Phantom and clinical evaluation of the effect of full Monte Carlo collimator modelling in post-SIRT yttrium-90 Bremsstrahlung SPECT imaging

Background: Post-therapy SPECT/CT imaging of Y-90 microspheres delivered to hepatic malignancies is difficult, owing to the continuous, high-energy Bremsstrahlung spectrum emitted by Y-90. This study aimed to evaluate the utility of a commercially available software package (HybridRecon, Hermes Medical Solutions AB) which incorporates full Monte Carlo collimator modelling. Analysis of image quality was performed on both phantom and clinical images in order to ultimately provide a recommendation of an optimum reconstruction for post-therapy Y-90 microsphere SPECT/CT imaging. A 3D-printed anthropomorphic liver phantom was filled with Y-90 with a sphere-to-background ratio of 4:1 and imaged on a GE Discovery 670 SPECT/CT camera. Datasets were reconstructed using ordered-subsets expectation maximization (OSEM) 1-7 iterations in order to identify the optimal OSEM reconstruction (5 iterations, 15 subsets). Quantitative analysis was subsequently carried out on phantom datasets obtained using four reconstruction algorithms: the default OSEM protocol (2 iterations, 10 subsets) and the optimised OSEM protocol, both with and without full Monte Carlo collimator modelling. The quantitative metrics contrast recovery (CR) and background variability (BV) were calculated. The four algorithms were then used to retrospectively reconstruct 10 selective internal radiation therapy (SIRT) patient datasets which were subsequently blind scored for image quality by a consultant radiologist. Results: The optimised OSEM reconstruction (5 iterations, 15 subsets with full MC collimator modelling) increased the CR by 42% (p <0.001) compared to the default OSEM protocol (2 iterations, 10 subsets). The use of full Monte Carlo collimator modelling was shown to further improve CR by 14% (30 mm sphere, CR = 90%, p <0.05). The consultant radiologist had a significant preference for the optimised OSEM over the default OSEM protocol (p <0. 001), with the optimised OSEM being the favoured reconstruction in every one of the 10 clinical cases presented. Conclusions: OSEM (5 iterations, 15 subsets) with full Monte Carlo collimator modelling is quantitatively the optimal image reconstruction for post-SIRT 90Y Bremsstrahlung SPECT/CT imaging. The use of full Monte Carlo collimator modelling for correction of image-degrading effects significantly increases contrast recovery without degrading clinical image quality.Peer reviewe

Testing the limits of SMILES-based de novo molecular generation with curriculum and deep reinforcement learning

Deep reinforcement learning methods have been shown to be potentially powerful tools for de novo design. Recurrent-neural-network-based techniques are the most widely used methods in this space. In this work we examine the behaviour of recurrent-neural-network-based methods when there are few (or no) examples of molecules with the desired properties in the training data. We find that targeted molecular generation is usually possible, but the diversity of generated molecules is often reduced and it is not possible to control the composition of generated molecular sets. To help overcome these issues, we propose a new curriculum-learning-inspired recurrent iterative optimization procedure that enables the optimization of generated molecules for seen and unseen molecular profiles, and allows the user to control whether a molecular profile is explored or exploited. Using our method, we generate specific and diverse sets of molecules with up to 18 times more scaffolds than standard methods for the same sample size; however, our results also point to substantial limitations of one-dimensional molecular representations, as used in this space. We find that the success or failure of a given molecular optimization problem depends on the choice of simplified molecular-input line-entry system (SMILES)

A randomized, controlled, double-blind crossover study on the effects of isoeffective and isovolumetric intravenous crystalloid and gelatin on blood volume, and renal and cardiac hemodynamics

