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Background: Blood transfusion (BT) may be associated with an increased risk of thromboembolism. The associations between transfusion reactions (TRs) during BTs and potential risk factors for the development of thromboembolism in patients underwent blood transfusion have not been analyzed. Therefore, this study aimed to compare risk factors associated with the development of venous thromboembolism (VTE) or pulmonary embolism (PE) between patients underwent blood transfusion with and without TRs. Study Designs and Methods: The retrospective study was conducted between April 1, 2017, and March 31, 2020, at a medical center in Taiwan. Blood‐transfused patients were grouped into two cohorts as follows: those who experienced TRs and those who did not experience TRs. Both cohorts were subjected to follow‐up until March 31, 2021. The endpoints for both groups were the occurrence of VTE or PE or the date of March 31, 2021. To investigate between‐cohort risk differences, a Kaplan–Meier survival analysis and multiple Cox proportional hazard model was used. Results: A total of 10,759 patients underwent 59,385 transfusion procedures, with 703 patients in the TR group, and 10,056 patients in the non‐TR group. The risk of VTE or PE was twice as high in the TR group than in the non‐TR group (adjusted hazard ratio 2.53, 95% confidence interval 1.49–4.29, p =.001). Meanwhile, age, female sex, transfusion frequency increment, and being nondiabetic was associated with an increased risk of developing thromboembolism. Conclusion: TRs are associated with increased long‐term thromboembolism risk in patients underwent blood transfusion. It is imperative for clinicians to acknowledge this and maintain rigorous follow‐up. [ABSTRACT FROM AUTHOR]

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) [1‐13C]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 13C echoplanar imaging. Assessment: Time‐resolved HP [1‐13C]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 [1‐13C]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 [ABSTRACT FROM AUTHOR]

Purpose: Improving the quality and maintaining the fidelity of large coverage abdominal hyperpolarized (HP) 13C 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 [1‐13C]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 [1‐13C]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 [1‐13C]pyruvate, [1‐13C]lactate, and [1‐13C]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 [1‐13C]alanine and quantification of [1‐13C]pyruvate metabolism in large FOV HP 13C MRI studies of the human abdomen. [ABSTRACT FROM AUTHOR]

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) [2‐13C]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 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 [2‐13C]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 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 [2‐13C]pyruvate imaging is safe and permits noninvasive 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. [ABSTRACT FROM AUTHOR]

Objective: Thrombotic microangiopathy (TMA) in pregnancy can rapidly progress, leading to severe morbidities. This study aimed to compare baseline demographics and clinical outcomes between pregnant women with and without TMA. Methods: Using the National Health Insurance Research Database, 207 patients with pregnancy‐related TMA from January 1, 2006 to December 31, 2015 were enrolled. Their data were compared with a 1:4 propensity score–matched cohort of 828 pregnant women without TMA to evaluate mortality and end‐stage renal disease (ESRD) risks. Cox proportional hazards models were used to estimate the adjusted hazard ratio and 95% confidence intervals. Results: A total of 1035 participants were included. The risks of mortality and ESRD were 4.46 and 5.97 times higher for the TMA cohort, respectively. Subgroup analysis revealed higher mortality and ESRD risks in patients with TMA aged >40 years with a history of hypertension, stroke, cancer, concomitant stroke, malignant hypertension, or gastroenterocolitis than in the matched cohort. Conclusion: Pregnant patients with TMA, especially those older and with comorbidities and organ involvement, faced increased mortality and ESRD risks. Physicians should collaborate with obstetricians throughout the prenatal and postpartum periods for these patients. Synopsis: Patients with pregnant thrombotic microangiopathy, particularly older patients with comorbidities and organ involvement, have an increased risk of mortality and end‐stage renal disease. [ABSTRACT FROM AUTHOR]

China and Taiwan (so‐called Greater China) are representative of two of the fastest‐growing economies in the Pacific Rim region. This study uses Taiwanese high‐tech firms as sample and explores whether boards of directors attempt to avoid opportunistic reductions in research and development (R&D) investments by CEOs. This study considers a scenario in which high‐tech firms face a small earnings decline or a small loss but their CEOs could opportunistically cut R&D investments to improve financial results. The focus of this study is to examine how corporate control (whether or not a firm is controlled by a family) and market competition affect the relationship between R&D investments and CEO compensation schemes. Overall, we find that the stock‐based incentive compensation is more effective than the cash compensation in deterring managerial opportunism. In non‐family firms, we find there exists a positive significant relationship between changes in R&D expenditures and changes in CEO stock‐based compensation when a firm is faced with a small earnings decline or a small loss. Specifically, compared to family firms, the boards of directors of non‐family firms face more severe agency problems (as a result of the separation of ownership and control) and therefore tend to significantly adjust the incentive components in CEO compensation schemes to deter managerial opportunism. Regarding the effect of market competition, we find that incentives to adjust compensation plan to remove CEOs from opportunistically reducing discretionary R&D investments are greater in firms facing more intense market competition. [ABSTRACT FROM AUTHOR]

