A simple, clinically usable whole-body MRI system of joint assessment in adolescents and young people with juvenile idiopathic arthritis.

OBJECTIVES: To introduce and evaluate a simple method for assessing joint inflammation and structural damage on whole-body MRI (WBMRI) in juvenile idiopathic arthritis (JIA), which is usable in clinical practice. METHODS: The proposed system utilises post-contrast Dixon WBMRI scans. Joints are assessed for synovitis (grade 0-2) and structural damage (present/absent) at 81 sites. The synovitis grading is based on features including above-normal intensity synovial enhancement, synovial hypertrophy, joint effusion, subarticular bone marrow oedema and peri-articular soft tissue oedema.This system was evaluated in a prospective study of 60 young people (47 patients with JIA and 13 controls with non-inflammatory musculoskeletal pain) who underwent a WBMRI. Three readers (blinded to diagnosis) independently reviewed all images and re-reviewed 20 individual scans. The intra- and inter-reader overall agreement (OA) and the intra- and inter-reader Gwet's agreement coefficients 2 (GAC2) were measured for the detection of a) participants with ≥1 joint with inflammation or structural damage and b) joint inflammation or structural damage for each joint. RESULTS: The inter-reader OA for detecting patients with ≥1 joint with inflammation, defined as grade 2 synovitis (G2), and ≥1 joint with structural damage were 80% and 73%, respectively. The intra-reader OA for readers 1-3 were 80-90% and 75-90% respectively. The inter-reader OA and GAC2 for joint inflammation (G2) at each joint were both ≥85% for all joints but were lower if grade 1 synovitis was included as positive. CONCLUSION: The intra- and inter-reader agreements of this WBMRI assessment system are adequate for assessing objective joint inflammation and damage in JIA.

Detection of inflammation by whole-body MRI in young people with juvenile idiopathic arthritis.

OBJECTIVES: To assess the frequency of joint inflammation detected by whole-body MRI (WBMRI) in young people (YP) with JIA and controls, and to determine the relationship between WBMRI-detected inflammation and clinical findings. METHODS: YP aged 14-24 years, with JIA (patients) or arthralgia without JIA (controls), recruited from one centre, underwent a WBMRI scan after formal clinical assessment. Consensus between at least two of the three independent radiologists was required to define inflammation and damage on WBMRI, according to predefined criteria. YP with JIA were deemed clinically active as per accepted definitions. The proportions of YP with positive WBMRI scans for joint inflammation (≥1 inflamed joint) as well as serum biomarkers were compared between active vs inactive JIA patients and controls. RESULTS: Forty-seven YP with JIA (25 active and 22 inactive patients) and 13 controls were included. WBMRI detected joint inflammation in 60% (28/47) patients with JIA vs 15% (2/13) controls (difference: 44%, 95% CI 20%, 68%). More active than inactive JIA patients had WBMRI-detected inflammation [76% (19/25) vs 41% (9/22), difference: 35% (95% CI 9%, 62%)], and this was associated with a specific biomarker signature. WBMRI identified inflammation in ≥ 1 clinically inactive joint in 23/47 (49%) patients (14/25 active vs 9/22 inactive JIA patients). CONCLUSIONS: WBMRI's validity in joint assessment was demonstrated by the higher frequency of inflammation in JIA patients vs controls, and in active vs inactive JIA patients. WBMRI found unsuspected joint inflammation in 49% YP with JIA, which needs further investigation of potential clinical implications.

Melatonin reduces brain injury following inflammation-amplified hypoxia-ischemia in a translational newborn piglet study of neonatal encephalopathy.

There is a need to develop therapies for neonatal encephalopathy (NE) in low- and middle-income countries (LMICs) where the burden of disease is greatest and therapeutic hypothermia (HT) is not effective. We aimed to assess the efficacy of melatonin following inflammation-amplified hypoxia-ischaemia (IA-HI) in the newborn piglet. The IA-HI model accounts for the contribution of infection/inflammation in this setting and HT is not cytoprotective. We hypothesised that intravenous melatonin (5% ethanol, at 20 mg/kg over 2 h at 1 h after HI + 10 mg/kg/12 h between 24 and 60 h) is safe and associated with: (i) reduction in magnetic resonance spectroscopy lactate/N-acetylaspartate (MRS Lac/sNAA); (ii) preservation of phosphorus MRS phosphocreatine/phosphate exchange pool (PCr/Epp); (iii) improved aEEG/EEG recovery and (iv) cytoprotection on immunohistochemistry. Male and female piglets underwent IA-HI by carotid artery occlusion and reduction in FiO2 to 6% at 4 h into Escherichia coli lipopolysaccharide sensitisation (2 µg/kg bolus + 1 µg/kg/h over 12 h). At 1 h after IA-HI, piglets were randomised to HI-saline (n = 12) or melatonin (n = 11). There were no differences in insult severity between groups. Target melatonin levels (15-30 mg/L) were achieved within 3 h and blood ethanol levels were <0.25 g/L. At 60 h, compared to HI-saline, melatonin was associated with a reduction of 0.197 log10 units (95% CrI [-0.366, -0.028], Pr(sup) 98.8%) in basal-ganglia and thalamic Lac/NAA, and 0.257 (95% CrI [-0.676, 0.164], Pr(sup) 89.3%) in white matter Lac/NAA. PCr/Epp was higher in melatonin versus HI-saline (Pr(sup) 97.6%). Melatonin was associated with earlier aEEG/EEG recovery from 19 to 24 h (Pr(sup) 95.4%). Compared to HI-saline, melatonin was associated with increased NeuN+ cell density (Pr(sup) 99.3%) across five of eight regions and reduction in TUNEL-positive cell death (Pr(sup) 89.7%). This study supports the translation of melatonin to early-phase clinical trials. Melatonin is protective following IA-HI where HT is not effective. These data guide the design of future dose-escalation studies in the next phase of the translational pipeline.

