Data Format Standardization and DICOM Integration for Hyperpolarized 13C MRI.

Hyperpolarized (HP) 13C MRI has shown promise as a valuable modality for in vivo measurements of metabolism and is currently in human trials at 15 research sites worldwide. With this growth, it is important to adopt standardized data storage practices as it will allow sites to meaningfully compare data. In this paper, we (1) describe data that we believe should be stored and (2) demonstrate pipelines and methods that utilize the Digital Imaging and Communications in Medicine (DICOM) standard. This includes proposing a set of minimum set of information that is specific to HP 13C MRI studies. We then show where the majority of these can be fit into existing DICOM attributes, primarily via the "Contrast/Bolus" module. We also demonstrate pipelines for utilizing DICOM for HP 13C MRI. DICOM is the most common standard for clinical medical image storage and provides the flexibility to accommodate the unique aspects of HP 13C MRI, including the HP agent information but also spectroscopic and metabolite dimensions. The pipelines shown include creating DICOM objects for studies on human and animal imaging systems with various pulse sequences. We also show a python-based method to efficiently modify DICOM objects to incorporate the unique HP 13C MRI information that is not captured by existing pipelines. Moreover, we propose best practices for HP 13C MRI data storage that will support future multi-site trials, research studies, and technical developments of this imaging technique.

Identifying factors associated with substantially reduced adult height in patients with juvenile idiopathic arthritis: a retrospective cohort study.

BACKGROUND: Juvenile idiopathic arthritis (JIA), an autoimmune disease affecting children or adolescents and causing joint or systemic symptoms, reportedly has a negative effect on the patients' body height. This study aimed to identify factors attributable to substantially reduced adult height (SRAH) in JIA patients. METHODS: This single-center retrospective cohort study included patients from 2009 to 2019 in Taiwan. We collected JIA patients aged > 18 years at enrollment with a definite diagnosis and undergoing regular outpatient clinic follow-up or disease remission. Target height difference (THD), defined by adult height minus mid-parental height, was calculated for each patient. The calculation results yielded two groups, of which positive THD was defined as the optimal height (OH group) and those with THD below two standardized deviations as the SRAH group. Descriptive statistics and logistic regression analysis were used to analyze the data. RESULTS: Of 92 JIA patients, 57 and 12 were in the OH and the SRAH groups. Earlier disease onset, especially before the six-year-old, was noted in the SRAH group (p = 0.026). The distribution of JIA subtypes differed significantly between the two groups (p < 0.001); enthesis-related arthritis was the commonest subtype in the OH group, and systemic JIA was the commonest in the SRAH group. Half of the patients in the SRAH group had an active disease status at enrollment, which was higher than the OH group (50.0% vs. 21.1%, p = 0.066). More patients in the SRAH group had received orthopedic surgery due to JIA (25% vs. 3.5%, p = 0.034). Multiple logistic regression analysis showed that SRAH was independently related to systemic JIA (OR = 37.6, 95%CI 1.2-1210.5; p = 0.041). CONCLUSION: The subtype of systemic JIA, with its characteristics of early disease onset and active disease status, was the essential factor that significantly impacted adult height.

Data Format Standardization and DICOM Integration for Hyperpolarized 13C MRI.

Hyperpolarized (HP) 13C MRI has shown promise as a valuable modality for in vivo measurements of metabolism and is currently in human trials at 15 research sites worldwide. With this growth it is important to adopt standardized data storage practices as it will allow sites to meaningfully compare data. In this paper we (1) describe data that we believe should be stored and (2) demonstrate pipelines and methods that utilize the Digital Imaging and Communications in Medicine (DICOM) standard. This includes proposing a set of minimum set of information that is specific to HP 13C MRI studies. We then show where the majority of these can be fit into existing DICOM Attributes, primarily via the "Contrast/Bolus" module. We also demonstrate pipelines for utilizing DICOM for HP 13C MRI. DICOM is the most common standard for clinical medical image storage and provides the flexibility to accommodate the unique aspects of HP 13C MRI, including the HP agent information but also spectroscopic and metabolite dimensions. The pipelines shown include creating DICOM objects for studies on human and animal imaging systems with various pulse sequences. We also show a python-based method to efficiently modify DICOM objects to incorporate the unique HP 13C MRI information that is not captured by existing pipelines. Moreover, we propose best practices for HP 13C MRI data storage that will support future multi-site trials, research studies and technical developments of this imaging technique.

