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Exertional heat illness (EHI) and malignant hyperthermia (MH) are life threatening conditions associated with muscle breakdown in the setting of triggering factors including volatile anesthetics, exercise, and high environmental temperature. To identify new genetic variants that predispose to EHI and/or MH, we performed genomic sequencing on a cohort with EHI/MH and/or abnormal caffeine-halothane contracture test. In five individuals, we identified rare, pathogenic heterozygous variants in ASPH , a gene encoding junctin, a regulator of excitation-contraction coupling. We validated the pathogenicity of these variants using orthogonal pre-clinical models, CRISPR-edited C2C12 myotubes and transgenic zebrafish. In total, we demonstrate that ASPH variants represent a new cause of EHI and MH susceptibility. The genetic cause(s) of malignant hyperthermia and exertional heat illness are unknown in approximately 30% of cases. To address this barrier, the authors performed genome sequencing on a large cohort of cases, identifying rare variants in ASPH , a gene encoding junctin, and validating them in animal and cell models.

Over the past decade, the development of ‘simple’ blood tests that enable cancer screening, diagnosis or monitoring and facilitate the design of personalized therapies without the need for invasive tumour biopsy sampling has been a core ambition in cancer research. Data emerging from ongoing biomarker development efforts indicate that multiple markers, used individually or as part of a multimodal panel, are required to enhance the sensitivity and specificity of assays for early stage cancer detection. The discovery of cancer-associated molecular alterations that are reflected in blood at multiple dimensions (genome, epigenome, transcriptome, proteome and metabolome) and integration of the resultant multi-omics data have the potential to uncover novel biomarkers as well as to further elucidate the underlying molecular pathways. Herein, we review key advances in multi-omics liquid biopsy approaches and introduce the ‘nano-omics’ paradigm: the development and utilization of nanotechnology tools for the enrichment and subsequent omics analysis of the blood-circulating cancerome.Liquid biopsy assays of diverse cancer-associated molecular alterations in blood, including genomic, epigenomic, transcriptomic, proteomic and metabolomics changes, offer considerable opportunities for early detection of cancer as well as improved management of the disease. In this Perspective, the authors review key advances in liquid biopsy-based multi-omics approaches for biomarker discovery. They also introduce the ‘nano-omics’ paradigm, whereby nanotechnology tools are used to capture and enrich various cancer-derived analytes from biofluids for subsequent omics analyses, with the aim of developing novel biomarker panels for early cancer detection.

BackgroundWe aimed to identify rare (minor allele frequency ≤1%), potentially pathogenic non-synonymous variants in a well-characterised cohort with a clinical history of exertional heat illness (EHI) or exertional rhabdomyolysis (ER). The genetic link between malignant hyperthermia (MH) and EHI was investigated due to their phenotypic overlap.MethodsThe coding regions of 38 genes relating to skeletal muscle calcium homeostasis or exercise intolerance were sequenced in 64 patients (mostly military personnel) with a history of EHI, or ER and who were phenotyped using skeletal muscle in vitro contracture tests. We assessed the pathogenicity of variants using prevalence data, in silico analysis, phenotype and segregation evidence and by review of the literature.ResultsWe found 51 non-polymorphic, potentially pathogenic variants in 20 genes in 38 patients. Our data indicate that RYR1 p.T3711M (previously shown to be likely pathogenic for MH susceptibility) and RYR1 p.I3253T are likely pathogenic for EHI. PYGM p.A193S was found in 3 patients with EHI, which is significantly greater than the control prevalence (p=0.000025). We report the second case of EHI in which a missense variant at CACNA1S p.R498 has been found. Combinations of rare variants in the same or different genes are implicated in EHI.ConclusionWe confirm a role of RYR1 in the heritability of EHI as well as ER but highlight the likely genetic heterogeneity of these complex conditions. We propose defects, or combinations of defects, in skeletal muscle calcium homeostasis, oxidative metabolism and membrane excitability are associated with EHI.

