Scleral buckling-a brief historical overview and current indications.

The key to successful management of rhegmatogenous retinal detachment (RRD) is to find and seal all of the retinal breaks, and the two main surgical techniques used to achieve this are scleral bucking (SB) or pars plana vitrectomy (PPV). Techniques for SB have remained mostly unchanged for the last 60 years, whilst PPV techniques and instruments have developed substantially over that time and have greatly contributed to increased success rate for types and configurations of retinal detachments unsuitable or difficult to manage with buckling alone. However, there is a growing dependency to rely on PPV as the sole and only approach for repair of all types of retinal detachment, such that some centres are no longer offering training in scleral buckling. There are also many studies comparing SB with PPV, but many of these lack information on the type, technique or rationale for deployment of the buckle. Many studies deploy the same scleral buckle technique without customising it to the type, position or number of tears being treated. Scleral buckling is not a one-size-fits-all technique. It requires careful patient selection and careful buckle selection and orientation tailored to the tear(s) to ensure success. When used appropriately, it is a simple and highly effective technique, particularly for retinal dialyses, round retinal hole detachments and selected cases of retinal detachment associated with horseshoe retinal tears. There is no doubt that for some more complex cases, such as multiple large breaks, giant retinal tears, bullous detachments and cases complicated by proliferative retinopathy, PPV offers a safer and more effective management. However, SB remains an important and relevant surgical technique, and for the right cases, the results can be superior to PPV with reduced comorbidity

Inherited and de novo biallelic pathogenic variants in COL11A1 result in type 2 Stickler syndrome with severe hearing loss.

BACKGROUND: Type 2 Stickler syndrome is usually a dominant disorder resulting from pathogenic variants in COL11A1 encoding the alpha 1 chain of type XI collagen. Typical molecular changes result in either substitution of an obligate glycine within the Gly-Xaa-Yaa amino acid sequence repeat region of the molecule, mRNA missplicing or deletions/duplications that typically leaves the message in-frame. Clinical features include myopia, retinal detachment, craniofacial, joint, and hearing problems. Fibrochondrogenesis is also a COL11A1 related disorder, but here disease-associated variants are recessive and may be either null alleles or substitutions of glycine, and the condition is usually lethal in infancy. METHODS: The patient was assessed in the NHS England Stickler syndrome diagnostic service. DNA from the patient and family were analyzed with Next Generation Sequencing on a panel of genes known to cause Stickler Syndrome. The effect of sequence variants was assessed using minigene analysis. Allele-specific RT-PCR was performed. RESULTS: This patient had clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. We identified a de novo in frame deletion of COL11A1 (c.4109_4126del) consistent with dominantly inherited Stickler syndrome but also a second inherited variant (c.1245+2T>C), on the other allele, affecting normal splicing of COL11A1 exon 9. CONCLUSION: Exon 9 of COL11A1 is alternatively expressed and disease causing changes affecting only this exon modify the phenotype resulting from biallelic COL11A1 disease-associated variants and, instead of fibrochondrogenesis, produce a form of Stickler syndrome with severe hearing loss. Disease phenotypes from de novo pathogenic variants can be modified by inherited recessive variants on the other allele. This highlights the need for functional and family analysis to confirm the mode of inheritance in COL11A1-related disorders, particularly for those variants that may alter normal pre-mRNA splicing

Bone morphogenetic protein 4 (BMP4) loss-of-function variant associated with autosomal dominant Stickler syndrome and renal dysplasia.

Stickler syndrome is a genetic disorder that can lead to joint problems, hearing difficulties and retinal detachment. Genes encoding collagen types II, IX and XI are usually responsible, but some families have no causal variant identified. We investigate a variant in the gene encoding growth factor BMP4 in a family with Stickler syndrome with associated renal dysplasia. Next generation sequencing of the coding region of COL2A1, COL11A1 and a panel of genes associated with congenital anomalies of the kidney and urinary tract (CAKUT) was performed. A novel heterozygous BMP4 variant causing a premature stop codon, c. 130G>T, p.(Gly44Ter), which segregated with clinical features of Stickler syndrome in multiple family members, was identified. No variant affecting gene function was detected in COL2A1 or COL11A1. Skin fibroblasts were cultured with and without emetine, and the mRNA extracted and analysed by Sanger sequencing to assess whether the change was causing nonsense-mediated decay. Nonsense-mediated decay was not observed from the extracted BMP4 mRNA. BMP4 is a growth factor known to contribute to eye development in animals, and gene variants in humans have been linked to microphthalmia/anophthalmia as well as CAKUT. The variant identified here further demonstrates the importance of BMP4 in eye development. This is the first report of a BMP4 DNA variant causing Stickler syndrome, and we suggest BMP4 be added to standard diagnostic gene panels for this condition

