IMPORTANCE: Myopia is a leading cause of untreatable visual impairment and is increasing in prevalence worldwide. Interventions for slowing childhood myopia progression have shown success in ...randomized clinical trials; hence, there is a need to identify which children would benefit most from treatment intervention. OBJECTIVES: To examine whether genetic information alone can identify children at risk of myopia development and whether including a child’s genetic predisposition to educational attainment is associated with improved genetic prediction of the risk of myopia. DESIGN, SETTING, AND PARTICIPANTS: Meta-analysis of 3 genome-wide association studies (GWAS) including a total of 711 984 individuals. These were a published GWAS for educational attainment and 2 GWAS for refractive error in the UK Biobank, which is a multisite cohort study that recruited participants between January 2006 and October 2010. A polygenic risk score was applied in a population-based validation sample examined between September 1998 and September 2000 (Avon Longitudinal Study of Parents and Children ALSPAC mothers). Data analysis was performed from February 2018 to May 2019. MAIN OUTCOMES AND MEASURES: The primary outcome was the area under the receiver operating characteristic curve (AUROC) in analyses for predicting myopia, using noncycloplegic autorefraction measurements for myopia severity levels of less than or equal to −0.75 diopter (D) (any), less than or equal to -3.00 D (moderate), or less than or equal to −5.00 D (high). The predictor variable was a polygenic risk score (PRS) derived from genome-wide association study data for refractive error (n = 95 619), age of onset of spectacle wear (n = 287 448), and educational attainment (n = 328 917). RESULTS: A total of 383 067 adults aged 40 to 69 years from the UK Biobank were included in the new GWAS analyses. The PRS was evaluated in 1516 adults aged 24 to 51 years from the ALSPAC mothers cohort. The PRS had an AUROC of 0.67 (95% CI, 0.65-0.70) for myopia, 0.75 (95% CI, 0.70-0.79) for moderate myopia, and 0.73 (95% CI, 0.66-0.80) for high myopia. Inclusion in the PRS of information associated with genetic predisposition to educational attainment marginally improved the AUROC for myopia (AUROC, 0.674 vs 0.668; P = .02), but not those for moderate and high myopia. Individuals with a PRS in the top 10% were at 6.1-fold higher risk (95% CI, 3.4–10.9) of high myopia. CONCLUSIONS AND RELEVANCE: A personalized medicine approach may be feasible for detecting very young children at risk of myopia. However, accuracy must improve further to merit uptake in clinical practice; currently, cycloplegic autorefraction remains a better indicator of myopia risk (AUROC, 0.87).
The soil management assessment framework (SMAF) has been widely used as a tool to quantify soil health. However, SMAF was developed using data from only a few climate conditions in the United States ...and regional verification is often suggested. We evaluated SMAF's short-term performance in a thermic/hyperthermic region, aiming to 1) evaluate the sensitivity of SMAF scores to changes in individual soil properties and 2) quantify soil health changes using SMAF. Treatments include two levels of summer crop and two levels of tillage in an annually planted wheat system. SMAF soil health metrics were measured for Burleson clay soil (BC site) and Parrita sandy clay loam soil (PSCL site) for 0–5 cm soil depth. At the BC site, βgluc and SOC SMAF scores displayed no statistical differences when compared to their respective soil properties. βgluc measurement also helped to highlight the treatment difference observed for wheat yield. This suggests that scoring curves of βgluc used in SMAF may need to be modified, especially for clayey soils. The results also show that SMAF scores were not correlated with wheat yield at both sites, suggesting that multiple year data may be needed to understand this relationship. Overall, in a thermic region, SMAF was found to be helpful to understand short-term soil health status. However, due to clay correction in SMAF algorithm, SMAF scores can show lower sensitivity in the clayey soils of these thermic regions.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The aim of this study was to define the frequency and associated clinical phenotype of anti-MDA5 autoantibodies in a large UK based, predominantly Caucasian, cohort of patients with juvenile ...dermatomyositis (JDM).
Serum samples and clinical data were obtained from 285 patients with JDM recruited to the UK Juvenile Dermatomyositis Cohort and Biomarker Study. The presence of anti-MDA5 antibodies was determined by immunoprecipitation and confirmed by ELISA using recombinant MDA5 protein. Results were compared with matched clinical data, muscle biopsies (scored by an experienced paediatric neuropathologist) and chest imaging (reviewed by an experienced paediatric radiologist).