MAGORINO: Magnitude-only fat fraction and R* 2 estimation with Rician noise modeling.

PURPOSE: Magnitude-based fitting of chemical shift-encoded data enables proton density fat fraction (PDFF) and R 2 * $$ {R}_2^{\ast } $$ estimation where complex-based methods fail or when phase data are inaccessible or unreliable. However, traditional magnitude-based fitting algorithms do not account for Rician noise, creating a source of bias. To address these issues, we propose an algorithm for magnitude-only PDFF and R 2 * $$ {R}_2^{\ast } $$ estimation with Rician noise modeling (MAGORINO). METHODS: Simulations of multi-echo gradient-echo signal intensities are used to investigate the performance and behavior of MAGORINO over the space of clinically plausible PDFF, R 2 * $$ {R}_2^{\ast } $$ , and SNR values. Fitting performance is assessed through detailed simulation, including likelihood function visualization, and in a multisite, multivendor, and multi-field-strength phantom data set and in vivo. RESULTS: Simulations show that Rician noise-based magnitude fitting outperforms existing Gaussian noise-based fitting and reveals two key mechanisms underpinning the observed improvement. First, the likelihood functions exhibit two local optima; Rician noise modeling increases the chance that the global optimum corresponds to the ground truth. Second, when the global optimum corresponds to ground truth for both noise models, the optimum from Rician noise modeling is closer to ground truth. Multisite phantom experiments show good agreement of MAGORINO PDFF with reference values, and in vivo experiments replicate the performance benefits observed in simulation. CONCLUSION: The MAGORINO algorithm reduces Rician noise-related bias in PDFF and R 2 * $$ {R}_2^{\ast } $$ estimation, thus addressing a key limitation of existing magnitude-only fitting methods. Our results offer insight into the importance of the noise model for selecting the correct optimum when multiple plausible optima exist.

A multiparametric alternative to short inversion-time inversion recovery for imaging inflammation: T2water and fat fraction measurement using chemical shift-encoded turbo spin-echo MRI.

PURPOSE: Short-inversion-time inversion-recovery MRI is used widely for imaging bone and soft-tissue inflammation in rheumatic inflammatory diseases, but there is no widely available quantitative equivalent of this sequence. This limits our ability to objectively assess inflammation and distinguish it from other processes. To address this, we investigate the use of the widely available Dixon turbo spin echo (TSE Dixon) sequence as a practical approach to simultaneous water-specific T2 (T2water ) and fat fraction (FF) measurement. METHODS: We use a series of TSE Dixon acquisitions with varying effective TEs (TEeff ) to quantify T2water and FF. The validity of this approach is assessed in a series of phantom and in vivo experiments, with reference values provided by Carr-Purcell-Meiboom-Gill acquisitions, MRS, and phantoms. The effect of inflammation on parameter values is evaluated in patients with spondyloarthritis. RESULTS: The T2water estimates obtained from TSE Dixon were accurate compared with the reference values from Carr-Purcell-Meiboom-Gill and spectroscopy in both fat-free environments and in the presence of fat. FF measurements with T2water correction from TSE Dixon were accurate from 0% to 60% FF and were not confounded by T2water variations. In vivo imaging produced good quality images that were artifact free, produced plausible T2 values, separating and quantifying the effect of inflammation on T2water and FF. CONCLUSION: The T2water and FF measurements based on TSE Dixon with effective TE increments are accurate over a range of T2 and FF values and could provide a widely available quantitative alternative to the short-inversion-time inversion-recovery sequence for imaging inflamed tissue.

Quantification of Prostate Cancer Metabolism Using 3D Multiecho bSSFP and Hyperpolarized [1-13 C] Pyruvate: Metabolism Differs Between Tumors of the Same Gleason Grade.

