Reproducibility of quantitative indices of lung function and microstructure from 129Xe chemical shift saturation recovery (CSSR) MR spectroscopy

Purpose To evaluate the reproducibility of indices of lung microstructure and function derived from 129Xe chemical shift saturation recovery (CSSR) spectroscopy in healthy volunteers and patients with chronic obstructive pulmonary disease (COPD), and to study the sensitivity of CSSR-derived parameters to pulse sequence design and lung inflation level. Methods Preliminary data were collected from five volunteers on three occasions, using two implementations of the CSSR sequence. Separately, three volunteers each underwent CSSR at three different lung inflation levels. After analysis of these preliminary data, five COPD patients were scanned on three separate days, and nine age-matched volunteers were scanned three times on one day, to assess reproducibility. Results CSSR-derived alveolar septal thickness (ST) and surface-area-to-volume (S/V) ratio values decreased with lung inflation level (P < 0.001; P = 0.057, respectively). Intra-subject standard deviations of ST were lower than the previously measured differences between volunteers and subjects with interstitial lung disease. The mean coefficient of variation (CV) values of ST were 3.9 ± 1.9% and 6.0 ± 4.5% in volunteers and COPD patients, respectively, similar to CV values for whole-lung carbon monoxide diffusing capacity. The mean CV of S/V in volunteers and patients was 14.1 ± 8.0% and 18.0 ± 19.3%, respectively. Conclusion 129Xe CSSR presents a reproducible method for estimation of alveolar septal thickness

Comparison of 3He and129Xe MRI for evaluation of lung microstructure and ventilation at 1.5T

BACKGROUND: To support translational lung MRI research with hyperpolarized129Xe gas, comprehensive evaluation of derived quantitative lung function measures against established measures from3He MRI is required. Few comparative studies have been performed to date, only at 3T, and multisession repeatability of129Xe functional metrics have not been reported. PURPOSE/HYPOTHESIS: To compare hyperpolarized129Xe and3He MRI-derived quantitative metrics of lung ventilation and microstructure, and their repeatability, at 1.5T. STUDY TYPE: Retrospective. POPULATION: Fourteen healthy nonsmokers (HN), five exsmokers (ES), five patients with chronic obstructive pulmonary disease (COPD), and 16 patients with nonsmall-cell lung cancer (NSCLC). FIELD STRENGTH/SEQUENCE: 1.5T. NSCLC, COPD patients and selected HN subjects underwent 3D balanced steady-state free-precession lung ventilation MRI using both3He and129Xe. Selected HN, all ES, and COPD patients underwent 2D multislice spoiled gradient-echo diffusion-weighted lung MRI using both hyperpolarized gas nuclei. ASSESSMENT: Ventilated volume percentages (VV%) and mean apparent diffusion coefficients (ADC) were derived from imaging. COPD patients performed the whole MR protocol in four separate scan sessions to assess repeatability. Same-day pulmonary function tests were performed. STATISTICAL TESTS: Intermetric correlations: Spearman's coefficient. Intergroup/internuclei differences: analysis of variance / Wilcoxon's signed rank. Repeatability: coefficient of variation (CV), intraclass correlation (ICC) coefficient. RESULTS: A significant positive correlation between3He and129Xe VV% was observed (r = 0.860, P < 0.001). VV% was larger for3He than129Xe (P = 0.001); average bias, 8.79%. A strong correlation between mean3He and129Xe ADC was obtained (r = 0.922, P < 0.001). MR parameters exhibited good correlations with pulmonary function tests. In COPD patients, mean CV of3He and129Xe VV% was 4.08% and 13.01%, respectively, with ICC coefficients of 0.541 (P = 0.061) and 0.458 (P = 0.095). Mean3He and129Xe ADC values were highly repeatable (mean CV: 2.98%, 2.77%, respectively; ICC: 0.995, P < 0.001; 0.936, P < 0.001). DATA CONCLUSION:129Xe lung MRI provides near-equivalent information to3He for quantitative lung ventilation and microstructural MRI at 1.5T. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage

A Generative Programming Approach to Interactive Information Retrieval:Insights and Experiences

Abstract. We describe the application of generative programming to a problem in interactive information retrieval. The particular interactive information retrieval problem we study is the support for ‘out of turn interaction ’ with a website – how a user can communicate input to a website when the site is not soliciting such information on the current page, but will do so on a subsequent page. Our solution approach makes generous use of program transformations (partial evaluation, currying, and slicing) to delay the site’s current solicitation for input until after the user’s out-of-turn input is processed. We illustrate how studying out-of-turn interaction through a generative lens leads to several valuable in-sights: (i) the concept of a web dialog, (ii) an improved understanding of web taxonomies, and (iii) new web interaction techniques and interfaces. These notions allow us to cast the design of interactive (and responsive) websites in terms of the underlying dialog structure and, further, suggest a simple implementation strategy with a clean separation of concerns. We also highlight new research directions opened up by the generative pro-gramming approach to interactive information retrieval such as the idea of web interaction axioms.

Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error.

Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia

Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification. Funding: UK Research and Innovation and National Institute for Health Research

Highly-parallelized simulation of a pixelated LArTPC on a GPU

The rapid development of general-purpose computing on graphics processing units (GPGPU) is allowing the implementation of highly-parallelized Monte Carlo simulation chains for particle physics experiments. This technique is particularly suitable for the simulation of a pixelated charge readout for time projection chambers, given the large number of channels that this technology employs. Here we present the first implementation of a full microphysical simulator of a liquid argon time projection chamber (LArTPC) equipped with light readout and pixelated charge readout, developed for the DUNE Near Detector. The software is implemented with an end-to-end set of GPU-optimized algorithms. The algorithms have been written in Python and translated into CUDA kernels using Numba, a just-in-time compiler for a subset of Python and NumPy instructions. The GPU implementation achieves a speed up of four orders of magnitude compared with the equivalent CPU version. The simulation of the current induced on 10^3 pixels takes around 1 ms on the GPU, compared with approximately 10 s on the CPU. The results of the simulation are compared against data from a pixel-readout LArTPC prototype