Molecular Imaging of Pulmonary Tuberculosis in an Ex-Vivo Mouse Model Using Spectral Photon-Counting Computed Tomography and Micro-CT

Assessment of disease burden and drug efficacy is achieved preclinically using high resolution micro computed tomography (CT). However, micro-CT is not applicable to clinical human imaging due to operating at high dose. In addition, the technology differences between micro-CT and standard clinical CT prevent direct translation of preclinical applications. The current proof-of-concept study presents spectral photon-counting CT as a clinically translatable, molecular imaging tool by assessing contrast uptake in an ex-vivo mouse model of pulmonary tuberculosis (TB). Iodine, a common contrast used in clinical CT imaging, was introduced into a murine model of TB. The excised mouse lungs were imaged using a standard micro-CT subsystem (SuperArgus) and the contrast enhanced TB lesions quantified. The same lungs were imaged using a spectral photoncounting CT system (MARS small-bore scanner). Iodine and soft tissues (water and lipid) were materially separated, and iodine uptake quantified. The volume of the TB infection quantified by spectral CT and micro-CT was found to be 2.96 mm(3) and 2.83 mm(3), respectively. This proof-of-concept study showed that spectral photon-counting CT could be used as a predictive preclinical imaging tool for the purpose of facilitating drug discovery and development. Also, as this imaging modality is available for human trials, all applications are translatable to human imaging. In conclusion, spectral photon-counting CT could accelerate a deeper understanding of infectious lung diseases using targeted pharmaceuticals and intrinsic markers, and ultimately improve the efficacy of therapies by measuring drug delivery and response to treatment in animal models and later in humans

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Components of carotid atherosclerotic plaque in spectral photon-counting CT with histopathologic comparison

Objectives This study aimed to demonstrate the effectiveness of spectral photon-counting CT (SPCCT) in quantifying fibrous cap (FC) thickness, FC area, and lipid-rich necrotic core (LRNC) area, in excised carotid atherosclerotic plaques by comparing it with histopathological measurements. Methods This is a single-center ex vivo cross-sectional observational study. Excised plaques of 20 patients (71 +/- 6 years; 13 men), obtained from carotid endarterectomy were scanned with SPCCT using standardized acquisition settings (120k Vp/19 mu A; 7-18 keV, 18-30 keV, 30-45 keV, 45-75 keV, and 75-118 keV). FC thickness, FC area, and LRNC area were quantified and compared between high-resolution 3D multi-energy CT images and histopathology using the Wilcoxon signed-ranks test and Bland-Altman analysis. Images were interpreted twice by two radiologists separately, blinded to the histopathology; inter- and intra-rater reliability were assessed with the intra-class correlation coefficients (ICC). Results FC thickness and FC area did not show significant differences between the SPCCT-derived radiological measurements versus the histopathological measurements (p value range 0.15-0.51 for FC thickness and 0.053-0.30 for FC area). For the LRNC area, the p value was statistically non-significant for reader 1 (range 0.36-0.81). The Bland-Altman analysis showed mean difference and 95% confidence interval for FC thickness, FC area, and LRNC area, 0.04 (-0.36 to 0.12) square root mm, -0.18 (-0.34 to -0.02) log(10) mm(2) and 0.10 (-0.088. to 0.009) log(10) mm(2) respectively. Conclusion The result demonstrated a viable technique for quantifying FC thickness, FC area, and LRNC area due to the combined effect of high spatial and energy resolution of SPCCT

Multi-energy spectral photon-counting CT in crystal-related arthropathies: initial experience and diagnostic performance in vitro

Purpose: We aimed to determine the in-vitro diagnostic performance of multi-energy spectral photon-counting CT (SPCCT) in crystal-related arthropathies. Methods: Four crystal types (monosodium urate, MSU; calcium pyrophosphate, CPP; octacalcium phosphate, OCP; and calcium hydroxyapatite, CHA) were synthesized and blended with agar at the following concentrations: 240, 88, 46, and 72 mg/mL, respectively. Crystal suspensions were scanned on a pre-clinical SPCCT system at 80 kVp using the following four energy thresholds: 20, 30, 40, and 50 keV. Differences in linear attenuation coefficients between the various crystal suspensions were compared using the receiver operating characteristic (ROC) paradigm. Areas under the ROC curves (AUC), sensitivities, specificities, and diagnostic accuracies were calculated. Crystal differentiation was considered successful if AUC&gt;0.95. Results: For each paired comparison of crystal suspensions, AUCs were significantly higher in the first energy range (20-30 keV). In the first energy range, MSU was confidently differentiated from CPP (sensitivity, 0.978; specificity, 0.990; accuracy, 0.984) and CHA (sensitivity, 0.957; specificity, 0.970; accuracy, 0.964), while only moderately distinguished from OCP (sensitivity, 0.663; specificity, 0.714; accuracy, 0.688). CPP was confidently differentiated from OCP (sensitivity, 0.950; specificity, 0.954; accuracy, 0.952), while only moderately from CHA (sensitivity, 0.564; specificity, 0.885; accuracy, 0.727). OCP was accurately differentiated from CHA (sensitivity, 0.898; specificity, 0.917; accuracy, 0.907). Conclusions: Multi-energy SPCCT can accurately differentiate MSU from CPP and CHA, CPP from OCP, and OCP from CHA in vitro. The distinction between MSU and OCP, and CPP and CHA is more challenging

