Recurrent rare copy number variants increase risk for esotropia

Purpose: To determine whether rare copy number variants (CNVs) increase risk for comitant esotropia. Methods: CNVs were identified in 1614 Caucasian individuals with comitant esotropia and 3922 Caucasian controls from Illumina SNP genotyping using two Hidden Markov model (HMM) algorithms, PennCNV and QuantiSNP, which call CNVs based on logR ratio and B allele frequency. Deletions and duplications greater than 10 kb were included. Common CNVs were excluded. Association testing was performed with 1 million permutations in PLINK. Significant CNVs were confirmed with digital droplet polymerase chain reaction (ddPCR). Whole genome sequencing was performed to determine insertion location and breakpoints. Results: Esotropia patients have similar rates and proportions of CNVs compared with controls but greater total length and average size of both deletions and duplications. Three recurrent rare duplications significantly (P = 1 × 10-6) increase the risk of esotropia: chromosome 2p11.2 (hg19, 2:87428677-87965359), spanning one long noncoding RNA (lncRNA) and two microRNAs (OR 14.16; 95% confidence interval [CI] 5.4-38.1); chromosome 4p15.2 (hg19, 4:25554332-25577184), spanning one lncRNA (OR 11.1; 95% CI 4.6-25.2); chromosome 10q11.22 (hg19, 10:47049547-47703870) spanning seven protein-coding genes, one lncRNA, and four pseudogenes (OR 8.96; 95% CI 5.4-14.9). Overall, 114 cases (7%) and only 28 controls (0.7%) had one of the three rare duplications. No case nor control had more than one of these three duplications. Conclusions: Rare CNVs are a source of genetic variation that contribute to the genetic risk for comitant esotropia, which is likely polygenic. Future research into the functional consequences of these recurrent duplications may shed light on the pathophysiology of esotropia

Optic nerve head and retinal abnormalities associated with congenital fibrosis of the extraocular muscles

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduced in CFEOM patients compared to controls (p < 0.005). Situs inversus of retinal vessels was seen in five patients. Our study provides evidence of structural optic nerve and retinal changes in CFEOM. We show for the first time that there are widespread retinal changes beyond the retinal ganglion cells in patients with CFEOM. This study shows that the phenotype in CFEOM extends beyond the motor nerves

Familial hypercholesterolaemia: identification and management. Evidence reviews for case-finding, diagnosis and statin monotherapy

This guideline covers identifying and managing familial hypercholesterolaemia (FH), a specific type of high cholesterol that runs in the family, in children, young people and adults. It aims to help identify people at increased risk of coronary heart disease as a result of having FH. In November 2017, we reviewed the evidence for case finding and diagnosis, identification using cascade testing, and management using statins. We amended recommendations in sections 1.1, 1.2 and 1.3

Ophthalmology

To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH). Multicenter, observational study. A total of 907 patients with a confirmed molecular diagnosis of albinism, PAX6, SLC38A8, FRMD7, AHR, or achromatopsia from 12 centers in 9 countries (n = 523) or extracted from publicly available datasets from previously reported literature (n = 384). Individuals with a confirmed molecular diagnosis and availability of foveal OCT scans were identified from 12 centers or from the literature between January 2011 and March 2021. A genetic diagnosis was confirmed by sequence analysis. Grading of FH was derived from OCT scans. Grade of FH, presence or absence of photoreceptor specialization (PRS+ vs. PRS-), molecular diagnosis, and visual acuity (VA). The most common genetic etiology for typical FH in our cohort was albinism (67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%), and FRMD7 (3.5%) variants. AHR variants were rare (0.4%). Atypical FH was seen in 67.4% of achromatopsia cases. Atypical FH in achromatopsia had significantly worse VA than typical FH (P < 0.0001). There was a significant difference in the spectrum of FH grades based on the molecular diagnosis (chi-square = 60.4, P < 0.0001). All SLC38A8 cases were PRS- (P = 0.003), whereas all FRMD7 cases were PRS+ (P < 0.0001). Analysis of albinism subtypes revealed a significant difference in the grade of FH (chi-square = 31.4, P < 0.0001) and VA (P = 0.0003) between oculocutaneous albinism (OCA) compared with ocular albinism (OA) and Hermansky-Pudlak syndrome (HPS). Ocular albinism and HPS demonstrated higher grades of FH and worse VA than OCA. There was a significant difference (P < 0.0001) in VA between FRMD7 variants compared with other diagnoses associated with FH. We characterized the phenotypic and genotypic spectrum of FH. Atypical FH is associated with a worse prognosis than all other forms of FH. In typical FH, our data suggest that arrested retinal development occurs earlier in SLC38A8, OA, HPS, and AHR variants and later in FRMD7 variants. The defined time period of foveal developmental arrest for OCA and PAX6 variants seems to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and have significant prognostic and diagnostic value

Oil and Cocoa in the Political Economy of Ghana-EU Relations: Whither Sustainable Development?

