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09.36 A tumultuous case of episodic apnoea
Glycine-receptor(GlyR) antibodies are well defined in progressive encephalomyelitis with rigidity and myoclonus (PERM), and are associated with a limited spectrum of immunotherapy-responsive syndromes. Whilst paradigms of autoantibody pathogenicity have been proposed, the trigger and propagation of GlyR antibodies remains unclear. We herein describe and define clinical and immunobiological observations of a GlyR antibody positive patient with PERM with the rare association of an ovarian teratoma.A 36-year-old woman presented with subacute axial and limb rigidity, stimulus-sensitive myoclonus, startle, ataxia, anxiety and episodic apnoea. GlyR antibodies were present in serum and CSF. CT revealed a 53 mm left ovarian teratoma. Despite improvement following immunotherapy, she relapsed with respiratory arrest, therefore removal of the left ovarian teratoma was performed.The fresh teratoma tissue was cultured in B-cell stimulating and plasma cell maintaining conditions, based on similar work with ovarian teratomas from patients with NMDAR-antibody encephalitis (Makuch et al., Annals of Neurology 2018).This teratoma secreted GlyR antibodies into culture supernatants consistent with intra-tumoral synthesis of glycine-receptor antibodies. Whilst marked post-surgical improvement was observed, relapses persisted in correspondence with persistent glycine-receptor antibodies.Our case highlights key areas for clinical consideration; GlyR antibody-mediated disease can be paraneoplastic in nature; ovarian teratomas can produce pathogenic autoantibodies; late tumour removal or immunotherapy worsens prognosis.
Premorbid brain structure influences risk of amyotrophic lateral sclerosis.
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease of the motor network associated with brain structure and functional connectivity alterations that are implicated in disease progression. Whether such changes have a causal role in ALS, fitting with a postulated influence of premorbid cerebral architecture on the phenotypes associated with neurodegenerative disorders is not known. METHODS: This study considered causal effects and shared genetic risk of 2240 structural and functional MRI brain scan imaging-derived phenotypes (IDPs) on ALS using two sample Mendelian randomisation, with putative associations further examined with extensive sensitivity analysis. Shared genetic predisposition between IDPs and ALS was explored using genetic correlation analysis. RESULTS: Increased white matter volume in the cerebral hemispheres was causally associated with ALS. Weaker causal associations were observed for brain stem grey matter volume, parieto-occipital white matter surface and volume of the left thalamic ventral anterior nucleus. Genetic correlation was observed between ALS and intracellular volume fraction and isotropic free water volume fraction within the posterior limb of the internal capsule. CONCLUSIONS: This study provides evidence that premorbid brain structure, in particular white matter volume, contributes to the risk of ALS.
Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations.
Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that is most prevalent in Northern Europe. Although it is known that inherited risk for MS is located within or in close proximity to immune-related genes, it is unknown when, where and how this genetic risk originated1. Here, by using a large ancient genome dataset from the Mesolithic period to the Bronze Age2, along with new Medieval and post-Medieval genomes, we show that the genetic risk for MS rose among pastoralists from the Pontic steppe and was brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the steppe population and later in Europe, probably driven by pathogenic challenges coinciding with changes in diet, lifestyle and population density. This study highlights the critical importance of the Neolithic period and Bronze Age as determinants of modern immune responses and their subsequent effect on the risk of developing MS in a changing environment.
Altered Impulsivity Across Drug-Naïve Parkinsonism, Isolated Rapid Eye Movement Sleep Behavior Disorder, and Their High-Risk Relatives.
OBJECTIVE: To determine multidimensional impulsivity levels across different early stages of α-synucleinopathy. METHODS: This cross-sectional study investigated motor and decisional impulsivity levels using a panel of computerized tasks among drug-naïve parkinsonism patients, isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) patients and their first-degree relatives (iRBD-FDRs), and control participants. Trait impulsivity and impulse control behaviors were assessed by self-reported questionnaires. RESULTS: A total of 27 drug-naïve parkinsonism patients, 157 iRBD patients, 66 iRBD-FDRs, and 82 control participants were recruited. Parkinsonism and iRBD patients had fewer numbers of extracted beads in beads task 1 and 2 (both p
The selection landscape and genetic legacy of ancient Eurasians.