Background & aimsBlood volume expanding properties of colloids are superior to crystalloids. In addition to oncotic/osmotic properties, the electrolyte composition of infusions may have important effects on visceral perfusion, with infusions containing supraphysiological chloride causing hyperchloremic acidosis and decreased renal blood flow. In this non-inferiority study, a validated healthy human subject model was used to compare effects of colloid (4% succinylated gelatin) and crystalloid fluid regimens on blood volume, renal function, and cardiac output.MethodsHealthy male participants were given infusions over 60 min > 7 days apart in a randomized, crossover manner. Reference arm (A): 1.5 L of Sterofundin ISO, isoeffective arm (B): 0.5 L of 4% Gelaspan®, isovolumetric arm (C): 0.5 L of 4% Gelaspan® and 1 L of Sterofundin ISO (all B. Braun, Melsungen, Germany). Participants were studied over 240 min. Changes in blood volume were calculated from changes in weight and hematocrit. Renal volume, renal artery blood flow (RABF), renal cortex perfusion and diffusion, and cardiac index were measured with magnetic resonance imaging.ResultsTen of 12 males [mean (SE) age 23.9 (0.8) years] recruited, completed the study. Increase in body weight and extracellular fluid volume were significantly less after infusion B than infusions A and C, but changes in blood volume did not significantly differ between infusions. All infusions increased renal volume, with no significant differences between infusions. There was no significant difference in RABF across the infusion time course or between infusion types. Renal cortex perfusion decreased during the infusion (mean 18% decrease from baseline), with no significant difference between infusions. There was a trend for increased renal cortex diffusion (4.2% increase from baseline) for the crystalloid infusion. All infusions led to significant increases in cardiac index.ConclusionsA smaller volume of colloid (4% succinylated gelatin) was as effective as a larger volume of crystalloid at expanding blood volume, increasing cardiac output and changing renal function. Significantly less interstitial space expansion occurred with the colloid

A New Class of Changing-Look LINERs

We report the discovery of six active galactic nuclei (AGN) caught "turning on" during the first nine months of the Zwicky Transient Facility (ZTF) survey. The host galaxies were classified as LINERs by weak narrow forbidden line emission in their archival SDSS spectra, and detected by ZTF as nuclear transients. In five of the cases, we found via follow-up spectroscopy that they had transformed into broad-line AGN, reminiscent of the changing-look LINER iPTF 16bco. In one case, ZTF18aajupnt/AT2018dyk, follow-up HST UV and ground-based optical spectra revealed the transformation into a narrow-line Seyfert 1 (NLS1) with strong [Fe VII, X, XIV] and He II 4686 coronal lines. Swift monitoring observations of this source reveal bright UV emission that tracks the optical flare, accompanied by a luminous soft X-ray flare that peaks ~60 days later. Spitzer follow-up observations also detect a luminous mid-infrared flare implying a large covering fraction of dust. Archival light curves of the entire sample from CRTS, ATLAS, and ASAS-SN constrain the onset of the optical nuclear flaring from a prolonged quiescent state. Here we present the systematic selection and follow-up of this new class of changing-look LINERs, compare their properties to previously reported changing-look Seyfert galaxies, and conclude that they are a unique class of transients well-suited to test the uncertain physical processes associated with the LINER accretion state.Comment: Submitted to ApJ, 31 pages, 17 Figures (excluding Appendix due to file size constraints but will be available in electronic version

Cell non-autonomous requirement of p75 in the development of geniculate oral sensory neurons

During development of the peripheral taste system, oral sensory neurons of the geniculate ganglion project via the chorda tympani nerve to innervate taste buds in fungiform papillae. Germline deletion of the p75 neurotrophin receptor causes dramatic axon guidance and branching deficits, leading to a loss of geniculate neurons. To determine whether the developmental functions of p75 in geniculate neurons are cell autonomous, we deleted p75 specifically in Phox2b + oral sensory neurons (Phox2b-Cre; p75fx/fx) or in neural crest-derived cells (P0-Cre; p75fx/fx) and examined geniculate neuron development. In germline p75−/− mice half of all geniculate neurons were lost. The proportion of Phox2b + neurons, as compared to Phox2b-pinna-projecting neurons, was not altered, indicating that both populations were affected similarly. Chorda tympani nerve recordings demonstrated that p75−/− mice exhibit profound deficits in responses to taste and tactile stimuli. In contrast to p75−/− mice, there was no loss of geniculate neurons in either Phox2b-Cre; p75fx/fx or P0-Cre; p75fx/fx mice. Electrophysiological analyses demonstrated that Phox2b-Cre; p75fx/fx mice had normal taste and oral tactile responses. There was a modest but significant loss of fungiform taste buds in Phox2b-Cre; p75fx/fx mice, although there was not a loss of chemosensory innervation of the remaining fungiform taste buds. Overall, these data suggest that the developmental functions of p75 are largely cell non-autonomous and require p75 expression in other cell types of the chorda tympani circuit

“Because It Kind of Falls in Between, Doesn’t It? Like an Acute Thing and a Chronic”: the Psychological Experience of Anaphylaxis in Adulthood

Anaphylaxis is a serious, rare condition increasing in prevalence. This study explored the psychological experience of adult-onset anaphylaxis from patient, family and staff perspectives. Semi-structured interviews were conducted with twelve participants. Two global themes emerged from thematic analysis: ‘controllability’ (‘an unknown and distressing experience’, ‘the importance of control over triggers’ and ‘responsibility but no control: the impact on others’) and ‘conflict’ (‘rejecting illness identity’, ‘minimisation of risk’, ‘accessing specialist care: running in slow motion’ and ‘patient-centred versus service-centred care’). Findings highlight the importance of perceived control and emphasise the presence of conflict in the experience of this complex, episodic condition