Oil and cocoa represent strategic export commodities for the Ghanaian economy, prioritised within the Ghana Shared Growth and Development Agenda. This article examines these sectors in the context of Ghana’s relations with the European Union (EU). Notably, the EU constitutes the most important market for Ghanaian exports. The European Commission, moreover, has pledged to tangibly assist private sector development in Ghana, with particular reference to the UN Sustainable Development Goals (SDGs). Through its focus on oil and cocoa, the article problematises certain aspects of EU aid and trade interventions with respect to normative SDG development pledges

'New agriculture' for sustainable development? Biofuels and agrarian change in post-war Sierra Leone

ABSTRACTIn sub-Saharan Africa, commercial bioenergy production has been hailed as a new form of ‘green capitalism’ that will deliver ‘win-win’ outcomes and ‘pro poor’ development. Yet in an era of global economic recession and soaring food prices, biofuel ‘sustainability’ has been at the centre of controversy. This paper focuses on the case of post-war Sierra Leone, a country that has over the last decade been consistently ranked as one of the poorest in the world, facing food insecurity, high unemployment and entrenched poverty. Following a recent government strategy to secure foreign direct investment in biofuels production in agriculturally rich regions of the country, the largest foreign investment in Sierra Leone since the end of its civil war has been secured: a Swiss company is to invest US$368 million into a large-scale biofuels project over the course of 3 years, and promises to simultaneously stimulate an enabling environment for investment, provide job opportunities for youth and increase food production. For multiple actors involved in the project, the concept of ‘sustainability’ is crucial but accordingly there are varying interpretations of its meaning. Such differences in interpretation and the complex contradictions within discourses of sustainability are in turn framed by the various scales within which these actors are situated. While attempts have been made to manage these contradictions through global sustainability standards, the unequal power relations between different actors will ultimately determine the ways in which they are likely to be resolved. The paper concludes by reflecting on how these processes may be contributing to a changing governance landscape and wider global political economy within which bioenergy is being produced, processed and consumed.</jats:p

Gender Life Course Transitions from the Nuclear Family in England and Wales 1981-2001

In recent years there has been much political debate in the popular media about the fate of the nuclear family in the UK. Very little work has been done, using population data, to actually demonstrate the decline, or indeed continuance of this type of household formation. In this paper we use Office for National Statistics (ONS) longitudinal census data, from England and Wales, to explore the formation, dissolution and continuance of the nuclear family household over a twenty year period (1981- 2001). Our findings indicate a continuing importance of this household arrangement, however routes into and trajectories from nuclear family households take different forms for men and women across the life course

Mechanical and thermal characterisation of AlSi10Mg SLM block support structures

Selective Laser Melting (SLM) is an Additive Manufacturing (AM) process based on the local fusion of powdered metal. SLM requires support structures that enable heat transfer and structural support during fabrication while being frangible to enable removal. Despite the criticality of support structures, very little quantitative data exists to characterise their behaviour. AlSi10Mg is an important SLM alloy which is particularly appropriate for laser applications due to its ease of processing. Block support structures are the most versatile of the commercially implemented support structure designs. This research presents an experimental study of the mechanical strength and numerical analysis of the thermal behaviour during SLM fabrication of ALSi10Mg block support structures. It was found that: support structure peel strength is significantly lower than normal strength due to fundamentally different failure mechanisms; support strength is influenced by height; and, reduced support spacing increases heat transfer and load bearing capability. Design equations were generated to enable prediction of the strength of a given support structure. This previously unavailable data allows AM designers to unambiguously specify support structures that are optimal for a specific design scenario. Furthermore, these insights potentially allow the redesign of block support structures such that response is independent of geometry