GIFTed Demons: deformable image registration with local structure-preserving regularization using supervoxels for liver applications.

Deformable image registration, a key component of motion correction in medical imaging, needs to be efficient and provides plausible spatial transformations that reliably approximate biological aspects of complex human organ motion. Standard approaches, such as Demons registration, mostly use Gaussian regularization for organ motion, which, though computationally efficient, rule out their application to intrinsically more complex organ motions, such as sliding interfaces. We propose regularization of motion based on supervoxels, which provides an integrated discontinuity preserving prior for motions, such as sliding. More precisely, we replace Gaussian smoothing by fast, structure-preserving, guided filtering to provide efficient, locally adaptive regularization of the estimated displacement field. We illustrate the approach by applying it to estimate sliding motions at lung and liver interfaces on challenging four-dimensional computed tomography (CT) and dynamic contrast-enhanced magnetic resonance imaging datasets. The results show that guided filter-based regularization improves the accuracy of lung and liver motion correction as compared to Gaussian smoothing. Furthermore, our framework achieves state-of-the-art results on a publicly available CT liver dataset

Tumour subregion analysis of colorectal liver metastases using semi-automated clustering based on DCE-MRI: Comparison with histological subregions and impact on pharmacokinetic parameter analysis.

PURPOSE: To use a novel segmentation methodology based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to define tumour subregions of liver metastases from colorectal cancer (CRC), to compare these with histology, and to use these to compare extracted pharmacokinetic (PK) parameters between tumour subregions. MATERIALS AND METHODS: This ethically-approved prospective study recruited patients with CRC and ≥1 hepatic metastases scheduled for hepatic resection. Patients underwent DCE-MRI pre-metastasectomy. Histological sections of resection specimens were spatially matched to DCE-MRI acquisitions and used to define histological subregions of viable and non-viable tumour. A semi-automated voxel-wise image segmentation algorithm based on the DCE-MRI contrast-uptake curves was used to define imaging subregions of viable and non-viable tumour. Overlap of histologically-defined and imaging subregions was compared using the Dice similarity coefficient (DSC). DCE-MRI PK parameters were compared for the whole tumour and histology-defined and imaging-derived subregions. RESULTS: Fourteen patients were included in the analysis. Direct histological comparison with imaging was possible in nine patients. Mean DSC for viable tumour subregions defined by imaging and histology was 0.738 (range 0.540-0.930). There were significant differences between Ktrans and kep for viable and non-viable subregions (p < 0.001) and between whole lesions and viable subregions (p < 0.001). CONCLUSION: We demonstrate good concordance of viable tumour segmentation based on pre-operative DCE-MRI with a post-operative histological gold-standard. This can be used to extract viable tumour-specific values from quantitative image analysis, and could improve treatment response assessment in clinical practice

Hansenula polymorpha Swi1p and Snf2p are essential for methanol utilisation

We have cloned the Hansenula polymorpha SWI1 and SNF2 genes by functional complementation of mutants that are defective in methanol utilisation. These genes encode proteins similar to Saccharomyces cerevisiae Swi1p and Snf2p, which are subunits of the SWI/SNF complex. This complex belongs to the family of nucleosome-remodeling complexes that play a role in transcriptional control of gene expression. Analysis of the phenotypes of constructed H. polymorpha SWI1 and SNF2 disruption strains indicated that these genes are not necessary for growth of cells on glucose, sucrose, or various organic nitrogen sources which involve the activity of peroxisomal oxidases. Both disruption strains showed a moderate growth defect on glycerol and ethanol, but were fully blocked in methanol utilisation. In methanol-induced cells of both disruption strains, two peroxisomal enzymes involved in methanol metabolism, alcohol oxidase and dihydroxyacetone synthase, were hardly detectable, whereas in wild-type cells these proteins were present at very high levels. We show that the reduction in alcohol oxidase protein levels in H. polymorpha SWI1 and SNF2 disruption strains is due to strongly reduced expression of the alcohol oxidase gene. The level of Pex5p, the receptor involved in import of alcohol oxidase and dihydroxyacetone synthase into peroxisomes, was also reduced in both disruption strains compared to that in wild-type cells.

Whatever happened to curriculum theory? Critical realism and curriculum change

In the face of what has been characterised as a ‘crisis’ in curriculum – an apparent decline of some aspects of curriculum studies combined with the emergence of new types of national curriculum which downgrade knowledge – some writers have been arguing for the use of realist theory to address these issues. This paper offers a contribution to this debate, drawing upon critical realism, and especially upon the social theory of Margaret Archer. The paper first outlines the supposed crisis in curriculum, before providing an overview of some of the key tenets of critical realism. The paper concludes by speculating on how critical realism may offer new ways of thinking to inform policy and practice in a key curricular problematic. This is the issue of curriculum change

Planck-HFI optical design and pre-flight performances

Planck is a European Space Agency (ESA) satellite, launched in May 2009, which is mapping the Cosmic Microwave Background anisotropies in intensity and polarisation with unprecedented detail and sensitivity. It will also provide full-sky maps of astrophysical foregrounds. An accurate knowledge of the telescope beam patterns is an essential element for a correct analysis of the acquired astrophysical data. We present the optical design of the High Frequency Instrument (HFI) together with the optical performances measured during the ground calibration campaigns. We report on the evolution of the knowledge of the pre-launch HFI beam patterns when coupled to the telescope, and on their significance for the HFI data analysis procedure