BACKGROUND: Three-dimensional (3D) multiecho balanced steady-state free precession (ME-bSSFP) has previously been demonstrated in preclinical hyperpolarized (HP) 13 C-MRI in vivo experiments, and it may be suitable for clinical metabolic imaging of prostate cancer (PCa). PURPOSE: To validate a signal simulation framework for the use of sequence parameter optimization. To demonstrate the feasibility of ME-bSSFP for HP 13 C-MRI in patients. To evaluate the metabolism in PCa measured by ME-bSSFP. STUDY TYPE: Retrospective single-center cohort study. PHANTOMS/POPULATION: Phantoms containing aqueous solutions of [1-13 C] lactate (2.3 M) and [13 C] urea (8 M). Eight patients (mean age 67 ± 6 years) with biopsy-confirmed Gleason 3 + 4 (n = 7) and 4 + 3 (n = 1) PCa. FIELD STRENGTH/SEQUENCES: 1 H MRI at 3 T with T2 -weighted turbo spin-echo sequence used for spatial localization and spoiled dual gradient-echo sequence used for B0 -field measurement. ME-bSSFP sequence for 13 C MR spectroscopic imaging with retrospective multipoint IDEAL metabolite separation. ASSESSMENT: The primary endpoint was the analysis of pyruvate-to-lactate conversion in PCa and healthy prostate regions of interest (ROIs) using model-free area under the curve (AUC) ratios and a one-directional kinetic model (kP ). The secondary objectives were to investigate the correlation between simulated and experimental ME-bSSFP metabolite signals for HP 13 C-MRI parameter optimization. STATISTICAL TESTS: Pearson correlation coefficients with 95% confidence intervals and paired t-tests. The level of statistical significance was set at P < 0.05. RESULTS: Strong correlations between simulated and empirical ME-bSSFP signals were found (r > 0.96). Therefore, the simulation framework was used for sequence optimization. Whole prostate metabolic HP 13 C-MRI, observing the conversion of pyruvate into lactate, with a temporal resolution of 6 seconds was demonstrated using ME-bSSFP. Both assessed metrics resulted in significant differences between PCa (mean ± SD) (AUC = 0.33 ± 012, kP  = 0.038 ± 0.014) and healthy (AUC = 0.15 ± 0.10, kP  = 0.011 ± 0.007) ROIs. DATA CONCLUSION: Metabolic HP 13 C-MRI in the prostate using ME-bSSFP allows for differentiation between aggressive PCa and healthy tissue. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Early assessment of injury with optical markers in a piglet model of neonatal encephalopathy.

BACKGROUND: Opportunities for adjunct therapies with cooling in neonatal encephalopathy are imminent; however, robust biomarkers of early assessment are lacking. Using an optical platform of broadband near-infrared spectroscopy and diffuse correlation spectroscopy to directly measure mitochondrial metabolism (oxCCO), oxygenation (HbD), cerebral blood flow (CBF), we hypothesised optical indices early (1-h post insult) after hypoxia-ischaemia (HI) predicts insult severity and outcome. METHODS: Nineteen newborn large white piglets underwent continuous neuromonitoring as controls or following moderate or severe HI. Optical indices were expressed as mean semblance (phase difference) and coherence (spectral similarity) between signals using wavelet analysis. Outcome markers included the lactate/N-acetyl aspartate (Lac/NAA) ratio at 6 h on proton MRS and TUNEL cell count. RESULTS: CBF-HbD semblance (cerebrovascular dysfunction) correlated with BGT and white matter (WM) Lac/NAA (r2 = 0.46, p = 0.004, r2 = 0.45, p = 0.004, respectively), TUNEL cell count (r2 = 0.34, p = 0.02) and predicted both initial insult (r2 = 0.62, p = 0.002) and outcome group (r2 = 0.65 p = 0.003). oxCCO-HbD semblance (cerebral metabolic dysfunction) correlated with BGT and WM Lac/NAA (r2 = 0.34, p = 0.01 and r2 = 0.46, p = 0.002, respectively) and differentiated between outcome groups (r2 = 0.43, p = 0.01). CONCLUSION: Optical markers of both cerebral metabolic and vascular dysfunction 1 h after HI predicted injury severity and subsequent outcome in a pre-clinical model. IMPACT: This study highlights the possibility of using non-invasive optical biomarkers for early assessment of injury severity following neonatal encephalopathy, relating to the outcome. Continuous cot-side monitoring of these optical markers can be useful for disease stratification in the clinical population and for identifying infants who might benefit from future adjunct neuroprotective therapies beyond cooling.

Hypothermia is not therapeutic in a neonatal piglet model of inflammation-sensitized hypoxia-ischemia.

BACKGROUND: Perinatal inflammation combined with hypoxia-ischemia (HI) exacerbates injury in the developing brain. Therapeutic hypothermia (HT) is standard care for neonatal encephalopathy; however, its benefit in inflammation-sensitized HI (IS-HI) is unknown. METHODS: Twelve newborn piglets received a 2 µg/kg bolus and 1 µg/kg/h infusion over 52 h of Escherichia coli lipopolysaccharide (LPS). HI was induced 4 h after LPS bolus. After HI, piglets were randomized to HT (33.5 °C 1-25 h after HI, n = 6) or normothermia (NT, n = 6). Amplitude-integrated electroencephalogram (aEEG) was recorded and magnetic resonance spectroscopy (MRS) was acquired at 24 and 48 h. At 48 h, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive brain cell death, microglial activation/proliferation, astrogliosis, and cleaved caspase-3 (CC3) were quantified. Hematology and plasma cytokines were serially measured. RESULTS: Two HT piglets died. aEEG recovery, thalamic and white matter MRS lactate/N-acetylaspartate, and TUNEL-positive cell death were similar between groups. HT increased microglial activation in the caudate, but had no other effect on glial activation/proliferation. HT reduced CC3 overall. HT suppressed platelet count and attenuated leukocytosis. Cytokine profile was unchanged by HT. CONCLUSIONS: We did not observe protection with HT in this piglet IS-HI model based on aEEG, MRS, and immunohistochemistry. Immunosuppressive effects of HT and countering neuroinflammation by LPS may contribute to the observed lack of HT efficacy. Other immunomodulatory strategies may be more effective in IS-HI. IMPACT: Acute infection/inflammation is known to exacerbate perinatal brain injury and can worsen the outcomes in neonatal encephalopathy. Therapeutic HT is the current standard of care for all infants with NE, but the benefit in infants with coinfection/inflammation is unknown. In a piglet model of inflammation (LPS)-sensitized HI, we observed no evidence of neuroprotection with cooling for 24 h, based on our primary outcome measures: aEEG, MRS Lac/NAA, and histological brain cell death. Additional neuroprotective agents, with beneficial immunomodulatory effects, require exploration in IS-HI models.