Mitigating the Counterpart Selection Effect for Standard Sirens.

The disagreement in the Hubble constant measured by different cosmological probes highlights the need for a better understanding of the observations or new physics. The standard siren method, a novel approach using gravitational-wave observations to determine the distance to binary mergers, has great potential to provide an independent measurement of the Hubble constant and shed light on the tension in the next few years. To realize this goal, we must thoroughly understand the sources of potential systematic bias of standard sirens. Among the known sources of systematic uncertainties, selection effects originating from electromagnetic counterpart observations of gravitational-wave sources may dominate the measurements with percent-level bias and no method to mitigate this effect is currently established. In this Letter, we develop a new formalism to mitigate the counterpart selection effect. We show that our formalism can reduce the systematic uncertainty of standard siren Hubble constant measurement to less than the statistical uncertainty with a simulated population of 200 observations (≲1%) for a realistic electromagnetic emission model. We conclude with how to apply our formalism to different electromagnetic emissions and observing scenarios.

Computed tomography-based gastric volumetry for morbid obesity to assess weight loss and fatty liver change.

BACKGROUND/PURPOSE: Laparoscopic sleeve gastrectomy (LSG) is an effective treatment for patients with morbid obesity, but the optimal gastric volume (GV) for resection remains unclear. Accordingly, we aimed to determine the optimal percentage of excised stomach that could engender significant weight loss and improve fatty liver. METHODS: This prospective study included 63 patients. Computed tomography (CT) scans were performed before and 1 year after LSG to evaluate the gastric lumen (GL) and GV. Specifically, the stomach was distended with effervescent powder, following water-contrast mixture (20:1) and assessed by three-dimensional reconstruction. The correlations of reduced gastric lumen/volume (RGL/RGV) with total body weight (BW) loss and liver-spleen density ratio (LSDR) changes were analyzed, and optimal RGL/RGV associated with significant BW and fatty liver changes were determined. RESULTS: We noted a positive correlation between the percentage of RGV/RGL (%RGV/%RGL) and percentage of total weight loss (%TWL; r = 0.359, p = 0.004 and r = 0.271, p = 0.032). Furthermore, a %RGL value of >78.2% and %RGV value of >75.3% were associated with more significant BW loss than did limited excision (both p < 0.01). On the other hand, LSDR values increased significantly after LSG, corresponding to the improvement of fatty liver disease at %RGL and %RGV values of >59.1% and >56.4% (both p < 0.01), respectively. CONCLUSION: %RGV and %RGL were determined to be factors affecting LSG outcomes. LSG engendered significantly more BW loss when %RGV was >75.3% and resulted in fatty liver disease improvement when %RGV was >56.4%.

Unveiling the Incidence and Graft Survival Rate in Kidney Transplant Recipients With De Novo Thrombotic Microangiopathy: A Systematic Review and Meta-Analysis.

De novo thrombotic microangiopathy (TMA) is a rare and challenging condition in kidney transplant recipients, with limited research on its incidence and impact on graft survival. This study conducted a systematic review and meta-analysis of 28 cohorts/single-arm studies and 46 case series/reports from database inception to June 2022. In meta-analysis, among 14,410 kidney allograft recipients, de novo TMA occurred in 3.20% [95% confidence interval (CI): 1.93-4.77], with systemic and renal-limited TMA rates of 1.38% (95% CI: 06.5-2.39) and 2.80% (95% CI: 1.27-4.91), respectively. The overall graft loss rate of de novo TMA was 33.79% (95% CI: 26.14-41.88) in meta-analysis. This study provides valuable insights into the incidence and graft outcomes of de novo TMA in kidney transplant recipients.

