et al.
(author)
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Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:3, s. 234-239
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Journal article (peer-reviewed)abstract
- Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.
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| 6. |
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- 2019
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Journal article (peer-reviewed)
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| 7. |
- Adjuik, Martin A., et al.
(author)
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The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria : a meta-analysis of individual patient data
- 2015
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In: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 13
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Journal article (peer-reviewed)abstract
- Background: Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria. Methods: Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites. Results: Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites. Conclusions: There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.
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| 8. |
- Allan, Julie
(author)
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Emergent spaces : looking for the civic and the civil in initial professional education
- 2012. - 1
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In: The transformation of children’s services. - USA, Canada : Routledge. - 9780415618472 - 9780415618496 - 9780203818411 ; , s. 141-153
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Book chapter (other academic/artistic)abstract
- The role of the academic within universities has become increasingly constrained by the ‘audit culture’ (Strathern 1997: 305), what they write and for whom is more closely circumscribed than ever before, and the pressure to demonstrate ‘impact’, whatever that may be, limits their capacity to have any real influence on communities and on their values. Halsey (1992: 258) bemoans the ‘decline of the donnish dominion’, while Furedi (2004: vii) wonders ‘where have all the intellectuals gone?’ The undermining of academic culture and autonomy (Paterson 2003) and the regulatory practices within universities is ‘producing fear and little else’ (Evans 2004: 63) and is ‘killing thinking’ (ibid.) and, as Lyotard (1986) notes, in a world in which success is equated with saving time, thinking itself reveals its fundamental flaw to be its capacity to waste time. Edward Said (1994: 55) argues that a further danger for the intellectual comes from the limitations and constraints of professionalism which encourage conformity rather than critique:The particular threat to the intellectual today, whether in the West or the nonWestern world, is not the academy, nor the suburbs, not the appalling commercialism of journalism and publishing houses, but rather an attitude that I will call professionalism. By professionalism I mean thinking of your work as an intellectual as something you do for a living, between the hours of nine and five with one eye on the clock, and another cocked at what is considered to be proper, professional behaviour – not rocking the boat, not straying outside the accepted paradigms or limits, making yourself marketable and above all presentable, hence uncontroversial and unpolitical and ‘objective’.
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| 9. |
- Allan, Julie, et al.
(author)
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Etiska perspektiv på specialpedagogers yrkesroll och värdepedagogiska praktik
- 2022
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Book (other academic/artistic)abstract
- Yrkesetik handlar om att hantera motstridiga värden på ett professionellt sätt. Olika dilemman är ständigt närvarande i skolans vardag och kan handla om att minimera risken för att elever ska exkluderas eller om att säkerställa att elever får möjlighet att visa sina kunskaper på rätt sätt. I sin yrkesroll ställs specialpedagogen inför mångfacetterade arbetsuppgifter som omfattar att stödja barn och elever i svårigheter, vara en kvalificerad samtalspartner i pedagogiska frågor och samverka med andra yrkesgrupper för att utveckla skolans verksamhet. Arbetet innebär val mellan olika handlingsalternativ som kräver både kunskap och förmåga att urskilja och värdera etiska aspekter i komplexa sammanhang. I boken diskuteras både dilemman och möjligheter där etiska perspektiv spelar en viktig roll. Kapitlen tar upp frågor med praktiknära innehåll som lämpar sig för såväl individuell reflektion som kollegiala samtal med syftet att skapa ett gemensamt yrkesetiskt språk. Boken vänder sig till blivande och praktiserande specialpedagoger samt andra yrkeskategorier med arbetsuppgifter inom det specialpedagogiska området.
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| 10. |
- Allan, Julie, et al.
(author)
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Social capital and trust for inclusion in school and society
- 2018
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In: Education, Citizenship and Social Justice. - : SAGE Publications. - 1746-1979 .- 1746-1987.
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Journal article (peer-reviewed)abstract
- This article reports on the outcomes for students who experienced a strongly inclusive learning environment as a means for all to succeed. This Swedish lower secondary school dramatically improved its results, and the article reports the outcomes from the students’ perspectives. Social capital, with its emphasis on relationships, was used to structure interviews with students who had since moved on to high schools across Sweden and was also used to analyse the interview data. Two elements of social capital that appeared to be strongly associated with the students’ success – trust and confidence – are discussed in depth. The article concludes with a consideration of the significance of the role of schools in cultivating trust and the risks associated with schools ignoring this obligation.
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