Analysis of continuous glucose tracking data in people with type 1 diabetes after COVID-19 vaccination reveals unexpected link between immune and metabolic response, augmented by adjunctive oral medication

Introduction: The COVID-19 vaccination programme is under way worldwide. Anecdotal evidence is increasing that some people with type 1 diabetes mellitus (T1DM) experience temporary instability of blood glucose (BG) levels post-vaccination which normally settles within 2-3 days. We report an analysis of BG profiles of 20 individuals before/after vaccination. Methods: We examined the BG profile of 20 consecutive adults (18 years of age or more) with T1DM using the FreeStyle Libre flash glucose monitor in the period immediately before and after COVID-19 vaccination. The primary outcome measure was percentage (%) BG readings in the designated target range 3.9-10 mmmol/L as reported on the LibreView portal for 7 days prior to the vaccination (week −1) and the 7 days after the vaccination (week +1). Results: There was a significant decrease in the %BG on target following the COVID-vaccination for the 7 days following vaccination (mean 45.2% ± SE 4.2%) vs pre-COVID-19 vaccination (mean 52.6% ± SE 4.5%). This was mirrored by an increase in the proportion of readings in other BG categories 10.1%-13.9%/≥14%. There was no significant change in BG variability in the 7days post-COVID-19 vaccination. This change in BG proportion on target in the week following vaccination was most pronounced for people taking Metformin/Dapagliflozin+basal-bolus insulin (−23%) vs no oral hypoglycaemic agents (−4%), and median age <53 vs ≥53 years (greater reduction in %BG in target for older individuals (−18% vs −9%)). Conclusion: In T1DM, we have shown that COVID-19 vaccination can cause temporary perturbation of BG, with this effect more pronounced in patients talking oral hypoglycaemic medication plus insulin, and in older individuals. This may also have consequences for patients with T2DM who are currently not supported by flash glucose monitoring

A multidisciplinary consensus on dehydration: definitions, diagnostic methods and clinical implications

Background: Dehydration appears prevalent, costly and associated with adverse outcomes. We sought to generate consensus on such key issues and elucidate need for further scientific enquiry. Materials and Methods: A modified Delphi process combined expert opinion and evidence appraisal. 12 relevant experts addressed dehydration’s definition, objective markers and impact on physiology and outcome. Results: Fifteen consensus statements and seven research recommendations were generated. Key findings, evidenced in detail, were that there is no universally-accepted definition for dehydration; hydration assessment is complex and requires combining physiological and laboratory variables; ‘dehydration’ and ‘hypovolaemia’ are incorrectly used interchangeably; abnormal hydration status includes relative and/or absolute abnormalities in body water and serum/plasma osmolality (pOsm); raised pOsm usually indicates dehydration; direct measurement of pOsm is the gold standard for determining dehydration; pOsm >300 and ≤280 mOsm/kg classifies a person as hyper or hypo-osmolar; outside extremes, signs of adult dehydration are subtle and unreliable; dehydration is common in hospitals and care homes and associated with poorer outcomes. Discussion: Dehydration poses risk to public health. Dehydration is under-recognised and poorly managed in hospital and community-based care. Further research is required to improve assessment and management of dehydration and the authors have made recommendations to focus academic endeavours

Load-sharing and kinematics of the human cervical spine under multi-axial transverse shear loading: combined experimental and computational investigation

This preprint has not undergone peer review or any post-submission improvements or corrections. The Version of Record of this article is published in Journal of Biomechanical Engineering, and is available online at https://doi.org/10.1115/1.4050030The cervical spine experiences shear forces during everyday activities and injurious events yet there is a paucity of biomechanical data characterizing the cervical spine under shear loading. This study aimed to 1) characterise load transmission paths and kinematics of the subaxial cervical spine under shear loading, and 2) assess a contemporary finite element cervical spine model using this data. Subaxial functional spinal units (FSUs) were subjected to anterior, posterior and lateral shear forces (200 N) applied with and without superimposed axial compression preload (200 N) while monitoring spine kinematics. Load transmission paths were identified using strain gauges on the anterior vertebral body and lateral masses and a disc pressure sensor. Experimental conditions were simulated with cervical spine finite element model FSUs (GHBMC M50 version 5.0). The mean kinematics, vertebral body strains and disc pressures were compared to experimental results. The shear force-displacement response typically demonstrated a toe region followed by a linear response, with higher stiffness in the anterior shear direction relative to lateral and posterior shear. Compressive axial preload decreased posterior and lateral shear stiffness and increased anterior shear stiffness. Load transmission patterns and kinematics suggest the facet joints play a key role in limiting anterior shear while the disc governs motion in posterior shear. The main cervical spine shear responses and trends are faithfully predicted by the GHBMC finite element cervical spine model. These basic cervical spine biomechanics and the computational model can provide insight into mechanisms for facet dislocation in high severity impacts, and tissue distraction in low severity impacts

Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

John Clare and place

This chapter tackles issues of place in the self-presentation and critical reception of John Clare, and pursues it across a number of axes. The argument centres on the placing of Clare both socio-economically and ‘naturally’, and limitations exerted upon perceptions of his work. Interrogating criticism this chapter finds a pervasive awkwardness especially in relation to issues of class and labour. It assesses the contemporary ‘placing’ of Clare, and seemingly unavoidable insensitivities to labour and poverty in the history industry, place-naming, and polemical ecocriticism. It assesses the ways Clare represents place – in poverty, in buildings, in nature – and, drawing on Michel de Certeau, considers the tactics Clare uses to negotiate his place. It pursues trajectories to ‘un-place’ Clare: the flight of fame in Clare’s response to Byron; and the flight of an early poem in songbooks and beyond, across the nineteenth century

TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport

Tiina Paunio on työryhmän UK10K jäsen.The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.Peer reviewe

Whole-genome sequence-based analysis of thyroid function

Tiina Paunio on työryhmän UK10K Consortium jäsen.Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N = 2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF >= 1%) associated with TSH and FT4 (N = 16,335). For TSH, we identify a novel variant in SYN2 (MAF = 23.5%, P = 6.15 x 10(-9)) and a new independent variant in PDE8B (MAF = 10.4%, P = 5.94 x 10(-14)). For FT4, we report a low-frequency variant near B4GALT6/ SLC25A52 (MAF = 3.2%, P = 1.27 x 10(-9)) tagging a rare TTR variant (MAF = 0.4%, P = 2.14 x 10(-11)). All common variants explain >= 20% of the variance in TSH and FT4. Analysis of rare variants (MAFPeer reviewe