Anti-MDA5 antibodies were identified in 7.4% of JDM patients and were associated with a distinct clinical phenotype including skin ulceration (P = 0.03) oral ulceration (P = 0.01), arthritis (P <0.01) and milder muscle disease both clinically (as determined by Childhood Myositis Assessment Score (P = 0.03)) and histologically (as determined by a lower JDM muscle biopsy score (P <0.01)) than patients who did not have anti-MDA5 antibodies. A greater proportion of children with anti-MDA5 autoantibodies achieved disease inactivity at two years post-diagnosis according to PRINTO criteria (P = 0.02). A total of 4 out of 21 children with anti-MDA5 had interstitial lung disease; none had rapidly progressive interstitial lung disease.
Anti-MDA5 antibodies can be identified in a small but significant proportion of patients with JDM and identify a distinctive clinical sub-group. Screening for anti-MDA5 autoantibodies at diagnosis would be useful to guide further investigation for lung disease, inform on prognosis and potentially confirm the diagnosis, as subtle biopsy changes could otherwise be missed.
Adoption of new technology in both basic research and clinical settings requires rigorous validation of analytical performance. The OncoScan® FFPE Assay is a multiplexing tool that offers genome-wide ...copy number and loss of heterozygosity detection, as well as identification of frequently tested somatic mutations.
In this study, 162 formalin fixed paraffin embedded samples, representing six different tumour types, were profiled in triplicate across three independent laboratories. OncoScan® formalin fixed paraffin embedded assay data was then analysed for reproducibility of genome-wide copy number, loss of heterozygosity and somatic mutations. Where available, somatic mutation data was compared to data from orthogonal technologies (pyro/sanger sequencing).
Cross site comparisons of genome-wide copy number and loss of heterozygosity profiles showed greater than 95% average agreement between sites. Somatic mutations pre-validated by orthogonal technologies showed greater than 90% agreement with OncoScan® somatic mutation calls and somatic mutation concordance between sites averaged 97%.
Reproducibility of whole-genome copy number, loss of heterozygosity and somatic mutation data using the OncoScan® assay has been demonstrated with comparatively low DNA inputs from a range of highly degraded formalin fixed paraffin embedded samples. In addition, our data shows examples of clinically-relevant aberrations that demonstrate the potential utility of the OncoScan® assay as a robust clinical tool for guiding tumour therapy.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•Mutations in untranslated regions can affect gene expression.•Mutations in KIT are associated with increased degimentation in many mammals.•A mutation in KIT's 5′ untranslated region is associated ...with depigmentation in horses.
Mutations in KIT, a gene that influences melanoblast migration and pigmentation, often result in mammalian white spotting. As of February 2023, over 30 KIT variants associated with white spotting were documented in Equus caballus (horse). Here we report an association of increased white spotting on the skin and coat with a variant in the 5′UTR of KIT (rs1149701677: g.79,618,649A>C). Horses possessing at least one alternate allele demonstrate phenotypic characteristics similar to other KIT mutations: clear borders around unpigmented regions on the body, face, and limbs. Using a quantitative measure of depigmentation, we observed an average white score of 10.70 among individuals with rs1149701677, while the average score of the control, homozygous reference sample was 2.23 (P = 1.892e-11, n = 109, t-test). The rs1149701677 site has a cross-species conservation score of 3.4, one of the highest scores across the KIT 5′UTR, implying regulatory importance for this site. Ensembl also predicted a “moderately impactful” functional effect for the rs1149701677 variant. We propose that this single nucleotide variant likely alters the regulation of KIT, which in turn may disrupt melanoblast migration causing an increase in white spotting on the coat. Alternatively, the rs1149701677 variant may be in linkage with another nearby variant with an as-yet-undiscovered functional impact. We propose to term this new allele “Holiday White” or W35 based on conventional nomenclature.