Hyperpolarized 13 C metabolic imaging of the human abdomen with spatiotemporal denoising.

PURPOSE: Improving the quality and maintaining the fidelity of large coverage abdominal hyperpolarized (HP) 13 C MRI studies with a patch based global-local higher-order singular value decomposition (GL-HOVSD) spatiotemporal denoising approach. METHODS: Denoising performance was first evaluated using the simulated [1-13 C]pyruvate dynamics at different noise levels to determine optimal kglobal and klocal parameters. The GL-HOSVD spatiotemporal denoising method with the optimized parameters was then applied to two HP [1-13 C]pyruvate EPI abdominal human cohorts (n = 7 healthy volunteers and n = 8 pancreatic cancer patients). RESULTS: The parameterization of kglobal = 0.2 and klocal = 0.9 denoises abdominal HP data while retaining image fidelity when evaluated by RMSE. The kPX (conversion rate of pyruvate-to-metabolite, X = lactate or alanine) difference was shown to be <20% with respect to ground-truth metabolic conversion rates when there is adequate SNR (SNRAUC > 5) for downstream metabolites. In both human cohorts, there was a greater than nine-fold gain in peak [1-13 C]pyruvate, [1-13 C]lactate, and [1-13 C]alanine apparent SNRAUC . The improvement in metabolite SNR enabled a more robust quantification of kPL and kPA . After denoising, we observed a 2.1 ± 0.4 and 4.8 ± 2.5-fold increase in the number of voxels reliably fit across abdominal FOVs for kPL and kPA quantification maps. CONCLUSION: Spatiotemporal denoising greatly improves visualization of low SNR metabolites particularly [1-13 C]alanine and quantification of [1-13 C]pyruvate metabolism in large FOV HP 13 C MRI studies of the human abdomen.

Advanced Hyperpolarized 13C Metabolic Imaging Protocol for Patients with Gliomas: A Comprehensive Multimodal MRI Approach.

This study aimed to implement a multimodal 1H/HP-13C imaging protocol to augment the serial monitoring of patients with glioma, while simultaneously pursuing methods for improving the robustness of HP-13C metabolic data. A total of 100 1H/HP [1-13C]-pyruvate MR examinations (104 HP-13C datasets) were acquired from 42 patients according to the comprehensive multimodal glioma imaging protocol. Serial data coverage, accuracy of frequency reference, and acquisition delay were evaluated using a mixed-effects model to account for multiple exams per patient. Serial atlas-based HP-13C MRI demonstrated consistency in volumetric coverage measured by inter-exam dice coefficients (0.977 ± 0.008, mean ± SD; four patients/11 exams). The atlas-derived prescription provided significantly improved data quality compared to manually prescribed acquisitions (n = 26/78; p = 0.04). The water-based method for referencing [1-13C]-pyruvate center frequency significantly reduced off-resonance excitation relative to the coil-embedded [13C]-urea phantom (4.1 ± 3.7 Hz vs. 9.9 ± 10.7 Hz; p = 0.0007). Significantly improved capture of tracer inflow was achieved with the 2-s versus 5-s HP-13C MRI acquisition delay (p = 0.007). This study demonstrated the implementation of a comprehensive multimodal 1H/HP-13C MR protocol emphasizing the monitoring of steady-state/dynamic metabolism in patients with glioma.

Probing human heart TCA cycle metabolism and response to glucose load using hyperpolarized [2-13 C]pyruvate MRS.