Longitudinal lung function assessment of patients hospitalised with COVID-19 using 1H and 129Xe lung MRI

BACKGROUND: Microvascular abnormalities and impaired gas transfer have been observed in patients with COVID-19. The progression of pulmonary changes in these patients remains unclear. RESEARCH QUESTION: Do patients hospitalised due to COVID-19 without evidence of architectural distortion on structural imaging show longitudinal improvements in lung function measured using 1H and 129Xe magnetic resonance imaging between 6-52 weeks after hospitalisation? STUDY DESIGN AND METHODS: Patients who were hospitalised due to COVID-19 pneumonia underwent a pulmonary 1H and 129Xe MRI protocol at 6, 12, 25 and 51 weeks after hospital admission in a prospective cohort study between 11/2020 and 02/2022. Imaging protocol: 1H ultra-short echo time, contrast enhanced lung perfusion, 129Xe ventilation, 129Xe diffusion weighted and 129Xe spectroscopic imaging of gas exchange. RESULTS: 9 patients were recruited (57±14 [median±interquartile range] years, 6/9 male). Patients underwent MRI at 6 (N=9), 12 (N=9), 25 (N=6) and 51 (N=8) weeks after hospital admission. Patients with signs of interstitial lung damage were excluded. At 6 weeks, patients demonstrated impaired 129Xe gas transfer (red blood cell to membrane fraction) but lung microstructure was not increased (apparent diffusion coefficient and mean acinar airway dimensions). Minor ventilation abnormalities present in four patients were largely resolved in the 6-25 week period. At 12 weeks, all patients with lung perfusion data (N=6) showed an increase in both pulmonary blood volume and flow when compared to 6 weeks, though this was not statistically significant. At 12 weeks, significant improvements in 129Xe gas transfer were observed compared to 6-week examinations, however 129Xe gas transfer remained abnormally low at weeks 12, 25 and 51. INTERPRETATION: 129Xe gas transfer was impaired up to one year after hospitalisation in patients who were hospitalised due to COVID-19 pneumonia, without evidence of architectural distortion on structural imaging, whereas lung ventilation wa normal at 52 weeks

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation

SARS-CoV-2-specific immune responses and clinical outcomes after COVID-19 vaccination in patients with immune-suppressive disease

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune responses and infection outcomes were evaluated in 2,686 patients with varying immune-suppressive disease states after administration of two Coronavirus Disease 2019 (COVID-19) vaccines. Overall, 255 of 2,204 (12%) patients failed to develop anti-spike antibodies, with an additional 600 of 2,204 (27%) patients generating low levels (<380 AU ml−1). Vaccine failure rates were highest in ANCA-associated vasculitis on rituximab (21/29, 72%), hemodialysis on immunosuppressive therapy (6/30, 20%) and solid organ transplant recipients (20/81, 25% and 141/458, 31%). SARS-CoV-2-specific T cell responses were detected in 513 of 580 (88%) patients, with lower T cell magnitude or proportion in hemodialysis, allogeneic hematopoietic stem cell transplantation and liver transplant recipients (versus healthy controls). Humoral responses against Omicron (BA.1) were reduced, although cross-reactive T cell responses were sustained in all participants for whom these data were available. BNT162b2 was associated with higher antibody but lower cellular responses compared to ChAdOx1 nCoV-19 vaccination. We report 474 SARS-CoV-2 infection episodes, including 48 individuals with hospitalization or death from COVID-19. Decreased magnitude of both the serological and the T cell response was associated with severe COVID-19. Overall, we identified clinical phenotypes that may benefit from targeted COVID-19 therapeutic strategies

Post-acute COVID-19 neuropsychiatric symptoms are not associated with ongoing nervous system injury

A proportion of patients infected with severe acute respiratory syndrome coronavirus 2 experience a range of neuropsychiatric symptoms months after infection, including cognitive deficits, depression and anxiety. The mechanisms underpinning such symptoms remain elusive. Recent research has demonstrated that nervous system injury can occur during COVID-19. Whether ongoing neural injury in the months after COVID-19 accounts for the ongoing or emergent neuropsychiatric symptoms is unclear. Within a large prospective cohort study of adult survivors who were hospitalized for severe acute respiratory syndrome coronavirus 2 infection, we analysed plasma markers of nervous system injury and astrocytic activation, measured 6 months post-infection: neurofilament light, glial fibrillary acidic protein and total tau protein. We assessed whether these markers were associated with the severity of the acute COVID-19 illness and with post-acute neuropsychiatric symptoms (as measured by the Patient Health Questionnaire for depression, the General Anxiety Disorder assessment for anxiety, the Montreal Cognitive Assessment for objective cognitive deficit and the cognitive items of the Patient Symptom Questionnaire for subjective cognitive deficit) at 6 months and 1 year post-hospital discharge from COVID-19. No robust associations were found between markers of nervous system injury and severity of acute COVID-19 (except for an association of small effect size between duration of admission and neurofilament light) nor with post-acute neuropsychiatric symptoms. These results suggest that ongoing neuropsychiatric symptoms are not due to ongoing neural injury