B9D1 is revealed as a novel Meckel syndrome (MKS) gene by targeted exon-enriched next-generation sequencing and deletion analysis.

Meckel syndrome (MKS) is an embryonic lethal, autosomal recessive disorder characterized by polycystic kidney disease, central nervous system defects, polydactyly and liver fibrosis. This disorder is thought to be associated with defects in primary cilia; therefore, it is classed as a ciliopathy. To date, six genes have been commonly associated with MKS (MKS1, TMEM67, TMEM216, CEP290, CC2D2A and RPGRIP1L). However, mutation screening of these genes revealed two mutated alleles in only just over half of our MKS cohort (46 families), suggesting an even greater level of genetic heterogeneity. To explore the full genetic complexity of MKS, we performed exon-enriched next-generation sequencing of 31 ciliopathy genes in 12 MKS pedigrees using RainDance microdroplet-PCR enrichment and IlluminaGAIIx next-generation sequencing. In family M456, we detected a splice-donor site change in a novel MKS gene, B9D1. The B9D1 protein is structurally similar to MKS1 and has been shown to be of importance for ciliogenesis in Caenorhabditis elegans. Reverse transcriptase-PCR analysis of fetal RNA revealed, hemizygously, a single smaller mRNA product with a frameshifting exclusion of B9D1 exon 4. ArrayCGH showed that the second mutation was a 1.713 Mb de novo deletion completely deleting the B9D1 allele. Immunofluorescence analysis highlighted a significantly lower level of ciliated patient cells compared to controls, confirming a role for B9D1 in ciliogenesis. The fetus inherited an additional likely pathogenic novel missense change to a second MKS gene, CEP290; p.R2210C, suggesting oligogenic inheritance in this disorder.

Patient acceptability of, and attitudes towards, hepatitis B cure research - A scoping review and identification of knowledge gaps.

Functional cure, defined as durable loss of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA suppression off therapy, is an increasingly important goal in the treatment of chronic hepatitis B. Although novel treatments aimed at achieving functional cure are being developed and tested in clinical trials, it is important to assess the perspectives of people living with HBV towards these potential treatments and their participation in HBV functional cure research. We have performed a scoping review that revealed that there is limited knowledge regarding patient perspectives of HBV functional cure research and then identified gaps in knowledge for further investigation. Our work highlights the need for further studies in patient perspectives in HBV functional cure research.

Outcomes of Retinectomy without Lensectomy in Rhegmatogenous Retinal Detachments with Proliferative Vitreoretinopathy.

PURPOSE: To report the anatomic and functional outcomes of retinectomy without lensectomy in eyes with rhegmatogenous retinal detachment (RRD) and proliferative vitreoretinopathy (PVR). DESIGN: Retrospective, noncomparative, and interventional case series. SUBJECTS: One hundred twelve eyes of 112 patients with RRD complicated by PVR who underwent retinectomy without lensectomy. METHODS: Retrospective review of patients treated with vitrectomy and retinectomy without lensectomy from January 1, 2015, to January 1, 2020. MAIN OUTCOME MEASURES: The primary outcome was the final attachment rate and single surgery anatomic success (SSAS) at 3 and 6 months after retinectomy. Secondary outcomes included predictors of final visual acuity (VA), the mean number of subsequent operations required for complete retinal reattachment, cataract surgery, and the number of eyes that ultimately had successful silicone oil removal. RESULTS: Complete final retinal reattachment was achieved in 111 of 112 (99.1%) patients, with a mean (standard deviation [SD]) follow-up of 29 (14) months (range, 8-62 months) after retinectomy. The SSAS was achieved in 84 of 112 (75%) patients at 3 months and 73 of 112 (65.2%) patients at 6 months. The final VA improved or stabilized in 76 of 112 (67.9%) eyes. Silicone oil removal was performed in 72 of 112 patients (64.3%) at a mean (SD) of 6.6 (3.3) months, and cataract surgery was performed on 101 (90.2%) eyes before the last follow-up visit. CONCLUSIONS: Retinectomy without lensectomy to repair RRDs complicated by PVR showed acceptable anatomic and functional results. This study suggests that removing the lens when there is no significant cataract may not be necessary in these cases to obtain reasonable outcomes.

Wide-Field (15â€Š× 9 mm) Swept-Source Optical Coherence Tomography Angiography Following Plaque Radiotherapy of Choroidal Melanoma: An Analysis of 105 eyes.