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mutations in KIT, a gene that influences melanoblast migration and pigmentation, often result in mammalian white spotting. As of February 2023, over 30 KIT variants associated with white spotting ...were documented in Equus caballus (horse). Here we report an association of increased white spotting on the skin and coat with a variant in the 5'UTR of KIT (rs1149701677: g.79,618,649A>C). Horses possessing at least one alternate allele demonstrate phenotypic characteristics similar to other KIT mutations: clear borders around unpigmented regions on the body, face, and limbs. Using a quantitative measure of depigmentation, we observed an average white score of 10.70 among individuals with rs1149701677, while the average score of the control, homozygous reference sample was 2.23 (P = 1.892e-11, n = 109, t-test). The rs1149701677 site has a cross-species conservation score of 3.4, one of the highest scores across the KIT 5'UTR, implying regulatory importance for this site. Ensembl also predicted a "moderately impactful" functional effect for the rs1149701677 variant. We propose that this single nucleotide variant likely alters the regulation of KIT, which in turn may disrupt melanoblast migration causing an increase in white spotting on the coat. Alternatively, the rs1149701677 variant may be in linkage with another nearby variant with an as-yet-undiscovered functional impact. We propose to term this new allele "Holiday White" or W35 based on conventional nomenclature.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
IMPORTANCE: Uncertainty currently exists about whether the same genetic variants are associated with susceptibility to low myopia (LM) and high myopia (HM) and to myopia and hyperopia. Addressing ...this question is fundamental to understanding the genetics of refractive error and has clinical relevance for genotype-based prediction of children at risk for HM and for identification of new therapeutic targets. OBJECTIVE: To assess whether a common set of genetic variants are associated with susceptibility to HM, LM, and hyperopia. DESIGN, SETTING, AND PARTICIPANTS: This genetic association study assessed unrelated UK Biobank participants 40 to 69 years of age of European and Asian ancestry. Participants 40 to 69 years of age living in the United Kingdom were recruited from January 1, 2006, to October 31, 2010. Of the total sample of 502 682 participants, 117 279 (23.3%) underwent an ophthalmic assessment. Data analysis was performed from December 12, 2019, to June 23, 2020. EXPOSURES: Four refractive error groups were defined: HM, −6.00 diopters (D) or less; LM, −3.00 to −1.00 D; hyperopia, +2.00 D or greater; and emmetropia, 0.00 to +1.00 D. Four genome-wide association study (GWAS) analyses were performed in participants of European ancestry: (1) HM vs emmetropia, (2) LM vs emmetropia, (3) hyperopia vs emmetropia, and (4) LM vs hyperopia. Polygenic risk scores were generated from GWAS summary statistics, yielding 4 sets of polygenic risk scores. Performance was assessed in independent replication samples of European and Asian ancestry. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) of polygenic risk scores in replication samples. RESULTS: A total of 51 841 unrelated individuals of European ancestry and 2165 unrelated individuals of Asian ancestry were assigned to a specific refractive error group and included in our analyses. Polygenic risk scores derived from all 4 GWAS analyses were predictive of all categories of refractive error in both European and Asian replication samples. For example, the polygenic risk score derived from the HM vs emmetropia GWAS was predictive in the European sample of HM vs emmetropia (OR, 1.58; 95% CI, 1.41-1.77; P = 1.54 × 10−15) as well as LM vs emmetropia (OR, 1.15; 95% CI, 1.07-1.23; P = 8.14 × 10−5), hyperopia vs emmetropia (OR, 0.83; 95% CI, 0.77-0.89; P = 4.18 × 10−7), and LM vs hyperopia (OR, 1.45; 95% CI, 1.33-1.59; P = 1.43 × 10−16). CONCLUSIONS AND RELEVANCE: Genetic risk variants were shared across HM, LM, and hyperopia and across European and Asian samples. Individuals with HM inherited a higher number of variants from among the same set of myopia-predisposing alleles and not different risk alleles compared with individuals with LM. These findings suggest that treatment interventions targeting common genetic risk variants associated with refractive error could be effective against both LM and HM.
•Splash White 9 and Splash White 10 found in Pura Raza Espanola horses.•Novel Mutations in PAX3 and MITF associated with depigmentation in horses.•Coat color mutations can influence equine health and ...sentimental value.