Liver perfusion MRI in a rodent model of cirrhosis: Agreement with bulk-flow phase-contrast MRI and noninvasive evaluation of inflammation in chronic liver disease using flow-sensitive alternating inversion recovery arterial spin labelling and tissue T1.

Noninvasive measurements of liver perfusion and fibrosis in cirrhotic small animals can help develop treatments for haemodynamic complications of liver disease. Here, we measure liver perfusion in cirrhotic rodents using flow-sensitive alternating inversion recovery arterial spin labelling (FAIR ASL), evaluating agreement with previously validated caval subtraction phase-contrast magnetic resonance imaging (PCMRI) total liver blood flow (TLBF). Baseline differences in cirrhotic rodents and the haemodynamic effects of acute inflammation were investigated using FAIR ASL and tissue T1. Sprague-Dawley rats (nine bile duct ligated [BDL] and ten sham surgery controls) underwent baseline hepatic FAIR ASL with T1 measurement and caval subtraction PCMRI (with two-dimensional infra-/supra-hepatic inferior vena caval studies), induction of inflammation with intravenous lipopolysaccharide (LPS) and repeat liver FAIR ASL with T1 measurement after ~90 minutes. The mean difference between FAIR ASL hepatic perfusion and caval subtraction PCMRI TLBF was -51 ± 30 ml/min/100 g (Bland-Altman 95% limits-of-agreement ±258 ml/min/100 g). The FAIR ASL coefficient of variation was smaller than for caval subtraction PCMRI (29.3% vs 50.1%; P = .03). At baseline, FAIR ASL liver perfusion was lower in BDL rats (199 ± 32 ml/min/100 g vs sham 316 ± 24 ml/min/100 g; P = .01) but liver T1 was higher (BDL 1533 ± 50 vs sham 1256 ± 18 ms; P = .0004). Post-LPS FAIR ASL liver perfusion response differences were observed between sham/BDL rats (P = .02), approaching significance in sham (+78 ± 33 ml/min/100 g; P = .06) but not BDL rats (-49 ± 40 ml/min/100 g; P = .47). Post-LPS differences in liver tissue T1 were nonsignificant (P = .35). FAIR ASL hepatic perfusion and caval subtraction PCMRI TLBF agreement was modest, with significant baseline FAIR ASL liver perfusion and tissue T1 differences in rodents with advanced cirrhosis compared with controls. Following inflammatory stress, differences in hepatic perfusion response were detected between cirrhotic/control animals, but liver T1 was unaffected. Findings underline the potential of FAIR ASL in the assessment of vasoactive treatments for patients with chronic liver disease and inflammation.

Human umbilical cord mesenchymal stromal cells as an adjunct therapy with therapeutic hypothermia in a piglet model of perinatal asphyxia.

BACKGROUND: With therapeutic hypothermia (HT) for neonatal encephalopathy, disability rates are reduced, but not all babies benefit. Pre-clinical rodent studies suggest mesenchymal stromal cells (MSCs) augment HT protection. AIMS: The authors studied the efficacy of intravenous (IV) or intranasal (IN) human umbilical cord-derived MSCs (huMSCs) as adjunct therapy to HT in a piglet model. METHODS: A total of 17 newborn piglets underwent transient cerebral hypoxia-ischemia (HI) and were then randomized to (i) HT at 33.5°C 1-13 h after HI (n = 7), (ii) HT+IV huMSCs (30 × 106 cells) at 24 h and 48 h after HI (n = 5) or (iii) HT+IN huMSCs (30 × 106 cells) at 24 h and 48 h after HI (n = 5). Phosphorus-31 and hydrogen-1 magnetic resonance spectroscopy (MRS) was performed at 30 h and 72 h and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells and oligodendrocytes quantified. In two further piglets, 30 × 106 IN PKH-labeled huMSCs were administered. RESULTS: HI severity was similar between groups. Amplitude-integrated electroencephalogram (aEEG) recovery was more rapid for HT+IN huMSCs compared with HT from 25 h to 42 h and 49 h to 54 h (P ≤ 0.05). MRS phosphocreatine/inorganic phosphate was higher on day 2 in HT+IN huMSCs than HT (P = 0.035). Comparing HT+IN huMSCs with HT and HT+IV huMSCs, there were increased OLIG2 counts in hippocampus (P = 0.011 and 0.018, respectively), internal capsule (P = 0.013 and 0.037, respectively) and periventricular white matter (P = 0.15 for IN versus IV huMSCs). Reduced TUNEL-positive cells were seen in internal capsule with HT+IN huMSCs versus HT (P = 0.05). PKH-labeled huMSCs were detected in the brain 12 h after IN administration. CONCLUSIONS: After global HI, compared with HT alone, the authors saw beneficial effects of HT+IN huMSCs administered at 24 h and 48 h (30 × 106 cells/kg total dose) based on more rapid aEEG recovery, improved 31P MRS brain energy metabolism and increased oligodendrocyte survival at 72 h.