CoNIC Challenge: Pushing the Frontiers of Nuclear Detection, Segmentation, Classification and Counting

Nuclear detection, segmentation and morphometric profiling are essential in helping us further understand the relationship between histology and patient outcome. To drive innovation in this area, we setup a community-wide challenge using the largest available dataset of its kind to assess nuclear segmentation and cellular composition. Our challenge, named CoNIC, stimulated the development of reproducible algorithms for cellular recognition with real-time result inspection on public leaderboards. We conducted an extensive post-challenge analysis based on the top-performing models using 1,658 whole-slide images of colon tissue. With around 700 million detected nuclei per model, associated features were used for dysplasia grading and survival analysis, where we demonstrated that the challenge's improvement over the previous state-of-the-art led to significant boosts in downstream performance. Our findings also suggest that eosinophils and neutrophils play an important role in the tumour microevironment. We release challenge models and WSI-level results to foster the development of further methods for biomarker discovery

Sintering and mechanical properties of β‐SiC powder obtained from waste tires

Plasma synthesized SiC powder obtained from quartz and carbonaceous residue of waste tires was successfully sintered at 1925 ℃ by pressureless liquid-phase method using yttria and alumina as sintering aids (T-SiC). Comparison with sintered SiC obtained from commercial powder (C-SiC) put in evidence of similar sintered density (98%T.D.), but much finer microstructure of T-SiC than that of C-SiC. T-SiC also showed higher flexural strength than C-SiC both at room temperature (508 vs. 458 MPa) and at 1500 ℃ (280 vs. 171 MPa). Difference in liquid phase was responsible for the differences in hardness and fracture toughness. The high value of the Young's modulus of T-SiC (427 MPa) confirmed the high degree of sinterability of this powder and that it can be a promising candidate for structural applications with high added value. © 2016, The Author(s)

Prevention of Blindness in Stickler Syndrome.

Stickler syndromes are inherited conditions caused by abnormalities of structural proteins in the eye, inner ear and cartilage. The risk of retinal detachment, particularly due to the development of giant retinal tears, is high. Stickler syndrome is the most common cause of childhood retinal detachment. Although retinal detachment surgery in the general population has a high success rate, outcomes from surgical repair in Stickler syndrome patients are notoriously poor, providing a strong argument for prophylactic intervention. Variable case selection, absence of molecular genetic sub-typing and inconsistent treatment strategies have all contributed to the historic uncertainty regarding the safety and efficacy of prophylactic treatment. This paper reviews the major published clinical studies that have evaluated different methods and strategies for prophylaxis. Based on the current body of literature, there is extremely strong evidence from cohort comparison studies demonstrating the efficacy and safety of prophylactic retinopexy to reduce, but not eliminate, the risk of retinal detachment in Stickler syndrome patients. It is vital that this body of evidence is provided to Stickler syndrome patients, to enable them to make their own fully informed choice about whether to receive prophylaxis for themselves and particularly on behalf of their affected children, to reduce the risk of retinal detachment

Posterior vitreous detachment in absentia.

The relationship between the vitreous body, posterior vitreous detachment (PVD) and retina has been the focus of much research for over a hundred years [1-10 and references therein] and yet in spite of such prolonged investigation, there is still much that is not understood, particularly: a) The changes preceding and initiating uncomplicated (or “physiological”) separation of the posterior hyaloid membrane (PHM) from the retina and, b) The pathological variations of this process that influence so many of the vitreoretinal disorders dealt with today and thereby their management. Historically, much has been theorised on the combined biological changes of syneresis and synchisis leading in some ill-defined manner to weakening adhesion at the vitreoretinal interface, inducing the outer vitreous cortex to separate from the inner limiting membrane of the retina. In contrast, more recent research [11-14] has demonstrated that PVD is not simply an inevitable consequence of age related syneresis but more a distinct immunohistochemically confirmed separation of the posterior hyaloid membrane (PHM) from the retinal surface and that separation of this type IV collagen basement membrane can still occur in individuals in whom all cortical gel (syneretic or otherwise) has been previously removed during by vitrectomy surgery.University of Cambridge Retinal Research Fun