Mutations causing depigmentation are relatively common in Equus caballus (horse). Over 40 alleles in multiple genes are associated with increased white spotting (as of February 2023). The splashed white phenotype, a coat spotting pattern described as appearing like the horse has been splashed with white paint, was previously associated with variants in the PAX3 and MITF genes. Both genes encode transcription factors known to control melanocyte migration and pigmentation. We report two novel mutations, a stop-gain mutation in PAX3 (XM_005610643.3:c.927C>T, ECA6:11,196,181, EquCab3.0) and a missense mutation in a binding domain of MITF (NM_001163874.1:c.993A>T, ECA16:21,559,940, EquCab3.0), each with a strong association with increased depigmentation in Pura Raza Española horses (P = 1.144E-11, N = 30, P = 4.441E-16, N = 39 respectively). Using a quantitative method to score depigmentation, the PAX3 and MITF mutations were found to have average white scores of 25.50 and 24.45, respectively, compared to the average white coat spotting score of 1.89 in the control set. The functional impact for each mutation was predicted to be moderate to extreme (I-TASSER, SMART, Variant Effect Predictor, SIFT). We propose to designate the MITF mutant allele as Splashed White 9 and the PAX3 mutant allele as Splashed White 10 per convention.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
People with multiple sclerosis have problems with memory and attention. The effectiveness of cognitive rehabilitation has not been established.
The objectives were to assess the clinical ...effectiveness and cost-effectiveness of a cognitive rehabilitation programme for people with multiple sclerosis.
This was a multicentre, randomised controlled trial in which participants were randomised in a ratio of 6 : 5 to receive cognitive rehabilitation plus usual care or usual care alone. Participants were assessed at 6 and 12 months after randomisation.
The trial was set in hospital neurology clinics and community services.
Participants were people with multiple sclerosis who had cognitive problems, were aged 18-69 years, could travel to attend group sessions and gave informed consent.
The intervention was a group cognitive rehabilitation programme delivered weekly by an assistant psychologist to between four and six participants for 10 weeks.
The primary outcome was the Multiple Sclerosis Impact Scale - Psychological subscale at 12 months. Secondary outcomes included results from the Everyday Memory Questionnaire, the 30-Item General Health Questionnaire, the EuroQol-5 Dimensions, five-level version and a service use questionnaire from participants, and the Everyday Memory Questionnaire - relative version and the Modified Carer Strain Index from a relative or friend of the participant.
Of the 449 participants randomised, 245 were allocated to cognitive rehabilitation (intervention group) and 204 were allocated to usual care (control group). Of these, 214 in the intervention group and 173 in the control group were included in the primary analysis. There was no clinically important difference in the Multiple Sclerosis Impact Scale - Psychological subscale score between the two groups at the 12-month follow-up (adjusted difference in means -0.6, 95% confidence interval -1.5 to 0.3;
= 0.20). There were no important differences between the groups in relation to cognitive abilities, fatigue, employment, or carer strain at follow-up. However, there were differences, although small, between the groups in the Multiple Sclerosis Impact Scale - Psychological subscale score at 6 months (adjusted difference in means -0.9, 95% confidence interval -1.7 to -0.1;
= 0.03) and in everyday memory on the Everyday Memory Questionnaire as reported by participants at 6 (adjusted difference in means -5.3, 95% confidence interval -8.7 to -1.9) and 12 months (adjusted difference in means -4.4, 95% confidence interval -7.8 to -0.9) and by relatives at 6 (adjusted difference in means -5.4, 95% confidence interval -9.1 to -1.7) and 12 months (adjusted difference in means -5.5, 95% confidence interval -9.6 to -1.5) in favour of the cognitive rehabilitation group. There were also differences in mood on the 30-Item General Health Questionnaire at 6 (adjusted difference in means -3.4, 95% confidence interval -5.9 to -0.8) and 12 months (adjusted difference in means -3.4, 95% confidence interval -6.2 to -0.6) in favour of the cognitive rehabilitation group. A qualitative analysis indicated perceived benefits of the intervention. There was no evidence of a difference in costs (adjusted difference in means -£574.93, 95% confidence interval -£1878.93 to £729.07) or quality-adjusted life-year gain (adjusted difference in means 0.00, 95% confidence interval -0.02 to 0.02). No safety concerns were raised and no deaths were reported.
The trial included a sample of participants who had relatively severe cognitive problems in daily life. The trial was not powered to perform subgroup analyses. Participants could not be blinded to treatment allocation.
This cognitive rehabilitation programme had no long-term benefits on quality of life for people with multiple sclerosis.
Future research should evaluate the selection of those who may benefit from cognitive rehabilitation.
Current Controlled Trials ISRCTN09697576.
This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in
; Vol. 24, No. 4. See the National Institute for Health Research Journals Library website for further project information.
PDF