Purpose: Model‐constrained reconstruction with Fourier‐based undersampling (MoReFUn) is introduced to accelerate the acquisition of dynamic MRI using hyperpolarized [1‐13C]‐pyruvate. Methods: The MoReFUn method resolves spatial aliasing using constraints introduced by a pharmacokinetic model that describes the signal evolution of both pyruvate and lactate. Acceleration was evaluated on three single‐channel data sets: a numerical digital phantom that is used to validate the accuracy of reconstruction and model parameter restoration under various SNR and undersampling ratios, prospectively and retrospectively sampled data of an in vitro dynamic multispectral phantom, and retrospectively undersampled imaging data from a prostate cancer patient to test the fidelity of reconstructed metabolite time series. Results: All three data sets showed successful reconstruction using MoReFUn. In simulation and retrospective phantom data, the restored time series of pyruvate and lactate maintained the image details, and the mean square residual error of the accelerated reconstruction increased only slightly (< 10%) at a reduction factor up to 8. In prostate data, the quantitative estimation of the conversion‐rate constant of pyruvate to lactate was achieved with high accuracy of less than 10% error at a reduction factor of 2 compared with the conversion rate derived from unaccelerated data. Conclusion: The MoReFUn technique can be used as an effective and reliable imaging acceleration method for metabolic imaging using hyperpolarized [1‐13C]‐pyruvate. [ABSTRACT FROM AUTHOR]

Purpose: To develop techniques and establish a workflow using hyperpolarized carbon‐13 (13C) MRI and the pyruvate‐to‐lactate conversion rate (kPL) biomarker to guide MR‐transrectal ultrasound fusion prostate biopsies. Methods: The integrated multiparametric MRI (mpMRI) exam consisted of a 1‐min hyperpolarized 13C‐pyruvate EPI acquisition added to a conventional prostate mpMRI exam. Maps of kPL values were calculated, uploaded to a picture archiving and communication system and targeting platform, and displayed as color overlays on T2‐weighted anatomic images. Abdominal radiologists identified 13C research biopsy targets based on the general recommendation of focal lesions with kPL >0.02(s−1), and created a targeting report for each study. Urologists conducted transrectal ultrasound‐guided MR fusion biopsies, including the standard 1H–mpMRI targets as well as 12–14 core systematic biopsies informed by the research 13C‐kPL targets. All biopsy results were included in the final pathology report and calculated toward clinical risk. Results: This study demonstrated the safety and technical feasibility of integrating hyperpolarized 13C metabolic targeting into routine 1H–mpMRI and transrectal ultrasound fusion biopsy workflows, evaluated via 5 men (median age 71 years, prostate‐specific antigen 8.4 ng/mL, Cancer of the Prostate Risk Assessment score 2) on active surveillance undergoing integrated scan and subsequent biopsies. No adverse event was reported. Median turnaround time was less than 3 days from scan to 13C‐kPL targeting, and scan‐to‐biopsy time was 2 weeks. Median number of 13C targets was 1 (range: 1–2) per patient, measuring 1.0 cm (range: 0.6–1.9) in diameter, with a median kPL of 0.0319 s−1 (range: 0.0198–0.0410). Conclusions: This proof‐of‐concept work demonstrated the safety and feasibility of integrating hyperpolarized 13C MR biomarkers to the standard mpMRI workflow to guide MR‐transrectal ultrasound fusion biopsies. [ABSTRACT FROM AUTHOR]

Background: Patients with idiopathic minimal change nephrotic syndrome (MCNS) undergoing immunosuppressive therapy are susceptible to infectious complications. Study specifically focusing on adult population's infectious complications is lacking. Methods: We retrospectively collected 101 adult patients with biopsy‐proven idiopathic MCNS and analysed for the infectious complications. Published literatures were also reviewed aiming to evaluate the feasibility of prophylactic antibiotic treatment. Results: Infectious complications developed in 17 of 101 (16.8%) patients, with pneumonia (n = 4), cellulitis/fasciitis (n = 4) and urinary tract infection (UTI) (n = 4) being the dominant diseases, and Gram‐negative bacilli the main cause. AKI stage ≥2 (Hazard ratio = 6.1; 95% CI: 1.2–31.9, p = 0.031) and non‐remission by treatment (Hazard ratio = 4.4; 95% CI: 1.2–15.6, p =.023) were the two independent risk factors relevant to developing infectious complications. Review of 16 published literatures and our data showed that even no prophylactic antibiotic therapy, only one case of Pneumocystis jirovecii pneumonia developed among the 1787 accumulative cases of MCNS. In contrast, 16 (44%) of acute flare cases were reported among the 36 patients with positive hepatitis B surface antigen that did not receive antiviral prophylactic therapy. Conclusions: Advanced acute kidney injury and non‐remission by treatment are the risk factors toward developing infectious complications in adult MCNS undergoing immunosuppressive therapy. It appears unnecessary to use prophylactic antibiotic for Pneumocystis jirovecii pneumonia or other bacterial infections, while screening and prophylactic therapy for hepatitis B and latent tuberculosis are critical for patients in prevalent area. Summary at a Glance: Advanced acute kidney injury and poor treatment response are independent risk factors relevant to developing infectious complications in adult patients with idiopathic minimal change nephrotic syndrome. It appears unnecessary to use prophylactic antibiotic for Pneumocystis jirovecii pneumonia or other bacterial infections, while screening and prophylactic therapy for hepatitis B and latent tuberculosis are critical for patients in prevalent area. [ABSTRACT FROM AUTHOR]