The Holocene (beginning around 12,000 years ago) encompassed some of the most significant changes in human evolution, with far-reaching consequences for the dietary, physical and mental health of present-day populations. Using a dataset of more than 1,600 imputed ancient genomes1, we modelled the selection landscape during the transition from hunting and gathering, to farming and pastoralism across West Eurasia. We identify key selection signals related to metabolism, including that selection at the FADS cluster began earlier than previously reported and that selection near the LCT locus predates the emergence of the lactase persistence allele by thousands of years. We also find strong selection in the HLA region, possibly due to increased exposure to pathogens during the Bronze Age. Using ancient individuals to infer local ancestry tracts in over 400,000 samples from the UK Biobank, we identify widespread differences in the distribution of Mesolithic, Neolithic and Bronze Age ancestries across Eurasia. By calculating ancestry-specific polygenic risk scores, we show that height differences between Northern and Southern Europe are associated with differential Steppe ancestry, rather than selection, and that risk alleles for mood-related phenotypes are enriched for Neolithic farmer ancestry, whereas risk alleles for diabetes and Alzheimer's disease are enriched for Western hunter-gatherer ancestry. Our results indicate that ancient selection and migration were large contributors to the distribution of phenotypic diversity in present-day Europeans.
Iron and erythropoietin to heal and recover after intensive care (ITHRIVE): A pilot randomised clinical trial
Objective: To determine the feasibility of a pivotal randomised clinical trial of intravenous (IV) iron and erythropoietin in adult survivors of critical illness with anaemia requiring treatment in the intensive care unit. Design: An investigator-initiated, parallel group, placebo-controlled, randomised feasibility trial. Setting: A tertiary intensive care unit (ICU) in Perth, Western Australia. Participants: Adults with anaemia (haemoglobin <100 g/L), requiring ICU-level care for more than 48 h, and likely to be ready for ICU discharge within 24 h. Interventions: A single dose of IV ferric carboxymaltose and Epoetin alfa (active group) or an equal volume of 0.9% saline (placebo group). Main outcome measures: Study feasibility was considered met if the pilot achieved a recruitment rate of ≥2 participants per site per month, ≥90% of participants received their allocated study treatment, and≥ 90% of participants were followed up for the proposed pivotal trial primary outcome - days alive and at home to day 90 (DAH90). Results: The 40-participant planned sample size included twenty in each group and was enrolled between 1/9/2021 and 2/3/2022. Participants spent a median of 3.4 days (interquartile range 2.8–5.1) in the ICU prior to enrolment and had a mean baseline haemoglobin of 83.7 g/L (standard deviation 6.7). The recruitment rate was 6.7 participants per month [95% confidence interval (CI) 4.8–9.0], DAH90 follow-up was 100% (95% CI 91.2%–100%), and 39 (97.5%, 95% CI 86.8%–99.9%) participants received the allocated study intervention. No serious adverse events were reported. Conclusion: The iron and erythropoietin to heal and recover after intensive care (ITHRIVE) pilot demonstrated feasibility based on predefined participant recruitment, study drug administration, and follow-up thresholds.
Variability between human experts and artificial intelligence in identification of anatomical structures by ultrasound in regional anaesthesia: a framework for evaluation of assistive artificial intelligence
Background: ScanNavTM Anatomy Peripheral Nerve Block (ScanNav™) is an artificial intelligence (AI)-based device that produces a colour overlay on real-time B-mode ultrasound to highlight key anatomical structures for regional anaesthesia. This study compares consistency of identification of sono-anatomical structures between expert ultrasonographers and ScanNav™. Methods: Nineteen experts in ultrasound-guided regional anaesthesia (UGRA) annotated 100 structures in 30 ultrasound videos across six anatomical regions. These annotations were compared with each other to produce a quantitative assessment of the level of agreement amongst human experts. The AI colour overlay was then compared with all expert annotations. Differences in human–human and human–AI agreement are presented for each structure class (artery, muscle, nerve, fascia/serosal plane) and structure. Clinical context is provided through subjective assessment data from UGRA experts. Results: For human–human and human–AI annotations, agreement was highest for arteries (mean Dice score 0.88/0.86), then muscles (0.80/0.77), and lowest for nerves (0.48/0.41). Wide discrepancy exists in consistency for different structures, both with human–human and human–AI comparisons; highest for sartorius muscle (0.91/0.92) and lowest for the radial nerve (0.21/0.27). Conclusions: Human experts and the AI system both showed the same pattern of agreement in sono-anatomical structure identification. The clinical significance of the differences presented must be explored; however the perception that human expert opinion is uniform must be challenged. Elements of this assessment framework could be used for other devices to allow consistent evaluations that inform clinical training and practice. Anaesthetists should be actively engaged in the development and adoption of new AI technology.