PURPOSE: The aim of this study was to evaluate retinal microvascular abnormalities following plaque radiotherapy of choroidal melanoma (CM) using wide-field swept-source optical coherence tomography angiography (OCTA). DESIGN: Single-centre retrospective review. METHODS: Retrospective case series of 105 CM patients treated with I-125 plaque radiotherapy and imaged with wide-field (15 × 9 mm) SS-OCTA from March 2018 to August 2018 at the Ocular Oncology Service, Wills Eye Hospital (Philadelphia, PA). RESULTS: At mean follow-up of 49 months (range 4-297) after plaque radiotherapy, there were 52 eyes (50%) with clinically evident radiation retinopathy (CERR) and 53 eyes (50%) without CERR. Comparison (CERR vs controls) revealed foveal avascular zone enlargement (1.7 vs 0.23 mm, P = 0.03) and reduction of capillary vascular density (CVD) in the superficial and deep plexus in the total wide-field (43% vs 47%, P < 0.001, and 46% vs 48%, P = 0.001, respectively), peripapillary region (66% vs 77%, P < 0.001, and 66% vs 72%, P = 0.001, respectively), and papillomacular bundle (60% vs 68%, P < 0.001, and 61% vs 64%, P = 0.03, respectively). Comparison (no CERR vs controls) revealed nonsignificant foveal avascular zone enlargement (1.20 vs 0.23 mm, P = 0.16) and reduction of CVD in the superficial plexus (46% vs 47%, P = 0.008), and not the deep plexus (48% vs 48%, P = 0.42) of the total wide-field. Comparison of irradiated eyes (CERR vs no CERR) showed reduction of CVD in the superficial and deep plexus of the total wide-field (43% vs 46%, P < 0.006, and 46% vs 48% P < 0.02, respectively), peripapillary region (66% vs 74%, P < 0.001, and 66% vs 72% P < 0.01, respectively), and superficial plexus in the papillomacular bundle (60% vs 65%, P = 0.03). CONCLUSIONS: Following plaque radiotherapy for choroidal melanoma, wide-field swept-source optical coherence tomography angiography demonstrates retinal microvascular abnormalities in the CVD in eyes with and without CERR. These findings are important in early detection and monitoring of radiation retinopathy.

Bivalved fiberglass cast compared with plaster splint immobilization for initial management of ankle fracture-dislocations: a treatment algorithm.

UNLABELLED: The initial management of ankle fracture-dislocations is the crucial step in the treatment of these emergent traumatic injuries. A stepwise approach is necessary to properly evaluate, diagnose, and treat ankle fracture-dislocations. The goal of initial management is to evaluate the vascular status of the extremity and then restore proper alignment of the talus underneath the tibia. A retrospective review was performed on 40 patients, who presented to a community-based hospital emergency room, treated by the foot and ankle service for ankle fracture-dislocation. An analysis of patient demographics, injury pattern/classification, number of reduction attempts, and immobilization method was performed and evaluated. This analysis was correlated with a review of the literature to develop an algorithm for the initial management of ankle fracture-dislocations recommending the use of a bivalved below-the-knee fiberglass cast for maintained stabilization post reduction. LEVEL OF EVIDENCE: Therapeutic Level IV.

Complex distribution patterns of voltage-gated calcium channel α-subunits in the spiral ganglion.

As with other elements of the peripheral auditory system, spiral ganglion neurons display specializations that vary as a function of location along the tonotopic axis. Previous work has shown that voltage-gated K(+) channels and synaptic proteins show graded changes in their density that confers rapid responsiveness to neurons in the high frequency, basal region of the cochlea and slower, more maintained responsiveness to neurons in the low frequency, apical region of the cochlea. In order to understand how voltage-gated calcium channels (VGCCs) may contribute to these diverse phenotypes, we identified the VGCC α-subunits expressed in the ganglion, investigated aspects of Ca(2+)-dependent neuronal firing patterns, and mapped the intracellular and intercellular distributions of seven VGCC α-subunits in the spiral ganglion in vitro. Initial experiments with qRT-PCR showed that eight of the ten known VGCC α-subunits were expressed in the ganglion and electrophysiological analysis revealed firing patterns that were consistent with the presence of both LVA and HVA Ca(2+) channels. Moreover, we were able to study seven of the α-subunits with immunocytochemistry, and we found that all were present in spiral ganglion neurons, three of which were neuron-specific (Ca(V)1.3, Ca(V)2.2, and Ca(V)3.3). Further characterization of neuron-specific α-subunits showed that Ca(V)1.3 and Ca(V)3.3 were tonotopically-distributed, whereas Ca(V)2.2 was uniformly distributed in apical and basal neurons. Multiple VGCC α-subunits were also immunolocalized to Schwann cells, having distinct intracellular localizations, and, significantly, appearing to distinguish putative compact (Ca(V)2.3, Ca(V)3.1) from loose (Ca(V)1.2) myelin. Electrophysiological evaluation of spiral ganglion neurons in the presence of TEA revealed Ca(2+) plateau potentials with slopes that varied proportionately with the cochlear region from which neurons were isolated. Because afterhyperpolarizations were minimal or absent under these conditions, we hypothesize that differential density and/or kinetics of one or more of the VGCC α-subunits could account for observed tonotopic differences. These experiments have set the stage for defining the clear multiplicity of functional control in neurons and Schwann cells of the spiral ganglion.