Background: Hyperpolarized 13C MRI quantitatively measures enzyme‐catalyzed metabolism in cancer and metabolic diseases. Whole‐abdomen imaging will permit dynamic metabolic imaging of several abdominal organs simultaneously in healthy and diseased subjects. Purpose: Image hyperpolarized [1‐13C]pyruvate and products in the abdomens of healthy volunteers, overcoming challenges of motion, magnetic field variations, and spatial coverage. Compare hyperpolarized [1‐13C]pyruvate metabolism across abdominal organs of healthy volunteers. Study Type: Prospective technical development. Subjects: A total of 13 healthy volunteers (8 male), 21–64 years (median 36). Field Strength/Sequence: A 3 T. Proton: T1‐weighted spoiled gradient echo, T2‐weighted single‐shot fast spin echo, multiecho fat/water imaging. Carbon‐13: echo‐planar spectroscopic imaging, metabolite‐specific echo‐planar imaging. Assessment: Transmit magnetic field was measured. Variations in main magnetic field (ΔB0) determined using multiecho proton acquisitions were compared to carbon‐13 acquisitions. Changes in ΔB0 were measured after localized shimming. Improvements in metabolite signal‐to‐noise ratio were calculated. Whole‐organ regions of interests were drawn over the liver, spleen, pancreas, and kidneys by a single investigator. Metabolite signals, time‐to‐peak, decay times, and mean first‐order rate constants for pyruvate‐to‐lactate (kPL) and alanine (kPA) conversion were measured in each organ. Statistical Tests: Linear regression, one‐sample Kolmogorov–Smirnov tests, paired t‐tests, one‐way ANOVA, Tukey's multiple comparisons tests. P ≤ 0.05 considered statistically significant. Results: Proton ΔB0 maps correlated with carbon‐13 ΔB0 maps (slope = 0.93, y‐intercept = −2.88, R2 = 0.73). Localized shimming resulted in mean frequency offset within ±25 Hz for all organs. Metabolite SNR significantly increased after denoising. Mean kPL and kPA were highest in liver, followed by pancreas, spleen, and kidneys (all comparisons with liver were significant). Data Conclusion: Whole‐abdomen coverage with hyperpolarized carbon‐13 MRI was feasible despite technical challenges. Multiecho gradient echo 1H acquisitions accurately predicted chemical shifts observed using carbon‐13 spectroscopy. Carbon‐13 acquisitions benefited from local shimming. Metabolite energetics in the abdomen compiled for healthy volunteers can be used to design larger clinical trials in patients with metabolic diseases. Evidence Level: 2 Technical Efficacy: Stage 1 [ABSTRACT FROM AUTHOR]

This study investigates the impact of international diversification on the lag effect of R&D performance for implementing an international diversification strategy. The study uses the sales base amount and the number of countries, respectively, to explain the depth and breadth of international diversification. The results suggest that the higher the level of international diversification, the more profound the positive impact of the international diversification on the R&D activities‐derived operating performance. The study also confirms that companies with broader international diversification have a higher positive R&D lag effect. The empirical results are robust to the problem of endogeneity. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to develop and demonstrate the in vivo feasibility of a 3D stack‐of‐spiral balanced steady‐state free precession(3D‐bSSFP) urea sequence, interleaved with a metabolite‐specific gradient echo (GRE) sequence for pyruvate and metabolic products, for improving the SNR and spatial resolution of the first hyperpolarized 13C‐MRI human study with injection of co‐hyperpolarized [1‐13C]pyruvate and [13C,15N2]urea. Methods: A metabolite‐specific bSSFP urea imaging sequence was designed using a urea‐specific excitation pulse, optimized TR, and 3D stack‐of‐spiral readouts. Simulations and phantom studies were performed to validate the spectral response of the sequence. The image quality of urea data acquired by the 3D‐bSSFP sequence and the 2D‐GRE sequence was evaluated with 2 identical injections of co‐hyperpolarized [1‐13C]pyruvate and [13C,15N2]urea formula in a rat. Subsequently, the feasibility of the acquisition strategy was validated in a prostate cancer patient. Results: Simulations and phantom studies demonstrated that 3D‐bSSFP sequence achieved urea‐only excitation, while minimally perturbing other metabolites (<1%). An animal study demonstrated that compared to GRE, bSSFP sequence provided an ∼2.5‐fold improvement in SNR without perturbing urea or pyruvate kinetics, and bSSFP approach with a shorter spiral readout reduced blurring artifacts caused by J‐coupling of [13C,15N2]urea. The human study demonstrated the in vivo feasibility and data quality of the acquisition strategy. Conclusion: The 3D‐bSSFP urea sequence with a stack‐of‐spiral acquisition demonstrated significantly increased SNR and image quality for [13C,15N2]urea in co‐hyperpolarized [1‐13C]pyruvate and [13C,15N2]urea imaging studies. This work lays the foundation for future human studies to achieve high‐quality and high‐SNR metabolism and perfusion images. [ABSTRACT FROM AUTHOR]