Haemodynamic changes in cirrhosis following terlipressin and induction of sepsis-a preclinical study using caval subtraction phase-contrast and cardiac MRI.

OBJECTIVES: Effects of liver disease on portal venous (PV), hepatic arterial (HA), total liver blood flow (TLBF), and cardiac function are poorly understood. Terlipressin modulates PV flow but effects on HA, TLBF, and sepsis/acute-on-chronic liver failure (ACLF)-induced haemodynamic changes are poorly characterised. In this study, we investigated the effects of terlipressin and sepsis/ACLF on hepatic haemodynamics and cardiac function in a rodent cirrhosis model using caval subtraction phase-contrast (PC) MRI and cardiac cine MRI. METHODS: Sprague-Dawley rats (n = 18 bile duct-ligated (BDL), n = 16 sham surgery controls) underwent caval subtraction PCMRI to estimate TLBF and HA flow and short-axis cardiac cine MRI for systolic function at baseline, following terlipressin and lipopolysaccharide (LPS) infusion, to model ACLF. RESULTS: All baseline hepatic haemodynamic/cardiac systolic function parameters (except heart rate and LV mass) were significantly different in BDL rats. Following terlipressin, baseline PV flow (sham 181.4 ± 12.1 ml/min/100 g; BDL 68.5 ± 10.1 ml/min/100 g) reduced (sham - 90.3 ± 11.1 ml/min/100 g, p < 0.0001; BDL - 31.0 ± 8.0 ml/min/100 g, p = 0.02), sham baseline HA flow (33.0 ± 11.3 ml/min/100 g) increased (+ 92.8 ± 21.3 ml/min/100 g, p = 0.0003), but BDL baseline HA flow (83.8 ml/min/100 g) decreased (- 34.4 ± 7.5 ml/min/100 g, p = 0.11). Sham baseline TLBF (214.3 ± 16.7 ml/min/100 g) was maintained (+ 2.5 ± 14.0 ml/min/100 g, p > 0.99) but BDL baseline TLBF (152.3 ± 18.7 ml/min/100 g) declined (- 65.5 ± 8.5 ml/min/100 g, p = 0.0004). Following LPS, there were significant differences between cohort and change in HA fraction (p = 0.03) and TLBF (p = 0.01) with BDL baseline HA fraction (46.2 ± 4.6%) reducing (- 20.9 ± 7.5%, p = 0.03) but sham baseline HA fraction (38.2 ± 2.0%) remaining unchanged (+ 2.9 ± 6.1%, p > 0.99). Animal cohort and change in systolic function interactions were significant only for heart rate (p = 0.01) and end-diastolic volume (p = 0.03). CONCLUSIONS: Caval subtraction PCMRI and cardiac MRI in a rodent model of cirrhosis demonstrate significant baseline hepatic haemodynamic/cardiac differences, failure of the HA buffer response post-terlipressin and an altered HA fraction response in sepsis, informing potential translation to ACLF patients. KEY POINTS: Caval subtraction phase-contrast and cardiac MRI demonstrate: • Significant differences between cirrhotic/non-cirrhotic rodent hepatic blood flow and cardiac systolic function at baseline. • Failure of the hepatic arterial buffer response in cirrhotic rodents in response to terlipressin. • Reductions in hepatic arterial flow fraction in the setting of acute-on-chronic liver failure.

Multimodal Measurements of Brain Tissue Metabolism and Perfusion in a Neonatal Model of Hypoxic-Ischaemic Injury.

This is the first multimodal study of cerebral tissue metabolism and perfusion post-hypoxic-ischaemic (HI) brain injury using broadband near-infrared spectroscopy (bNIRS), diffuse correlation spectroscopy (DCS), positron emission tomography (PET) and magnetic resonance spectroscopy (MRS). In seven piglet preclinical models of neonatal HI, we measured cerebral tissue saturation (StO2), cerebral blood flow (CBF), cerebral oxygen metabolism (CMRO2), changes in the mitochondrial oxidation state of cytochrome c oxidase (oxCCO), cerebral glucose metabolism (CMRglc) and tissue biochemistry (Lac+Thr/tNAA). At baseline, the parameters measured in the piglets that experience HI (not controls) were 64 ± 6% StO2, 35 ± 11 ml/100 g/min CBF and 2.0 ± 0.4 µmol/100 g/min CMRO2. After HI, the parameters measured were 68 ± 6% StO2, 35 ± 6 ml/100 g/min CBF, 1.3 ± 0.1 µmol/100 g/min CMRO2, 0.4 ± 0.2 Lac+Thr/tNAA and 9.5 ± 2.0 CMRglc. This study demonstrates the capacity of a multimodal set-up to interrogate the pathophysiology of HIE using a combination of optical methods, MRS, and PET.

Improved fetal blood oxygenation and placental estimated measurements of diffusion-weighted MRI using data-driven Bayesian modeling.

