Orbital Cellulitis Following Uncomplicated Glaucoma Drainage Device Surgery: Case Report and Review of Literature

Purpose: Orbital cellulitis (OC) is a rare postoperative complication of glaucoma drainage device (GDD) implantation. To date, there have only been 10 reported cases of OC following GDD implantation. Case Report: Here, we report a case of OC in a 57-year-old man who developed pain, proptosis, and limited extraocular motility two days after uneventful Ahmed FP7 implantation in the right eye. Contrast-enhanced computed tomography of the orbits demonstrated fat stranding and a small fluid collection, consistent with OC. He had minimal improvement with intravenous antibiotics and ultimately underwent GDD explantation. A systematic review of the literature showed that the development of OC following GDD implantation can occur in the early or late postoperative period. Immediate hospitalization with intravenous administration of broad-spectrum antibiotics is recommended. Explantation of the infected GDD is often required for source control. Conclusion: OC is a rare postoperative complication of GDD implantation. Prompt evaluation and treatment are required, often combined with GDD explantation

Brain Cell-Type Shifts in Alzheimer’s Disease, Autism, and Schizophrenia Interrogated Using Methylomics and Genetics

Few neuropsychiatric disorders have replicable biomarkers, prompting high-resolution and large-scale molecular studies. However, we still lack consensus on a more foundational question: whether quantitative shifts in cell types-the functional unit of life-contribute to neuropsychiatric disorders. Leveraging advances in human brain single-cell methylomics, we deconvolve seven major cell types using bulk DNA methylation profiling across 1270 postmortem brains, including from individuals diagnosed with Alzheimer\u27s disease, schizophrenia, and autism. We observe and replicate cell-type compositional shifts for Alzheimer\u27s disease (endothelial cell loss), autism (increased microglia), and schizophrenia (decreased oligodendrocytes), and find age- and sex-related changes. Multiple layers of evidence indicate that endothelial cell loss contributes to Alzheimer\u27s disease, with comparable effect size to APOE genotype among older people. Genome-wide association identified five genetic loci related to cell-type composition, involving plausible genes for the neurovascular unit (P2RX5 and TRPV3) and excitatory neurons (DPY30 and MEMO1). These results implicate specific cell-type shifts in the pathophysiology of neuropsychiatric disorders

A multimodal cell census and atlas of the mammalian primary motor cortex

ABSTRACT We report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex (MOp or M1) as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties, and cellular resolution input-output mapping, integrated through cross-modal computational analysis. Together, our results advance the collective knowledge and understanding of brain cell type organization: First, our study reveals a unified molecular genetic landscape of cortical cell types that congruently integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a unified taxonomy of transcriptomic types and their hierarchical organization that are conserved from mouse to marmoset and human. Third, cross-modal analysis provides compelling evidence for the epigenomic, transcriptomic, and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types and subtypes. Fourth, in situ single-cell transcriptomics provides a spatially-resolved cell type atlas of the motor cortex. Fifth, integrated transcriptomic, epigenomic and anatomical analyses reveal the correspondence between neural circuits and transcriptomic cell types. We further present an extensive genetic toolset for targeting and fate mapping glutamatergic projection neuron types toward linking their developmental trajectory to their circuit function. Together, our results establish a unified and mechanistic framework of neuronal cell type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Orbital Cellulitis Following Uncomplicated Glaucoma Drainage Device Surgery: Case Report and Review of Literature

Purpose: Orbital cellulitis (OC) is a rare postoperative complication of glaucoma drainage device (GDD) implantation. To date, there have only been 10 reported cases of OC following GDD implantation. Case Report: Here, we report a case of OC in a 57-year-old man who developed pain, proptosis, and limited extraocular motility two days after uneventful Ahmed FP7 implantation in the right eye. Contrast-enhanced computed tomography of the orbits demonstrated fat stranding and a small fluid collection, consistent with OC. He had minimal improvement with intravenous antibiotics and ultimately underwent GDD explantation. A systematic review of the literature showed that the development of OC following GDD implantation can occur in the early or late postoperative period. Immediate hospitalization with intravenous administration of broad-spectrum antibiotics is recommended. Explantation of the infected GDD is often required for source control. Conclusion: OC is a rare postoperative complication of GDD implantation. Prompt evaluation and treatment are required, often combined with GDD explantation

Visual field changes in professional wind versus non-wind musical instrument players in the Philadelphia orchestra

Purpose: We compare the prevalence of glaucoma in professional wind versus non-wind instrument players in the Philadelphia Orchestra. Visual field changes in individuals with glaucoma and glaucoma suspects were evaluated, and the results were correlated with cumulative practice time. Methods: In this cross-sectional, observational study, fifty-one Philadelphia Orchestra musicians were enrolled and categorized as wind or non-wind instrument players. All study participants underwent screening fundus photography. Participants with optic discs suspicious for glaucoma underwent further evaluation, including standard automated visual field perimetry and a comprehensive eye examination by a glaucoma specialist. Results: Of the 51 musicians enrolled, 9 of the 21 wind instrument players (43%) and 8 of the 30 non-wind instrument players (27%) were suspected of developing glaucoma in at least one eye (P = 0.25), with examinations performed on 12 of the 17 returning musicians (71%) for further confirmation. Wind instrument players exhibited significantly higher Octopus visual field mean defect scores (1.08 ± 1.5 dB) than non-wind instrument players (−0.43 ± 0.7 dB; P < 0.001). There was a significant association between cumulative hours playing wind instruments and visual field mean defect (P < 0.001). Conclusion: Among members of the Philadelphia Orchestra, the difference in prevalence of glaucoma suspicious optic discs between wind and non-wind instrument players was not significant. The clinical significance of the greater visual field mean defect found in wind instrument players, and the association between the degree of visual field mean defect and the cumulative practice-time of playing wind instruments, needs further investigation

Sex differences in oncogenic mutational processes

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.Peer reviewe