Research investigating incident malignancy risk in erythropoiesis‐stimulating agent (ESA) users with chronic kidney disease (CKD) is lacking. We aimed to compare the incident cancer risk between ESA and non‐ESA users with CKD or end‐stage renal disease (ESRD). In this retrospective cohort study, all adults newly diagnosed with CKD or ESRD between 2000 and 2012 were enrolled. The study population included 98,748 patients. After case–control matching, 7115 patients were included. The defined daily dose (DDD) of ESA was used as the unit for measuring the amount of ESA prescribed. The primary outcome was the risk of incident malignancy. The secondary outcomes were incident malignancy risk in different tertiles of cumulative ESA doses and the risk of different types of cancers. The risk of incident malignancy was 1.84 times higher with ESA treatment than without ESA treatment (hazard ratio, 1.84; 95% confidence interval, 1.43–2.36; p < 0.001). The malignancy risk was positively correlated with the cumulative dose of ESA (p‐for‐trend = 0.001) and a significant difference in the high annual cumulative DDD cohort (hazard ratio [HR], 2.39; 95% confidence interval [CI], 1.76–3.25; p < 0.001). The risk of genitourinary malignancy was 12.55 times higher with ESA treatment than without ESA treatment (HR, 12.55; 95% CI, 5.78–27.24; p < 0.001). ESA usage is associated with an increased risk of malignancy, particularly genitourinary cancers, in patients with CKD or ESRD. Clinicians should be aware of the occurrence of malignancy, and keep ESA dosage as low as possible. [ABSTRACT FROM AUTHOR]

Purpose: To develop a novel post‐processing pipeline for hyperpolarized (HP) 13C MRSI that integrates tensor denoising and B1+ correction to measure pyruvate‐to‐lactate conversion rates (kPL) in patients with liver tumors. Methods: Seven HP 13C MR scans of progressing liver tumors were acquired using a custom 13C surface transmit/receive coil and the echo‐planar spectroscopic imaging (EPSI) data analysis included B0 correction, tensor rank truncation, and zero‐ and first‐order phase corrections to recover metabolite signals that would otherwise be obscured by spectral noise as well as a correction for inhomogeneous transmit (B1+) using a B1+ map aligned to the coil position for each patient scan. Processed HP data and corrected flip angles were analyzed with an inputless two‐site exchange model to calculate kPL. Results: Denoising averages SNR increases of pyruvate, lactate, and alanine were 37.4‐, 34.0‐, and 20.1‐fold, respectively, with lactate and alanine dynamics most noticeably recovered and better defined. In agreement with Monte Carlo simulations, over‐flipped regions underestimated kPL and under‐flipped regions overestimated kPL. B1+ correction addressed this issue. Conclusion: The new HP 13C EPSI post‐processing pipeline integrated tensor denoising and B1+ correction to measure kPL in patients with liver tumors. These technical developments not only recovered metabolite signals in voxels that did not receive the prescribed flip angle, but also increased the extent and accuracy of kPL estimations throughout the tumor and adjacent regions including normal‐appearing tissue and additional lesions. [ABSTRACT FROM AUTHOR]

Purpose: To improve hyperpolarized 13C (HP‐13C) MRI by image denoising with a new approach, patch‐based higher‐order singular value decomposition (HOSVD). Methods: The benefit of using a patch‐based HOSVD method to denoise dynamic HP‐13C MR imaging data was investigated. Image quality and the accuracy of quantitative analyses following denoising were evaluated first using simulated data of [1‐13C]pyruvate and its metabolic product, [1‐13C]lactate, and compared the results to a global HOSVD method. The patch‐based HOSVD method was then applied to healthy volunteer HP [1‐13C]pyruvate EPI studies. Voxel‐wise kinetic modeling was performed on both non‐denoised and denoised data to compare the number of voxels quantifiable based on SNR criteria and fitting error. Results: Simulation results demonstrated an 8‐fold increase in the calculated SNR of [1‐13C]pyruvate and [1‐13C]lactate with the patch‐based HOSVD denoising. The voxel‐wise quantification of kPL (pyruvate‐to‐lactate conversion rate) showed a 9‐fold decrease in standard errors for the fitted kPL after denoising. The patch‐based denoising performed superior to the global denoising in recovering kPL information. In volunteer data sets, [1‐13C]lactate and [13C]bicarbonate signals became distinguishable from noise across captured time points with over a 5‐fold apparent SNR gain. This resulted in >3‐fold increase in the number of voxels quantifiable for mapping kPB (pyruvate‐to‐bicarbonate conversion rate) and whole brain coverage for mapping kPL. Conclusions: Sensitivity enhancement provided by this denoising significantly improved quantification of metabolite dynamics and could benefit future studies by improving image quality, enabling higher spatial resolution, and facilitating the extraction of metabolic information for clinical research. [ABSTRACT FROM AUTHOR]