PURPOSE: Motion correction in placental DW-MRI is challenging due to maternal breathing motion, maternal movements, and rapid intensity changes. Parameter estimates are usually obtained using least-squares methods for voxel-wise fitting; however, they typically give noisy estimates due to low signal-to-noise ratio. We introduce a model-driven registration (MDR) technique which incorporates a placenta-specific signal model into the registration process, and we present a Bayesian approach for Diffusion-rElaxation Combined Imaging for Detailed placental Evaluation model to obtain individual and population trends in estimated parameters. METHODS: MDR exploits the fact that a placenta signal model is available and thus we incorporate it into the registration to generate a series of target images. The proposed registration method is compared to a pre-existing method used for DCE-MRI data making use of principal components analysis. The Bayesian shrinkage prior (BSP) method has no user-defined parameters and therefore measures of parameter variation in a region of interest are determined by the data alone. The MDR method and the Bayesian approach were evaluated on 10 control 4D DW-MRI singleton placental data. RESULTS: MDR method improves the alignment of placenta data compared to the pre-existing method. It also shows a further reduction of the residual error between the data and the fit. BSP approach showed higher precision leading to more clearly apparent spatial features in the parameter maps. Placental fetal oxygen saturation (FO2 ) showed a negative linear correlation with gestational age. CONCLUSIONS: The proposed pipeline provides a robust framework for registering DW-MRI data and analyzing longitudinal changes of placental function.

An information-based comparison of diffusion attenuation models in normal and inflamed bone marrow.

Diffusion-weighted imaging has received attention as a method for characterizing inflammatory exudates in bone marrow in immune-mediated inflammatory diseases and reveals an increase in diffusivity in regions of bone marrow oedema. Various models of diffusion attenuation have been investigated but the model providing the best description of tissue pathophysiology in regions of marrow oedema is unknown. Determining the most appropriate model is an important step towards protocol optimization and the development of a robust and clinically useful method. We aimed to determine which of three candidate models of diffusion attenuation most accurately describes the acquired signal from normal and inflamed bone marrow. 11 subjects with spondyloarthritis and evidence of active inflammation (ie bone marrow oedema) on MRI and 17 patients with no evidence of active inflammation underwent diffusion-weighted imaging of the sacroiliac joints (b-values 0, 50, 100, 300 and 600 s/mm2 ). Monoexponential, intravoxel incoherent motion (IVIM) and kurtosis models were fitted to the acquired signal from regions of interest in areas of bone marrow oedema and normal marrow. The three models were compared in terms of sum of squared error and information content (corrected Akaike information criterion). Model parameters were compared between regions of bone marrow oedema and regions of normal marrow. f the three models investigated, the IVIM model provided the best description of the signal over the 0-600 s/mm2 range across normal and inflamed bone marrow. There was a particular advantage of the IVIM model in normal marrow, where it was best able to capture the pronounced fast diffusion component observed in several cases. However, IVIM and kurtosis effects both became smaller and the signal behaviour became closer to monoexponential in the presence of bone marrow oedema. Our data suggest that increases in Dtissue (in the IVIM framework) might account for the reduced deviation from monoexponential behaviour in oedematous bone.

Practical Approaches to Bone Marrow Fat Fraction Quantification Across Magnetic Resonance Imaging Platforms.

BACKGROUND: Quantification of fat by proton density fat fraction (PDFF) measurements may be valuable for the quantification and follow-up of pathology in multicenter clinical trials and routine practice. However, many centers do not have access to specialist methods (such as chemical shift imaging) for PDFF measurement. This is a barrier to more widespread trial implementation. PURPOSE/HYPOTHESIS: To determine the agreement between fat fraction (FF) measurements derived from 1) basic vendor-supplied sequences, 2) basic sequences with offline correction, and 3) specialist vendor-supplied methods. STUDY TYPE: Prospective. POPULATION: Two substudies with ten and five healthy volunteers. FIELD STRENGTH/SEQUENCE: Site A: mDixon Quant (Philips 3T Ingenia); Site B: IDEAL and FLEX (GE 1.5T Optima MR450W); Site C: DIXON, with additional 5-echo gradient echo acquisition for offline correction (Siemens 3T Skyra); Site D: DIXON, with additional VIBE acquisitions for offline correction (Siemens 1.5T Avanto). The specialist method at site A was used as a standard to compare to the basic methods at sites B, C, and D. ASSESSMENT: Regions of interest were placed on areas of subchondral bone on FF maps from the various methods in each volunteer. STATISTICAL TESTS: Relationships between FF measurements from the various sites and Dixon methods were assessed using Bland-Altman analysis and linear regression. RESULTS: Basic methods consisting of IDEAL, LAVA FLEX, and DIXON produced FF values that were linearly related to reference FF values (P < 0.0001), but produced mean biases of up to 10%. Offline correction produced a significant reduction in bias in both substudies (P < 0.001). DATA CONCLUSION: FF measurements derived using basic vendor-supplied methods are strongly linearly related with those derived using specialist methods but produce a bias of up to 10%. A simple offline correction that is accessible even when the scanner has only basic sequence options can significantly reduce bias. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2020;52:298-306.

Histographic analysis of oedema and fat in inflamed bone marrow based on quantitative MRI.