INTRODUCTION: The healthy heart has remarkable metabolic flexibility that permits rapid switching between mitochondrial glucose oxidation and fatty acid oxidation to generate ATP. Loss of metabolic flexibility has been implicated in the genesis of contractile dysfunction seen in cardiomyopathy. Metabolic flexibility has been imaged in experimental models, using hyperpolarized (HP) [2-13 C]pyruvate MRI, which enables interrogation of metabolites that reflect tricarboxylic acid (TCA) cycle flux in cardiac myocytes. This study aimed to develop methods, demonstrate feasibility for [2-13 C]pyruvate MRI in the human heart for the first time, and assess cardiac metabolic flexibility. METHODS: Good manufacturing practice [2-13 C]pyruvic acid was polarized in a 5 T polarizer for 2.5-3 h. Following dissolution, quality control parameters of HP pyruvate met all safety and sterility criteria for pharmacy release, prior to administration to study subjects. Three healthy subjects each received two HP injections and MR scans, first under fasting conditions, followed by oral glucose load. A 5 cm axial slab-selective spectroscopy approach was prescribed over the left ventricle and acquired at 3 s intervals on a 3 T clinical MRI scanner. RESULTS: The study protocol, which included HP substrate injection, MR scanning, and oral glucose load, was performed safely without adverse events. Key downstream metabolites of [2-13 C]pyruvate metabolism in cardiac myocytes include the glycolytic derivative [2-13 C]lactate, TCA-associated metabolite [5-13 C]glutamate, and [1-13 C]acetylcarnitine, catalyzed by carnitine acetyltransferase (CAT). After glucose load, 13 C-labeling of lactate, glutamate, and acetylcarnitine from 13 C-pyruvate increased by an average of 39.3%, 29.5%, and 114% respectively in the three subjects, which could result from increases in lactate dehydrogenase, pyruvate dehydrogenase, and CAT enzyme activity as well as TCA cycle flux (glucose oxidation). CONCLUSIONS: HP [2-13 C]pyruvate imaging is safe and permits noninvasive assessment of TCA cycle intermediates and the acetyl buffer, acetylcarnitine, which is not possible using HP [1-13 C]pyruvate. Cardiac metabolite measurement in the fasting/fed states provides information on cardiac metabolic flexibility and the acetylcarnitine pool.

Hyperpolarized 13 C Metabolic MRI of Patients with Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related death in the United States. However, early response assessment using the current approach of measuring changes in tumor size on computed tomography (CT) or MRI is challenging. PURPOSE: To investigate the feasibility of hyperpolarized (HP) [1-13 C]pyruvate MRI to quantify metabolism in the normal appearing pancreas and PDA, and to assess changes in PDA metabolism following systemic chemotherapy. STUDY TYPE: Prospective. SUBJECTS: Six patients (65.0 ± 7.6 years, 2 females) with locally advanced or metastatic PDA enrolled prior to starting a new line of systemic chemotherapy. FIELD STRENGTH/SEQUENCE: 3-T, T1-weighted gradient echo, metabolite-selective 13 C echoplanar imaging. ASSESSMENT: Time-resolved HP [1-13 C]pyruvate data were acquired before (N = 6) and 4-weeks after (N = 3) treatment initiation. Pyruvate metabolism, as quantified by pharmacokinetic modeling and metabolite area-under-the-curve ratios, was assessed in manually segmented PDA and normal appearing pancreas ROIs (N = 5). The change in tumor metabolism before and 4-weeks after treatment initiation was assessed in primary PDA (N = 2) and liver metastases (N = 1), and was compared to objective tumor response defined by response evaluation criteria in solid tumors (RECIST) on subsequent CTs. STATISTICAL TESTS: Descriptive tests (mean ± standard deviation), model fit error for pharmacokinetic rate constants. RESULTS: Primary PDA showed reduced alanine-to-lactate ratios when compared to normal pancreas, due to increased lactate-to-pyruvate or reduced alanine-to-pyruvate ratios. Of the three patients who received HP [1-13 C]pyruvate MRI before and 4-weeks after treatment initiation, one patient had a primary tumor with early metabolic response (increase in alanine-to-lactate) and subsequent partial response according to RECIST, one patient had a primary tumor with relatively stable metabolism and subsequent stable disease by RECIST, and one patient had metastatic PDA with increase in lactate-to-pyruvate of the liver metastases and corresponding progressive disease according to RECIST. DATA CONCLUSION: Altered pyruvate metabolism with increased lactate or reduced alanine was observed in the primary tumor. Early metabolic response assessed at 4-weeks after treatment initiation correlated with subsequent objective tumor response assessed using RECIST. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Risk analysis of breast cancer and breast fibrocystic change in female primary Sjögren's syndrome patients.