Assessment of Material Identification Errors, Image Quality, and Radiation Doses Using Small Animal Spectral Photon-Counting CT

Photon-counting CT offers the potential to provide new diagnostic information. In this study, we sought to determine the interplay between material identification errors, image quality indicators, and radiation doses using photon-counting spectral CT, and to determine whether this relationship is replicated in spectral CT scans of mice. Custom-built Perspex phantoms were used to measure signal-to-noise ratio (SNR) and spatial resolution, and to measure radiation dose using thermoluminescent dosimeters. A multicontrast calibration phantom containing inserts with different concentrations of gadolinium (1, 2, 4, and 8 mg/mL), hydroxyapatite rods (0, 54.3, 104.3, 211.7, 402.3, and 808.5 mg/mL) along with water and lipid was used to assess material identification errors. Image acquisition was performed using the MARS photon-counting scanner with four energy channels (30-45, 45-60, 60-78, and 78-118 keV) at four different tube currents (24, 34, 44, and 55 mu A). As increased tube current showed no significant effect on material characterization, small animal dosimetry was performed with 24-mu A tube current using two noncontrast mice and one mouse injected with gadolinium. Results demonstrated that a tube current increase from 24 to 54 mu A improved the SNR and spatial resolution by &lt;10%, gadolinium identification by &lt;20% (for 1 mg/mL) but radiation dose increased by &gt;160%. Imaging results of the mice showed no obvious artefacts, and the mean absorbed dose measured for the three mice was 27.3 +/- 2.4 mGy. The results suggest that the energy resolving capability of photon-counting CT maintains diagnostically relevant image quality with high levels of material discrimination at reduced radiation dose

MARS pre-clinical imaging: the benefits of small pixels and good energy data

Images from MARS spectral CT scanners show that there is much diagnostic value from using small pixels and good energy data. MARS scanners use energy-resolving photon-counting CZT Medipix3RX detectors that measure the energy of photons on a five-point scale and with a spatial resolution of 110 microns. The energy information gives good material discrimination and quantification. The 3D reconstruction gives a voxel size of 70 microns. We present images of pre-clinical specimens, including excised atheroma, bone and joint samples, and nanoparticle contrast agents along with images from living humans. Images of excised human plaque tissue show the location and extent of lipid and calcium deposition within the artery wall. The presence of intraplaque haemorrhage, where the blood leaks into the artery wall following a rupture, has also been visualised through the detection of iron. Several clinically important bone and joint problems have been investigated including: site-specific bone mineral density, bone-metal interfaces (spectral CT reduces metal artefacts), cartilage health using ionic contrast media, gout and pseudogout crystals, and microfracture assessment using nanoparticles. Metallic nanoparticles have been investigated as a cellular marker visible in MARS images. Cell lines of different cancer types (Raji and SK-BR3) were incubated with monoclonal antibody-functionalised AuNPs (Herceptin and Rituximab). We identified and quantified the labelled AuNPs demonstrating that Herceptin-functionalised AuNPs bound to SK-BR3 breast cancer cells but not to the Raji lymphoma cells. In vivo human images show the bone microstructure. Fat, water, and calcium concentrations are quantifiable

Medipix3RX neutron camera for ambient radiation measurements in the CMS cavern

We describe a CMS-Medipix3RX neutron camera developed by adapting and modifying detector readout electronics developed at the University of Canterbury. The readout electronics are part of the MARS x-ray scanner used for imaging applications [1]. The neutron cameras will be used for the precise evaluation of complex radiation fields in and around the Compact Muon Solenoid (CMS) detector on the Large Hadron Collider (LHC) at CERN. This evaluation will help to ascertain the performance of various sub-systems installed in the cavern as well as to predict their useful lifetimes. Medipix3RX detector can deliver real-time images of the flux and spectral composition of different particles, including slow and fast neutrons. In this neutron camera, slow neutrons are detected using a lithium fluoride conversion layer and fast neutrons by a polypropylene layer. These produce charged particles, which are then detected by a semiconductor sensor material, silicon. We modelled the mixed-field radiation at seven Medipix detector locations in the cavern by scoring the particle travelling through the detector location using FOCUS, a Monte-Carlo simulation tool, analysing the energy as well as their angular distributions of neutrons from the result of simulations.A good agreement was observed between the average flux predicted by standard FLUKA methods and those obtained from FOCUS output data integrated over time. Also, the response function of the Medipix detectors was modelled and simulated for different thicknesses of the neutron conversion layer. An algorithm was developed for track reconstruction and recognition using cluster analysis techniques. This labels and determines the density of clusters formed by groups of particles. The CMS-Medipix detectors with their conversion layers were calibrated in the CERN neutron facility and installed in the CMS cavern at the beginning of 2018. This paper discusses the calibration of the detector installation and presents early results of radiation measurements from 2018 run