Exertional heat illness (EHI) is an occupational health hazard for athletes and military personnel–characterised by the inability to thermoregulate during exercise. The ability to thermoregulate can be studied using a standardised heat tolerance test (HTT) developed by The Institute of Naval Medicine. In this study, we investigated whole blood gene expression (at baseline, 2 h post-HTT and 24 h post-HTT) in male subjects with either a history of EHI or known susceptibility to malignant hyperthermia (MHS): a pharmacogenetic condition with similar clinical phenotype. Compared to healthy controls at baseline, 291 genes were differentially expressed in the EHI cohort, with functional enrichment in inflammatory response genes (up to a four-fold increase). In contrast, the MHS cohort featured 1019 differentially expressed genes with significant down-regulation of genes associated with oxidative phosphorylation (OXPHOS). A number of differentially expressed genes in the inflammation and OXPHOS pathways overlapped between the EHI and MHS subjects, indicating a common underlying pathophysiology. Transcriptome profiles between subjects who passed and failed the HTT (based on whether they achieved a plateau in core temperature or not, respectively) were not discernable at baseline, and HTT was shown to elevate inflammatory response gene expression across all clinical phenotypes.

Exertional heat illness (EHI) is a clinically important disorder, notifiable in military personnel, and is characterised by an inability to thermoregulate. Research investigating the genetic risk factors contributing to this potentially fatal condition is limited and the pathophysiology of EHI remains poorly understood. EHI shares a similar clinical manifestation to malignant hyperthermia (MH), a pharmacogenetic disorder associated with calcium dysregulation in skeletal muscle. Interestingly, 34% of the EHI patients in this study developed muscle contractures during an in vitro contracture test (IVCT), the gold-standard diagnostic test for MH susceptibility. The coding regions of fifty genes relating to calcium homeostasis and energy metabolism were sequenced in sixty-four EHI patients using a next-generation sequencing (NGS) approach. Many of these genes have been previously implicated in MH, congenital myopathies and metabolic disorders. Seventy-nine rare (minor allele frequency ≤1%) and potentially pathogenic (CADD-score ≥15) non-synonymous variants were identified across twenty-four genes, potentially conferring susceptibility to EHI. Around 75% of MH susceptible individuals in the UK carry a diagnostic ryanodine receptor type-1 (RYR1) variant. Uncharacterised RYR1 variants were identified in 38% of EHI patients in this study, 16% of which were annotated as rare and potentially pathogenic. Global gene expression profiles were examined in a heterozygous RyR1 R163C mutant mouse model associated with EHI and MH to investigate the acute heat stress response. These mice demonstrated elevated basal O2 consumption and increased expression of heat shock proteins (HSPs) after heat exposure. RNA-seq was also used to explore the exertional heat stress response in a cohort of EHI, MH and healthy control volunteers. Elevated HSPs were detected in the blood of MH individuals along with a basal reduction of key oxidative phosphorylation enzymes, both suggestive of oxidative stress. In contrast, increased expression of metabolic enzymes required for acetyl-coA synthesis were detected in both EHI and MH susceptible patients relative to controls. This thesis highlights the likely role of calcium dysregulation and energy metabolism in the pathophysiology of this complex disorder.

Favorable official regulations are not enough to guarantee equal opportunity. More positive approaches—such as the small group technique the authors developed for use at a large military installation—are necessary to combat the subtle and elusive guises racial discrimination has increasingly assumed.

It will be fascinating to see what a low-key, intelligent, and unglossy man like [Stephane Dion] can accomplish. [Don Martin] and the other folks who crave \"charisma\" can go to the movies for their hero fix.

After enjoying The Da Vinci Code, I went looking for Dan Brown's other books. The one I bought was Deception Point, in which he sends a crew of NASA scientists to a secret military facility on Milne Ice Shelf off Ellesmere Island.