Sjögren's syndrome is an autoimmune disease with the chronic inflammation of glandular tissues, typically salivary and lacrimal glands. Since mammary tissue shares the glandular structure, Sjögren's syndrome may also target mammary tissue to cause breast diseases. We therefore determined whether primary Sjögren's syndrome (pSS) is associated with the increased risk of breast cancer (BC) and breast fibrocystic change (FC). Total 282 female patients with pSS were recruited from a medical center in Taiwan, and patients' medical records were reviewed to identify BC and ultrasonographic breast FC. The prevalence, incidence and risk factors for BC and breast FC in pSS patients were determined, and the risk factors for these breast diseases were subsequently analyzed. Our results showed that pSS patients had the increased prevalence and incidence of BC, and high anti-SSA(Ro) antibody titers were found to be associated with the increased risk of BC. Breast FC was also found highly prevalent in these patients. Comorbidity analysis as risk factor for BC in pSS patients showed diabetes mellitus was strongly associated with the increased risk of BC (odds ratio = 10.4, P = .0006), whereas breast FC was inversely associated with the risk of BC (odds ratio = 0.077 P = .0158). These data indicated that pSS is association with the increased risk of BC and with the high prevalence of ultrasonographic breast FC. Our results also suggest that, in pSS patients, the high anti-SSA(Ro) antibody titers and diabetes mellitus confer the increased risk of BC, whereas the absence of ultrasonographic breast FC predicts the higher risk of BC.

Antineutrophil Cytoplasmic Antibody-Associated Vasculitis and the Risk of Developing Incidental Tuberculosis: A Population-Based Cohort Study.

Background and Objectives: Treatment for antineutrophil cytoplasmic antibody-associated vasculitis (AAV) must deal with immunosuppression, as well as infections associated with a compromised immune system, such as tuberculosis (TB). Our aim was to examine the risk of incidental TB after diagnosis of AAV. Materials and Methods: This retrospective population-based cohort study was based on the data from the National Health Insurance Research Database in Taiwan. Patients with newly diagnosed granulomatous polyangiitis or microscopic polyangiitis were identified between 1 January 2000 and 31 December 2012. The primary outcome was risk of incidental TB. Cox proportional hazard models were used to evaluate the association between AAV and incidental TB. Results: A total of 2257 patients with AAV and a propensity-score matched cohort of 9028 patients were studied. Overall, patients with AAV were at a 1.48× higher risk of contracting incidental TB than the patients in the matched cohort (adjusted HR 1.48; 95% confidence interval [CI], 1.02-2.15). Note that the highest risk of contracting incidental TB was in the first two years following a diagnosis of AAV, with a nearly 1-fold increase in risk (adjusted HR, 1.91; 95% CI, 1.01-3.60). Female AAV patients were 3.24× more likely than females without AAV to develop TB (adjusted HR 3.24; 95% CI, 1.85-5.67). Conclusions: Patients with AAV exhibit a 48% elevated TB risk, notably, a 91% increase within the first two years postdiagnosis. Female AAV patients face a 3.24 times higher TB risk compared to females without AAV. This study is limited by potential misclassification and overestimation of AAV cases. Clinicians should closely monitor TB risk in AAV patients, especially in females and the initial two years following diagnosis.

Probing Human Heart TCA Cycle Metabolism and Response to Glucose Load using Hyperpolarized [2-13C]Pyruvate MR Spectroscopy.