Phenotype of ARDS alveolar and blood neutrophils

RATIONALE: Acute respiratory distress syndrome is refractory to pharmacological intervention. Inappropriate activation of alveolar neutrophils is believed to underpin this disease's complex pathophysiology, yet these cells have been little studied. OBJECTIVES: To examine the functional and transcriptional profiles of patient blood and alveolar neutrophils compared with healthy volunteer cells, and to define their sensitivity to phosphoinositide 3-kinase inhibition. METHODS: Twenty-three ventilated patients underwent bronchoalveolar lavage. Alveolar and blood neutrophil apoptosis, phagocytosis, and adhesion molecules were quantified by flow cytometry, and oxidase responses were quantified by chemiluminescence. Cytokine and transcriptional profiling were used in multiplex and GeneChip arrays. MEASUREMENTS AND MAIN RESULTS: Patient blood and alveolar neutrophils were distinct from healthy circulating cells, with increased CD11b and reduced CD62L expression, delayed constitutive apoptosis, and primed oxidase responses. Incubating control cells with disease bronchoalveolar lavage recapitulated the aberrant functional phenotype, and this could be reversed by phosphoinositide 3-kinase inhibitors. In contrast, the prosurvival phenotype of patient cells was resistant to phosphoinositide 3-kinase inhibition. RNA transcriptomic analysis revealed modified immune, cytoskeletal, and cell death pathways in patient cells, aligning closely to sepsis and burns datasets but not to phosphoinositide 3-kinase signatures. CONCLUSIONS: Acute respiratory distress syndrome blood and alveolar neutrophils display a distinct primed prosurvival profile and transcriptional signature. The enhanced respiratory burst was phosphoinositide 3-kinase-dependent but delayed apoptosis and the altered transcriptional profile were not. These unexpected findings cast doubt over the utility of phosphoinositide 3-kinase inhibition in acute respiratory distress syndrome and highlight the importance of evaluating novel therapeutic strategies in patient-derived cells.This work was funded by a non-commercial grant from GSK, with additional support from The Wellcome Trust, Papworth Hospital, The British Lung Foundation and the NIHR Cambridge Biomedical Research Centre. DMLS holds a Gates Cambridge Scholarship; CS is in receipt of a Wellcome Trust Early Postdoctoral Research Fellowship for Clinician Scientists [WT101692MA].This is the author accepted manuscript. The final version is available from ATS Journals via http://dx.doi.org/10.1164/rccm.201509-1818O

DYNamic assessment of multi‐organ level dysfunction in patients recovering from COVID‐19: DYNAMO COVID‐19

We evaluated the impacts of COVID‐19 on multi‐organ and metabolic function in patients following severe hospitalised infection compared to controls. Patients (n = 21) without previous diabetes, cardiovascular or cerebrovascular disease were recruited 5–7 months post‐discharge alongside controls (n = 10) with similar age, sex and body mass. Perceived fatigue was estimated (Fatigue Severity Scale) and the following were conducted: oral glucose tolerance (OGTT) alongside whole‐body fuel oxidation, validated magnetic resonance imaging and spectroscopy during resting and supine controlled exercise, dual‐energy X‐ray absorptiometry, short physical performance battery (SPPB), intra‐muscular electromyography, quadriceps strength and fatigability, and daily step‐count. There was a greater insulin response (incremental area under the curve, median (inter‐quartile range)) during the OGTT in patients [18,289 (12,497–27,448) mIU/min/L] versus controls [8655 (7948–11,040) mIU/min/L], P &lt; 0.001. Blood glucose response and fasting and post‐prandial fuel oxidation rates were not different. This greater insulin resistance was not explained by differences in systemic inflammation or whole‐body/regional adiposity, but step‐count (P = 0.07) and SPPB scores (P = 0.004) were lower in patients. Liver volume was 28% greater in patients than controls, and fat fraction adjusted liver T1, a measure of inflammation, was raised in patients. Patients displayed greater perceived fatigue scores, though leg muscle volume, strength, force‐loss, motor unit properties and post‐exercise muscle phosphocreatine resynthesis were comparable. Further, cardiac and cerebral architecture and function (at rest and on exercise) were not different. In this cross‐sectional study, individuals without known previous morbidity who survived severe COVID‐19 exhibited greater insulin resistance, pointing to a need for physical function intervention in recovery