Abstract Based on the expanding set of applications for hyperpolarized carbon‐13 (HP‐13C) MRI, this work aims to communicate standardized methodology implemented at the University of California, San Francisco, as a primer for conducting reproducible metabolic imaging studies of the prostate and brain. Current state‐of‐the‐art HP‐13C acquisition, data processing/reconstruction and kinetic modeling approaches utilized in patient studies are presented together with the rationale underpinning their usage. Organized around spectroscopic and imaging‐based methods, this guide provides an extensible framework for handling a variety of HP‐13C applications, which derives from two examples with dynamic acquisitions: 3D echo‐planar spectroscopic imaging of the human prostate and frequency‐specific 2D multislice echo‐planar imaging of the human brain. Details of sequence‐specific parameters and processing techniques contained in these examples should enable investigators to effectively tailor studies around individual‐use cases. Given the importance of clinical integration in improving the utility of HP exams, practical aspects of standardizing data formats for reconstruction, analysis and visualization are also addressed alongside open‐source software packages that enhance institutional interoperability and validation of methodology. To facilitate the adoption and further development of this methodology, example datasets and analysis pipelines have been made available in the supporting information. [ABSTRACT FROM AUTHOR]

MRI with hyperpolarized carbon‐13 agents has created a new type of noninvasive, in vivo metabolic imaging that can be applied in cell, animal, and human studies. The use of 13C‐labeled agents, primarily [1‐13C]pyruvate, enables monitoring of key metabolic pathways with the ability to image substrate and products based on their chemical shift. Over 10 sites worldwide are now performing human studies with this new approach for studies of cancer, heart disease, liver disease, and kidney disease. Hyperpolarized metabolic imaging studies must be performed within several minutes following creation of the hyperpolarized agent due to irreversible decay of the net magnetization back to equilibrium, so fast imaging methods are critical. The imaging methods must include multiple metabolites, separated based on their chemical shift, which are also undergoing rapid metabolic conversion (via label exchange), further exacerbating the challenges of fast imaging. This review describes the state‐of‐the‐art in fast imaging methods for hyperpolarized metabolic imaging. This includes the approach and tradeoffs between three major categories of fast imaging methods—fast spectroscopic imaging, model‐based strategies, and metabolite specific imaging—as well additional options of parallel imaging, compressed sensing, tailored RF flip angles, refocused imaging methods, and calibration methods that can improve the scan coverage, speed, signal‐to‐noise ratio (SNR), resolution, and/or robustness of these studies. To date, these approaches have produced extremely promising initial human imaging results. Improvements to fast hyperpolarized metabolic imaging methods will provide better coverage, SNR, resolution, and reproducibility for future human imaging studies. Level of Evidence: 5 Technical Efficacy Stage: 1 [ABSTRACT FROM AUTHOR]

Purpose: With the initiation of human hyperpolarized 13C (HP‐13C) trials at multiple sites and the development of improved acquisition methods, there is an imminent need to maximally extract diagnostic information to facilitate clinical interpretation. This study aims to improve human HP‐13C MR spectroscopic imaging through means of Tensor Rank truncation‐Image enhancement (TRI) and optimal receiver combination (ORC). Methods: A data‐driven processing framework for dynamic HP 13C MR spectroscopic imaging (MRSI) was developed. Using patient data sets acquired with both multichannel arrays and single‐element receivers from the brain, abdomen, and pelvis, we examined the theory and application of TRI, as well as 2 ORC techniques: whitened singular value decomposition (WSVD) and first‐point phasing. Optimal conditions for TRI were derived based on bias‐variance trade‐off. Results: TRI and ORC techniques together provided a 63‐fold mean apparent signal‐to‐noise ratio (aSNR) gain for receiver arrays and a 31‐fold gain for single‐element configurations, which particularly improved quantification of the lower‐SNR‐[13C]bicarbonate and [1‐13C]alanine signals that were otherwise not detectable in many cases. Substantial SNR enhancements were observed for data sets that were acquired even with suboptimal experimental conditions, including delayed (114 s) injection (8× aSNR gain solely by TRI), or from challenging anatomy or geometry, as in the case of a pediatric patient with brainstem tumor (597× using combined TRI and WSVD). Improved correlation between elevated pyruvate‐to‐lactate conversion, biopsy‐confirmed cancer, and mp‐MRI lesions demonstrated that TRI recovered quantitative diagnostic information. Conclusion: Overall, this combined approach was effective across imaging targets and receiver configurations and could greatly benefit ongoing and future HP 13C MRI research through major aSNR improvements. [ABSTRACT FROM AUTHOR]