Introduction: The normal heart has remarkable metabolic flexibility that permits rapid switching between mitochondrial glucose oxidation and fatty acid (FA) oxidation to generate ATP. Loss of metabolic flexibility has been implicated in the genesis of contractile dysfunction seen in cardiomyopathy. Metabolic flexibility has been imaged in experimental models, using hyperpolarized (HP) [2-13C]pyruvate MRI, which enables interrogation of metabolites that reflect tricarboxylic acid (TCA) cycle flux in cardiac myocytes. This study aimed to develop methods, demonstrate feasibility for [2-13C]pyruvate MRI in the human heart for the first time, and assess cardiac metabolic flexibility. Methods: Good Manufacturing Practice [2-13C]pyruvic acid was polarized in a 5T polarizer for 2.5-3 hours. Following dissolution, QC parameters of HP pyruvate met all safety and sterility criteria for pharmacy release, prior to administration to study subjects. Three healthy subjects each received two HP injections and MR scans, first under fasting conditions, followed by oral glucose load. A 5cm axial slab-selective spectroscopy approach was prescribed over the left ventricle and acquired at 3s intervals on a 3T clinical MRI scanner. Results: The study protocol which included HP substrate injection, MR scanning and oral glucose load, was performed safely without adverse events. Key downstream metabolites of [2-13C]pyruvate metabolism in cardiac myocytes include the glycolytic derivative [2-13C]lactate, TCA-associated metabolite [5-13C]glutamate, and [1-13C]acetylcarnitine, catalyzed by carnitine acetyltransferase (CAT). After glucose load, 13C-labeling of lactate, glutamate, and acetylcarnitine from 13C-pyruvate increased by 39.3%, 29.5%, and 114%, respectively in the three subjects, that could result from increases in lactate dehydrogenase (LDH), pyruvate dehydrogenase (PDH), and CAT enzyme activity as well as TCA cycle flux (glucose oxidation). Conclusions: HP [2-13C]pyruvate imaging is safe and permits non-invasive assessment of TCA cycle intermediates and the acetyl buffer, acetylcarnitine, which is not possible using HP [1-13C]pyruvate. Cardiac metabolite measurement in the fasting/fed states provides information on cardiac metabolic flexibility and the acetylcarnitine pool.

Electrospun nanofiber composite mat based on ulvan for wound dressing applications.

Wound dressings can be used to create a temporary healing environment and expedite the wound healing process. Ulvan (ULV) is a sulfated polysaccharide with potent antiviral and anti-inflammatory activities. Polycaprolactone (PCL) is a hydrophobic biodegradable polyester that exhibits slow degradation, strong mechanical strength, and excellent biocompatibility. Electrospun nanofiber matrices mimic the microstructure of the extracellular matrix, allowing them to promote cell proliferation and differentiation. Therefore, the primary objective of this study was to fabricate a polycaprolactone-ulvan fibrous composite mat (PCL-ULV) using the electrospinning technique and to investigate its physical and chemical properties. To assess the characteristics of PCL-ULV, scanning electron microscopy (SEM) was utilized to examine its morphology and diameter distribution. Fourier transform infrared (FTIR) spectroscopy, calcofluor white staining, and monosaccharide analysis were employed to analyze the components of PCL-ULV. Additionally, the water contact angle was measured to evaluate the hydrophilicity. Furthermore, the proliferation and morphology of and gene expression in NIH3T3 fibroblasts on PCL-ULV were assessed. The results showed that the average PCL-ULV fiber diameter was significantly smaller than that of the PCL fibers. The water contact angle measurements indicated that PCL-ULV exhibited better hydrophilicity than the PCL mat. FTIR, calcofluor white staining, and monosaccharide analyses demonstrated that ULV could be successfully coelectrospun with PCL. NIH3T3 fibroblasts cultured on PCL and PCL-ULV showed different cellular behaviors. On PCL-ULV, cell adhesion, proliferation, and stretching were greater than those on PCL. Moreover, the behavior of NIH3T3 fibroblasts on PCL and PCL-ULV differed, as the cells on PCL-ULV exhibited higher proliferation and more stretching. Furthermore, NIH3T3 fibroblasts cultured on ULV-PCL showed higher α-SMA and MMP-9 gene expression and a lower ratio of TIMP-1/MMP-9 than those cultured on PCL. Notably, scarless wounds display lower TIMP/MMP expression ratios than scarring wounds. Thus, the fibrous composite mat PCL-ULV shows potential as a wound dressing for scarless wound healing.