OBJECTIVE: To demonstrate proof-of-concept for a quantitative MRI method using histographic analysis to assess bone marrow oedema and fat metaplasia in the sacroiliac joints. MATERIALS AND METHODS: Fifty-three adolescents aged 12-23 with known or suspected sacroiliitis were prospectively recruited and underwent quantitative MRI (qMRI) scans, consisting of chemical shift-encoded (at 3 T) and diffusion-weighted imaging (at 1.5 T), plus conventional MRI (at 1.5 T) and clinical assessment. qMRI scans produced proton-density fat fraction (PDFF) and apparent diffusion coefficient (ADC) maps of the sacroiliac joints (SIJs), which were analysed using an in-house software tool enabling partially automated ROI definition and histographic analysis. Logistic regression and receiver operating characteristic (ROC) analyses assessed the predictive performance of ADC- and PDFF-based parameters in identifying active inflammation (oedema) and structural damage (fat metaplasia). RESULTS: ADC-based parameters were associated with increased odds of oedema (all p < 0.05); ROC-AUC was higher for histographic parameters representing the upper end of the ADC distribution than for simple averages. Similarly, PDFF-based parameters were associated with increased odds of fat metaplasia (all p < 0.05); ROC area-under-the-curve was higher for histographic parameters representing the upper end of the PDFF distribution than for simple averages. Both ADC- and PDFF-based histographic parameters demonstrated excellent inter- and intra-observer agreement (ICC > 0.9). CONCLUSIONS: ADC-based parameters can differentiate patients with bone marrow oedema from those without, whilst PDFF-based parameters can differentiate patients with fat metaplasia from those without. Histographic analysis might improve performance compared with simple averages such as the mean and median and offers excellent agreement within and between observers. KEY POINTS: • Quantitative MRI with histographic analysis can identify bone marrow oedema (an active inflammatory lesion) and fat metaplasia (a 'chronic' inflammatory lesion) in patients with spondyloarthritis. • The use of histographic analysis might improve the performance of quantitative MRI for detecting bone marrow oedema and fat metaplasia compared with simple averages such as the mean and median. • Bone marrow oedema and fat metaplasia are known to be of diagnostic and prognostic significance, and the proposed method could support clinical decisions around biologic (and other) therapies in spondyloarthritis.

Digging our own grave: A Marxian consideration of formal education as a destructive enterprise.

The negative impact of human activity has been known throughout history. The epic tale of Gilgamesh, Koranic and biblical texts all make clear the potential that humans have to destroy the world in which they live. Climate breakdown, biodiversity collapse and zoonotic diseases such as COVID-19 have also been predicted well in advance. The "wicked problem" (dilemma) to address is: "Why do humans still persist in 'digging their own graves' by damaging the environments they inhabit?" The author of this article argues that the motive to engage in education can be understood as an ancient human response to ecological change. This has led to a range of behaviours, including teaching and learning that serve only to further disrupt the relationship between the human and the "more-than-human" world. When formal education structures are viewed through a Marxian lens, it soon becomes clear that the unsustainable impact of humans on the more-than-human is the result of capitalist entrapment. Karl Marx's proposition of a metabolic rift helps make sense of the nonsensical, while a discussion of use and exchange value shows how formal education has become ensnared in the mire of capitalist productivity, concealing from view the educationally-induced destruction of planetary systems that support human flourishing. Fortunately, a more sustainable and sustaining education is possible - this is an education for a "long-life" that is no longer influenced by the machinery of neoliberalism.

Nous creusons notre propre tombe : une réflexion marxiste sur l'éducation formelle considérée comme une entreprise destructrice ­ L'impact négatif de l'humanité a été constaté à travers l'histoire tout entière. L'épopée de Gilgamesh ou encore les textes du Coran et de la Bible révèlent la propension de l'homme à détruire le monde dans lequel il vit. Le dérèglement climatique, l'effondrement de la biodiversité et les zoonoses comme la COVID-19 avait été prédits depuis bien longtemps. Le dilemme qui se pose quand on aborde cette question : « Pourquoi les hommes persistent-ils à 'creuser leur propre tombe' en portant atteinte à leur propre environnement ? ¼ L'auteur de cet article affirme que l'on voit dans la raison qui pousse à s'instruire une réponse humaine historique au changement écologique, ce qui a entraîné l'apparition de tout un ensemble de comportements, y compris l'enseignement et l'apprentissage qui servent juste à perturber encore plus les rapports entre le monde humain et le monde « au-delà de l'humain ¼. En observant les structures de l'éducation formelle à travers le prisme marxiste, on s'aperçoit rapidement que l'impact préjudiciable des humains sur le monde au-delà de l'humain est le résultat d'un piégeage capitaliste. La notion de rupture métabolique proposée par Karl Marx aide à comprendre cette absurdité, tandis qu'un débat sur la valeur d'usage et d'échange illustre comment l'éducation a été pris au piège du bourbier de la productivité capitaliste, dissimulant la destruction, induite par l'éducation, des systèmes planétaires qui soutiennent l'épanouissement de l'être humain. Heureusement, une éducation plus durable et plus nourrissante est possible ­ une éducation pour une « longue vie ¼ qui ne serait plus influencée par les rouages du néolibéralisme.

Melatonin as an adjunct to therapeutic hypothermia in a piglet model of neonatal encephalopathy: A translational study.