Purpose: To compare the performance of an 8‐channel surface coil/clamshell transmitter and 32‐channel head array coil/birdcage transmitter for hyperpolarized 13C brain metabolic imaging. Methods: To determine the field homogeneity of the radiofrequency transmitters, B1+ mapping was performed on an ethylene glycol head phantom and evaluated by means of the double angle method. Using a 3D echo‐planar imaging sequence, coil sensitivity and noise‐only phantom data were acquired with the 8‐ and 32‐channel receiver arrays, and compared against data from the birdcage in transceiver mode. Multislice frequency‐specific 13C dynamic echo‐planar imaging was performed on a patient with a brain tumor for each hardware configuration following injection of hyperpolarized [1‐13C]pyruvate. Signal‐to‐noise ratio (SNR) was evaluated from pre‐whitened phantom and temporally summed patient data after coil combination based on optimal weights. Results: The birdcage transmitter produced more uniform B1+ compared with the clamshell: 0.07 versus 0.12 (fractional error). Phantom experiments conducted with matched lateral housing separation demonstrated 8‐ versus 32‐channel mean transceiver‐normalized SNR performance: 0.91 versus 0.97 at the head center; 6.67 versus 2.08 on the sides; 0.66 versus 2.73 at the anterior; and 0.67 versus 3.17 on the posterior aspect. While the 8‐channel receiver array showed SNR benefits along lateral aspects, the 32‐channel array exhibited greater coverage and a more uniform coil‐combined profile. Temporally summed, parameter‐normalized patient data showed SNRmean,slice ratios (8‐channel/32‐channel) ranging 0.5‐2.00 from apical to central brain. White matter lactate‐to‐pyruvate ratios were conserved across hardware: 0.45 ± 0.12 (8‐channel) versus 0.43 ± 0.14 (32‐channel). Conclusion: The 8‐ and 32‐channel hardware configurations each have advantages in particular brain anatomy. [ABSTRACT FROM AUTHOR]

Purpose: To develop and translate a metabolite‐specific imaging sequence using a symmetric echo planar readout for clinical hyperpolarized (HP) Carbon‐13 (13C) applications. Methods: Initial data were acquired from patients with prostate cancer (N = 3) and high‐grade brain tumors (N = 3) on a 3T scanner. Samples of [1‐13C]pyruvate were polarized for at least 2 h using a 5T SPINlab system operating at 0.8 K. Following injection of the HP substrate, pyruvate, lactate, and bicarbonate (for brain studies) were sequentially excited with a singleband spectral‐spatial RF pulse and signal was rapidly encoded with a single‐shot echo planar readout on a slice‐by‐slice basis. Data were acquired dynamically with a temporal resolution of 2 s for prostate studies and 3 s for brain studies. Results: High pyruvate signal was seen throughout the prostate and brain, with conversion to lactate being shown across studies, whereas bicarbonate production was also detected in the brain. No Nyquist ghost artifacts or obvious geometric distortion from the echo planar readout were observed. The average error in center frequency was 1.2 ± 17.0 and 4.5 ± 1.4 Hz for prostate and brain studies, respectively, below the threshold for spatial shift because of bulk off‐resonance. Conclusion: This study demonstrated the feasibility of symmetric EPI to acquire HP 13C metabolite maps in a clinical setting. As an advance over prior single‐slice dynamic or single time point volumetric spectroscopic imaging approaches, this metabolite‐specific EPI acquisition provided robust whole‐organ coverage for brain and prostate studies while retaining high SNR, spatial resolution, and dynamic temporal resolution. [ABSTRACT FROM AUTHOR]

Numerous evidences have shown that chrysin induced cytotoxic effects via induced cell cycle arrest and induction of cell apoptosis in human cancer cell lines, however, no information showed that chrysin inhibited skin cancer cell migration and invasion. In this study, we investigated anti‐metastasis mechanisms of chrysin in human melanoma cancer A375.S2 cells in vitro. Under sub‐lethal concentrations of chrysin (0, 5, 10, and 15 μM) which inhibits cell mobility, migration and invasion of A375.S2 cells that were assayed by wound healing and Transwell filter. That chrysin inhibited MMP‐2 activity in A375.S2 cells was investigated by gelatin zymography assay. Western blotting was used to examine protein expression and results indicated that chrysin inhibited the expression of GRB2, SOS‐1, PKC, p‐AKT (Thr308), NF‐κBp65, and NF‐κBp50 at 24 and 48 hours treatment, but only at 10‐15 μM of chrysin decreased Ras, PI3K, p‐c‐Jun, and Snail only at 48 hours treatment and only decrease p‐AKT(Ser473) at 24 hours treatment. Furthermore, chrysin (5‐15 μM) decreased the expression of uPA, N‐cadherin and MMP‐1 at 24 and 48 hours treatment but only decreased MMP‐2 and VEGF at 48 hours treatment at 10‐15 μM and 5‐15 μM of chrysin, respectively, however, increased E‐cadherin at 5‐15 μM treatment. Results of confocal laser microscopy systems indicated that chrysin inhibited expression of NF‐κBp65 in A375.S2 cells. Based on these observations, we suggest that chrysin can be used in anti‐metastasis of human melanoma cells in the future. [ABSTRACT FROM AUTHOR]