Bridging geographical disparities across 368 townships with healthcare system and socioeconomic factors in Taiwan.

A universal health insurance program such as the National Health Insurance in Taiwan offers a wide coverage and increased access to healthcare services. Despite its ongoing efforts to enhance healthcare accessibility, differences in health for people living in urban and resource-deprived areas remain substantial. To investigate the longitudinal impact of the healthcare system and other potential structural drivers such as education and economic development on geographical disparities in health, we designed a panel study with longitudinal open secondary data, covering all 368 townships in Taiwan between 2013 and 2017. Our findings indicated higher mortality rates in the mountainous and rural areas near the east and south regions of the island in both years. Multivariate analyses showed an increase in the density of primary care physicians (PCP) was associated with lower all-cause mortality (ß = - 0.72, p < 0.0001) and cardiovascular disease mortality (ß = - 0.41, p < 0.0001). Effect of PCP is evident, but merely focusing on access to healthcare is still not enough. Additional measures are warranted to address the health disparities existing between urban and underprivileged areas.

Hyperpolarized [2-13C]pyruvate MR molecular imaging with whole brain coverage.

Hyperpolarized (HP) 13C Magnetic Resonance Imaging (MRI) was applied for the first time to image and quantify the uptake and metabolism of [2-13C]pyruvate in the human brain to provide new metabolic information on cerebral energy metabolism. HP [2-13C]pyruvate was injected intravenously and imaged in 5 healthy human volunteer exams with whole brain coverage in a 1-minute acquisition using a specialized spectral-spatial multi-slice echoplanar imaging (EPI) pulse sequence to acquire 13C-labeled volumetric and dynamic images of [2-13C]pyruvate and downstream metabolites [5-13C]glutamate and [2-13C]lactate. Metabolic ratios and apparent conversion rates of pyruvate-to-lactate (kPL) and pyruvate-to-glutamate (kPG) were quantified to investigate simultaneously glycolytic and oxidative metabolism in a single injection.

Multi-parametric hyperpolarized 13C/1H imaging reveals Warburg-related metabolic dysfunction and associated regional heterogeneity in high-grade human gliomas.

BACKGROUND: Dynamic hyperpolarized (HP)-13C MRI has enabled real-time, non-invasive assessment of Warburg-related metabolic dysregulation in glioma using a [1-13C]pyruvate tracer that undergoes conversion to [1-13C]lactate and [13C]bicarbonate. Using a multi-parametric 1H/HP-13C imaging approach, we investigated dynamic and steady-state metabolism, together with physiological parameters, in high-grade gliomas to characterize active tumor. METHODS: Multi-parametric 1H/HP-13C MRI data were acquired from fifteen patients with progressive/treatment-naïve glioblastoma [prog/TN GBM, IDH-wildtype (n = 11)], progressive astrocytoma, IDH-mutant, grade 4 (G4AIDH+, n = 2) and GBM manifesting treatment effects (n = 2). Voxel-wise regional analysis of the cohort with prog/TN GBM assessed imaging heterogeneity across contrast-enhancing/non-enhancing lesions (CEL/NEL) and normal-appearing white matter (NAWM) using a mixed effects model. To enable cross-nucleus parameter association, normalized perfusion, diffusion, and dynamic/steady-state (HP-13C/spectroscopic) metabolic data were collectively examined at the 13C resolution. Prog/TN GBM were similarly compared against progressive G4AIDH+ and treatment effects. RESULTS: Regional analysis of Prog/TN GBM metabolism revealed statistically significant heterogeneity in 1H choline-to-N-acetylaspartate index (CNI)max, [1-13C]lactate, modified [1-13C]lactate-to-[1-13C]pyruvate ratio (CELval > NELval > NAWMval); [1-13C]lactate-to-[13C]bicarbonate ratio (CELval > NELval/NAWMval); and 1H-lactate (CELval/NELval > NAWMundetected). Significant associations were found between normalized perfusion (cerebral blood volume, nCBV; peak height, nPH) and levels of [1-13C]pyruvate and [1-13C]lactate, as well as between CNImax and levels of [1-13C]pyruvate, [1-13C]lactate and modified ratio. GBM, by comparison to G4AIDH+, displayed lower perfusion %-recovery and modeled rate constants for [1-13C]pyruvate-to-[1-13C]lactate conversion (kPL), and higher 1H-lactate and [1-13C]pyruvate levels, while having higher nCBV, %-recovery, kPL, [1-13C]pyruvate-to-[1-13C]lactate and modified ratios relative to treatment effects. CONCLUSIONS: GBM consistently displayed aberrant, Warburg-related metabolism and regional heterogeneity detectable by novel HP-13C/1H imaging techniques.

