Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

The Need for Precision Therapies as Determined by Genetic Signature for Cystic Fibrosis

Cystic fibrosis (CF) is a devastating genetic infant-onset disease [...

The pathogenicity of copy number variants in children with intellectual disability

Intellectual disability affects 1-3% of individuals globally, and, for half the cases, the cause is unknown. Recent studies using whole genome microarray genomic hybridization have shown that submicroscopic genomic imbalance causes intellectual disability in at least 10% of idiopathic cases with normal conventional cytogenetic analysis. I established genotype-phenotype correlations for de novo copy number variants detected by previous whole genome array genome hybridization studies performed by our group in children with intellectual disability. These genotype-phenotype correlations show that genomic imbalance of genes belonging to the epigenetic regulatory category, among others, are causative of intellectual disability. I hypothesized that dosage changes in the broad functional category of genes encoding epigenetic regulatory proteins are more likely to be pathogenic for intellectual disability than dosage changes in other kinds of genes. Epigenetic regulatory proteins include those with DNA methylation, histone modification or chromatin remodeling activity. I have selected all known genes encoding epigenetic regulatory proteins and defined probes to interrogate these candidate genes for copy number alteration as part of a custom targeted microarray design that selectively investigates all candidate genes associated with intellectual disability. We have conducted comparative genome hybridization on 177 patients with idiopathic intellectual disability using this array and on both normal parents of each affected child. We identified and independently validated 16 cases with de novo CNVs involving the epigenetic regulatory candidates. 7 of the 16 CNVs involve the same exon of the JARID2 gene, while the other 9 CNVs affect different genes. I discuss genotype-phenotype correlations for these cases and show that epigenetic perturbation by way of disruption of genes that encode epigenetic regulators is an important cause for intellectual disability.Medicine, Faculty ofMedical Genetics, Department ofGraduat

Chromodomain helicase DNA-binding proteins and neurodevelopmental disorders

The significance of epigenomic regulation is now established in the etiology of neurodevelopmental disorders (NDDs). Epigenomic regulatory processes include chromatin remodeling as a major regulator of gene expression in development. Chromatin remodeling is an enzymatic process carried out by large multi-unit protein complexes, of which the chromodomain helicase DNA-binding proteins comprise one of four recognized major protein families, named the chromodomain helicase DNA-binding (CHD) family. There are nine CHD proteins (CHD1-9) encoded by nine correspondingly named CHD genes. Remarkably, five of the nine CHDs are already recognized to be causative of autosomal dominant syndromic NDD. In this review, we discuss the contribution of all CHDs to NDDs. And, we specifically focus on molecular studies involving CHD8 of which several have been recently published and scarcely reviewed. The widespread nature of downstream targeting for CHD8, as well as the finding of autosomal dominant disease for the majority of CHDs in general, implicates this family of chromatin remodelers as major players in NDD causation

Recent Major Transcriptomics and Epitranscriptomics Contributions toward Personalized and Precision Medicine

With the advent of genome-wide screening methods—beginning with microarray technologies and moving onto next generation sequencing methods—the era of precision and personalized medicine was born. Genomics led the way, and its contributions are well recognized. However, “other-omics” fields have rapidly emerged and are becoming as important toward defining disease causes and exploring therapeutic benefits. In this review, we focus on the impacts of transcriptomics, and its extension—epitranscriptomics—on personalized and precision medicine efforts. There has been an explosion of transcriptomic studies particularly in the last decade, along with a growing number of recent epitranscriptomic studies in several disease areas. Here, we summarize and overview major efforts for cancer, cardiovascular disease, and neurodevelopmental disorders (including autism spectrum disorder and intellectual disability) for transcriptomics/epitranscriptomics in precision and personalized medicine. We show that leading advances are being made in both diagnostics, and in investigative and landscaping disease pathophysiological studies. As transcriptomics/epitranscriptomics screens become more widespread, it is certain that they will yield vital and transformative precision and personalized medicine contributions in ways that will significantly further genomics gains.Medicine, Faculty ofNon UBCMedical Genetics, Department ofReviewedFacultyResearche

De novo pathogenic DNM1L variant in a patient diagnosed with atypical hereditary sensory and autonomic neuropathy

Background: Profiling the entire genome at base pair resolution in a single test offers novel insights into disease by means of dissection of genetic contributors to phenotypic features. Methods: We performed genome sequencing for a patient who presented with atypical hereditary sensory and autonomic neuropathy, severe epileptic encephalopathy, global developmental delay, and growth hormone deficiency. Results: Assessment of the variants detected by mapped sequencing reads followed by Sanger confirmation revealed that the proband is a compound heterozygote for rare variants within RETREG1 (FAM134B), a gene associated with a recessive form of hereditary sensory and autonomic neuropathy, but not with epileptic encephalopathy or global developmental delay. Further analysis of the data also revealed a heterozygous missense variant in DNM1L, a gene previously implicated in an autosomal dominant encephalopathy, epilepsy, and global developmental delay and confirmed by Sanger sequencing to be a de novo variant not present in parental genomes. Conclusions: Our findings emphasize the importance of genome-wide sequencing in patients with a well-characterized genetic disease with atypical presentation. This approach reduces the potential for misdiagnoses

Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability

Background: Intellectual Disability (ID) is among the most common global disorders, yet etiology is unknown in ~30% of patients despite clinical assessment. Whole genome sequencing (WGS) is able to interrogate the entire genome, providing potential to diagnose idiopathic patients. Methods: We conducted WGS on eight children with idiopathic ID and brain structural defects, and their normal parents; carrying out an extensive data analyses, using standard and discovery approaches. Results: We verified de novo pathogenic single nucleotide variants (SNV) in ARID1B c.1595delG and PHF6 c.820C > T, potentially causative de novo two base indels in SQSTM1 c.115_116delinsTA and UPF1 c.1576_1577delinsA, and de novo SNVs in CACNB3 c.1289G > A, and SPRY4 c.508 T > A, of uncertain significance. We report results from a large secondary control study of 2081 exomes probing the pathogenicity of the above genes. We analyzed structural variation by four different algorithms including de novo genome assembly. We confirmed a likely contributory 165 kb de novo heterozygous 1q43 microdeletion missed by clinical microarray. The de novo assembly resulted in unmasking hidden genome instability that was missed by standard re-alignment based algorithms. We also interrogated regulatory sequence variation for known and hypothesized ID genes and present useful strategies for WGS data analyses for non-coding variation. Conclusion: This study provides an extensive analysis of WGS in the context of ID, providing genetic and structural insights into ID and yielding diagnoses.Medicine, Faculty ofOther UBCNon UBCMedical Genetics, Department ofPediatrics, Department ofReviewedFacult