Hyperpolarized 13C MRI takes advantage of the unprecedented 50 000‐fold signal‐to‐noise ratio enhancement to interrogate cancer metabolism in patients and animals. It can measure the pyruvate‐to‐lactate conversion rate, kPL, a metabolic biomarker of cancer aggressiveness and progression. Therefore, it is crucial to evaluate kPL reliably. In this study, three sequence components and parameters that modulate kPL estimation were identified and investigated in model simulations and through in vivo animal studies using several specifically designed pulse sequences. These factors included a magnetization spoiling effect due to RF pulses, a crusher gradient‐induced flow suppression, and intrinsic image weightings due to relaxation. Simulation showed that the RF‐induced magnetization spoiling can be substantially improved using an inputless kPL fitting. In vivo studies found a significantly higher apparent kPL with an additional gradient that leads to flow suppression (kPL,FID‐Delay,Crush/kPL,FID‐Delay = 1.37 ± 0.33, P < 0.01, N = 6), which agrees with simulation outcomes (12.5% kPL error with Δv = 40 cm/s), indicating that the gradients predominantly suppressed flowing pyruvate spins. Significantly lower kPL was found using a delayed free induction decay (FID) acquisition versus a minimum‐TE version (kPL,FID‐Delay/kPL,FID = 0.67 ± 0.09, P < 0.01, N = 5), and the lactate peak had broader linewidth than pyruvate (Δωlactate/Δωpyruvate = 1.32 ± 0.07, P < 0.000 01, N = 13). This illustrated that lactate's T2*, shorter than that of pyruvate, can affect calculated kPL values. We also found that an FID sequence yielded significantly lower kPL versus a double spin‐echo sequence that includes spin‐echo spoiling, flow suppression from crusher gradients, and more T2 weighting (kPL,DSE/kPL,FID = 2.40 ± 0.98, P < 0.0001, N = 7). In summary, the pulse sequence, as well as its interaction with pharmacokinetics and the tissue microenvironment, can impact and be optimized for the measurement of kPL. The data acquisition and analysis pipelines can work synergistically to provide more robust and reproducible kPL measures for future preclinical and clinical studies. This study investigated three pulse sequence components and parameters that can affect estimates of kPL in HP‐13C MRI. In vivo animal tumor studies showed significant impact on kPL with crusher‐gradient induced flow suppression, and intrinsic image weighting due to relaxation, corroborated by signal‐model simulations. RF‐induced magnetization spoiling can be substantially improved using an inputless kPL fitting. These outcomes suggested that the pulse sequence, as well as its interaction with pharmacokinetics and tissue microenvironment, can impact the measurement of kPL. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to develop a new 3D dynamic carbon‐13 compressed sensing echoplanar spectroscopic imaging (EPSI) MR sequence and test it in phantoms, animal models, and then in prostate cancer patients to image the metabolic conversion of hyperpolarized [1‐13C]pyruvate to [1‐13C]lactate with whole gland coverage at high spatial and temporal resolution. Methods: A 3D dynamic compressed sensing (CS)‐EPSI sequence with spectral–spatial excitation was designed to meet the required spatial coverage, time and spatial resolution, and RF limitations of the 3T MR scanner for its clinical translation for prostate cancer patient imaging. After phantom testing, animal studies were performed in rats and transgenic mice with prostate cancers. For patient studies, a GE SPINlab polarizer (GE Healthcare, Waukesha, WI) was used to produce hyperpolarized sterile GMP [1‐13C]pyruvate. 3D dynamic 13C CS‐EPSI data were acquired starting 5 s after injection throughout the gland with a spatial resolution of 0.5 cm3, 18 time frames, 2‐s temporal resolution, and 36 s total acquisition time. Results: Through preclinical testing, the 3D CS‐EPSI sequence developed in this project was shown to provide the desired spectral, temporal, and spatial 5D HP 13C MR data. In human studies, the 3D dynamic HP CS‐EPSI approach provided first‐ever simultaneously volumetric and dynamic images of the LDH‐catalyzed conversion of [1‐13C]pyruvate to [1‐13C]lactate in a biopsy‐proven prostate cancer patient with full gland coverage. Conclusion: The results demonstrate the feasibility to characterize prostate cancer metabolism in animals, and now patients using this new 3D dynamic HP MR technique to measure kPL, the kinetic rate constant of [1‐13C]pyruvate to [1‐13C]lactate conversion. [ABSTRACT FROM AUTHOR]

Purpose: Hyperpolarized carbon‐13 (13C) metabolic imaging is a noninvasive imaging modality for evaluating real‐time metabolism. The purpose of this study was to develop and implement experimental strategies for using [1‐13C]pyruvate to probe in vivo metabolism for patients with brain tumors and other neurological diseases. Methods: The 13C radiofrequency coils and pulse sequences were tested in a phantom and were performed using a 3 Tesla whole‐body scanner. Samples of [1‐13C]pyruvate were polarized using a SPINlab system. Dynamic 13C data were acquired from 8 patients previously diagnosed with brain tumors, who had received treatment and were being followed with serial magnetic resonance scans. Results: The phantom studies produced good‐quality spectra with a reduction in signal intensity in the center attributed to the reception profiles of the 13C receive coils. Dynamic data obtained from a 3‐cm slice through a patient's brain following injection with [1‐13C]pyruvate showed the anticipated arrival of the agent, its conversion to lactate and bicarbonate, and subsequent reduction in signal intensity. A similar temporal pattern was observed in 2D dynamic patient studies, with signals corresponding to pyruvate, lactate, and bicarbonate being in normal appearing brain, but only pyruvate and lactate being detected in regions corresponding to the anatomical lesion. Physiological monitoring and follow‐up confirmed that there were no adverse events associated with the injection. Conclusion: This study has presented the first application of hyperpolarized 13C metabolic imaging in patients with brain tumor and demonstrated the safety and feasibility of using hyperpolarized [1‐13C]pyruvate to evaluate in vivo brain metabolism. Magn Reson Med 80:864–873, 2018. © 2018 International Society for Magnetic Resonance in Medicine. [ABSTRACT FROM AUTHOR]