Therapeutic hypothermia is only partially protective for neonatal encephalopathy; there is an urgent need to develop treatments that augment cooling. Our objective was to assess safety, efficacy and pharmacokinetics of 5 and 15 mg/kg/24 h melatonin (proprietary formulation) administered at 2 h and 26 h after hypoxia-ischemia (HI) with cooling in a piglet model. Following moderate cerebral HI, 30 piglets were eligible and randomized to: i) Hypothermia (33.5 °C, 2-26 h) and vehicle (HT + V;n = 13); b) HT and 5 mg/kg melatonin over 6 h at 2 h and 26 h after HI (HT + Mel-5;n = 4); c) HT and 15 mg/kg melatonin over 6 h at 2 h and 26 h after HI (HT + Mel-15;n = 13). Intensive care was maintained for 48 h; brain MRS was acquired and cell death (TUNEL) evaluated at 48 h. Comparing HT + V with HT + Mel-5 and HT + Mel-15, there was no difference in blood pressure or inotropic support needed, brain Lactate/N Acetylaspartate at 24 h and 48 h was similar, ATP/phosphate pool was higher for HT + Mel-15 versus HT + V at 24 h (p = 0.038) but not 48 h. A localized reduction in TUNEL positive cell death was observed in the sensorimotor cortex in the 15 mg/kg melatonin group (HT + Mel-15 versus HT + V; p < 0.003) but not in the 5 mg/kg melatonin group (HT + Mel-5 versus HT + V; p = 0.808). Putative therapeutic melatonin levels were reached 8 h after HI (104 increase from baseline; ~15-30 mg/l). Mean ±â€¯SD peak plasma melatonin levels after the first infusion were 0.0014 ±â€¯0.0012 mg/l in the HT + V group, 3.97 ±â€¯1.53 mg/l in the HT + Mel-5 group and 16.8 ±â€¯8.3 mg/l in the HT + Mel-15 group. Protection was dose dependent; 15 mg/kg melatonin started 2 h after HI, given over 6 h, was well tolerated and augmented hypothermic protection in sensorimotor cortex. Earlier attainment of therapeutic plasma melatonin levels may optimize protection by targeting initial events of reperfusion injury. The time window for intervention with melatonin, as adjunct therapy with cooling, is likely to be narrow and should be considered in designing future clinical studies.

Association of bone mineral density and fat fraction with magnetic susceptibility in inflamed trabecular bone.

PURPOSE: To evaluate the relationship between bone mineral density (BMD) and magnetic susceptibility, and between proton density fat fraction and susceptibility, in inflamed trabecular bone. METHODS: Two different phantoms modeling the fat fraction (FF) and BMD values of healthy bone marrow and disease states were scanned using a multiecho gradient echo acquisition at 3T. After correction for fat-water chemical shift, susceptibility mapping was performed, and susceptibility measurements were compared with BMD and FF values using linear regression. Patients with spondyloarthritis were scanned using the same protocol, and susceptibility values were calculated in areas of inflamed bone (edema) and fat metaplasia, both before and after accounting for the contribution of fat to the total susceptibility. RESULTS: Susceptibility values in the phantoms were accurately described by a 2D linear function, with a negative correlation between BMD and susceptibility and a positive correlation between FF and susceptibility (adjusted R2 = 0.77; P = 3·10-5 ). In patients, significant differences in susceptibility were observed between fat metaplasia and normal marrow, but these differences were eliminated by removing the fat contribution to the total susceptibility. CONCLUSIONS: BMD and proton density fat fraction both influence the total susceptibility of bone marrow and failure to account for the fat contribution could lead to errors in BMD quantification. We propose a method for removing the fat contribution from the total susceptibility, based on the observed linear relationship between susceptibility and FF. In inflamed bone, the overall increase in susceptibility in areas of fat metaplasia is at least partly due to increased fat content.

Separating fetal and maternal placenta circulations using multiparametric MRI.

PURPOSE: The placenta is a vital organ for the exchange of oxygen, nutrients, and waste products between fetus and mother. The placenta may suffer from several pathologies, which affect this fetal-maternal exchange, thus the flow properties of the placenta are of interest in determining the course of pregnancy. In this work, we propose a new multiparametric model for placental tissue signal in MRI. METHODS: We describe a method that separates fetal and maternal flow characteristics of the placenta using a 3-compartment model comprising fast and slowly circulating fluid pools, and a tissue pool is fitted to overlapping multiecho T2 relaxometry and diffusion MRI with low b-values. We implemented the combined model and acquisition on a standard 1.5 Tesla clinical system with acquisition taking less than 20 minutes. RESULTS: We apply this combined acquisition in 6 control singleton placentas. Mean myometrial T2 relaxation time was 123.63 (±6.71) ms. Mean T2 relaxation time of maternal blood was 202.17 (±92.98) ms. In the placenta, mean T2 relaxation time of the fetal blood component was 144.89 (±54.42) ms. Mean ratio of maternal to fetal blood volume was 1.16 (±0.6), and mean fetal blood saturation was 72.93 (±20.11)% across all 6 cases. CONCLUSION: The novel acquisition in this work allows the measurement of histologically relevant physical parameters, such as the relative proportions of vascular spaces. In the placenta, this may help us to better understand the physiological properties of the tissue in disease.