A metabolite specific 3D stack-of-spirals bSSFP sequence for improved bicarbonate imaging in hyperpolarized [1-13C]Pyruvate MRI.

13C-bicarbonate is a crucial measure of pyruvate oxidation and TCA cycle flux, but is challenging to measure due to its relatively low concentration and thus will greatly benefit from improved signal-to-noise ratio (SNR). To address this, we developed and investigated the feasibility of a 3D stack-of-spirals metabolite-specific balanced steady-state free precession (MS-bSSFP) sequence for improving the SNR and spatial resolution of dynamic 13C-bicarbonate imaging in hyperpolarized [1-13C]pyruvate studies. The bicarbonate MS-bSSFP sequence was evaluated by simulations, phantoms studies, preclinical studies on five rats, brain studies on two healthy volunteers and renal study on one renal cell carcinoma patient. The simulations and phantom results showed that the bicarbonate-specific pulse had minimal perturbation of other metabolites (<1%). In the animal studies, the MS-bSSFP sequence provided an approximately 2.6-3 × improvement in 13C-bicarbonate SNR compared to a metabolite-specific gradient echo (MS-GRE) sequence without altering the bicarbonate or pyruvate kinetics, and the shorter spiral readout in the MS-bSSFP approach reduced blurring. Using the SNR ratio between MS-bSSFP and MS-GRE, the T2 values of bicarbonate and lactate in the rat kidneys were estimated as 0.5 s and 1.1 s, respectively. The in-vivo feasibility of bicarbonate MS-bSSFP sequence was demonstrated in two human brain studies and one renal study. These studies demonstrate the potential of the sequence for in-vivo applications, laying the foundation for future studies to observe this relatively low concentration metabolite with high-quality images and improve measurements of pyruvate oxidation.

Single-Gate In-Transistor Readout of Current Superposition and Collapse Utilizing Quantum Tunneling and Ferroelectric Switching.

In nanostructure assemblies, the superposition of current paths forms microscopic electric circuits, and different circuit networks produce varying results, particularly when utilized as transistor channels for computing applications. However, the intricate nature of assembly networks and the winding paths of commensurate currents hinder standard circuit modeling. Inspired by the quantum collapse of superposition states for information decoding in quantum circuits, the implementation of analogous current path collapse to facilitate the detection of microscopic circuits by modifying their network topology is explored. Here, the superposition and collapse of current paths in gate-all-around polysilicon nanosheet arrays are demonstrated to enrich the computational resources within transistors by engineering the channel length and quantity. Switching the ferroelectric polarization of Hf0.5 Zr0.5 O2 gate dielectric, which drives these transistors out-of-equilibrium, decodes the output polymorphism through circuit topological modifications. Furthermore, a protocol for the single-electron readout of ferroelectric polarization is presented with tailoring the channel coherence. The introduction of lateral path superposition results into intriguing metal-to-insulator transitions due to transient behavior of ferroelectric switching. This ability to adjust the current networks within transistors and their interaction with ferroelectric polarization in polycrystalline nanostructures lays the groundwork for generating diverse current characteristics as potential physical databases for optimization-based computing.