Purpose Hyperpolarized 13C MRI is a powerful tool for studying metabolism, but can lack tissue specificity. Gadoxetate is a gadolinium-based MRI contrast agent that is selectively taken into hepatocytes. The goal of this project was to investigate whether gadoxetate can be used to selectively suppress the hyperpolarized signal arising from hepatocytes, which could in future studies be applied to generate specificity for signal from abnormal cell types. Methods Baseline gadoxetate uptake kinetics were measured using T1-weighted contrast enhanced imaging. Relaxivity of gadoxetate was measured for [1-13C]pyruvate, [1-13C]lactate, and [1-13C]alanine. Four healthy rats were imaged with hyperpolarized [1-13C]pyruvate using a three-dimensional (3D) MRSI sequence prior to and 15 min following administration of gadoxetate. The lactate:pyruvate ratio and alanine:pyruvate ratios were measured in liver and kidney. Results Overall, the hyperpolarized signal decreased approximately 60% as a result of pre-injection of gadoxetate. In liver, the lactate:pyruvate and alanine:pyruvate ratios decreased 42% and 78%, respectively ( P < 0.05) following gadoxetate administration. In kidneys, these ratios did not change significantly. Relaxivity of gadoxetate for [1-13C]alanine was 12.6 times higher than relaxivity of gadoxetate for [1-13C]pyruvate, explaining the greater selective relaxation effect on alanine. Conclusions The liver-specific gadolinium contrast-agent gadoxetate can selectively suppress normal hepatocyte contributions to hyperpolarized 13C MRI signals. Magn Reson Med 77:2356-2363, 2017. © 2016 International Society for Magnetic Resonance in Medicine [ABSTRACT FROM AUTHOR]

Purpose: Endoluminal ultrasound may serve as a minimally invasive option for delivering thermal ablation to pancreatic tumors adjacent to the stomach or duodenum. The objective of this study was to explore the basic feasibility of this treatment strategy through the design, characterization, and evaluation of proof-of-concept endoluminal ultrasound applicators capable of placement in the gastrointestinal (GI) lumen for volumetric pancreas ablation under MR guidance. Methods: Two variants of the endoluminal applicator, each containing a distinct array of two independently powered transducers (10 × 10 mm 3.2 MHz planar; or 8 × 10 × 20 mm radius of curvature 3.3 MHz curvilinear geometries) at the distal end of a meter long flexible catheter assembly, were designed and fabricated. Transducers and circulatory water flow for acoustic coupling and luminal cooling were contained by a low-profile polyester balloon covering the transducer assembly fixture. Each applicator incorporated miniature spiral MR coils and mechanical features (guiding tips and hinges) to facilitate tracking and insertion through the GI tract under MRI guidance. Acoustic characterization of each device was performed using radiation force balance and hydrophone measurements. Device delivery into the upper GI tract, adjacent to the pancreas, and heating characteristics for treatment of pancreatic tissue were evaluated in MR-guided ex vivo and in vivo porcine experiments. MR guidance was utilized for anatomical target identification, tracking/positioning of the applicator, and MR temperature imaging (MRTI) for PRF-based multislice thermometry, implemented in the real-time RTHawk software environment. Results: Force balance and hydrophone measurements indicated efficiencies of 48.8% and 47.8% and −3 dB intensity beam-widths of 3.2 and 1.2 mm for the planar and curvilinear transducers, respectively. Ex vivo studies on whole-porcine carcasses revealed capabilities of producing ablative temperature rise (ΔT > 15 °C) contours in pancreatic tissue 4-40 mm long and 4-28 mm wide for the planar transducer applicator (1-13 min sonication duration, ~4 W/cm² applied acoustic intensity). Curvilinear transducers produced more selective heating, with a narrower ΔT > 15 °C contour length and width of up to 1-24 mm and 2-7 mm, respectively (1-7 min sonication duration, ~4 W/cm² applied acoustic intensity). Active tracking of the miniature spiral coils was achieved using a Hadamard encoding tracking sequence, enabling real-time determination of each coil's coordinates and automated prescription of imaging planes for thermometry. In vivo MRTI-guided heating trials in three pigs demonstrated capability of ~20 °C temperature elevation in pancreatic tissue at 2 cm depths from the applicator, with 5-7 W/cm² applied intensity and 6-16 min sonication duration. Dimensions of thermal lesions in the pancreas ranged from 12 to 28 mm, 3 to 10 mm, and 5 to 10 mm in length, width, and depth, respectively, as verified through histological analysis of tissue sections. Multiple-baseline reconstruction and respiratory-gated acquisition were demonstrated to be effective strategies in suppressing motion artifacts for clear evolution of temperature profiles during MRTI in the in vivo studies. Conclusions: This study demonstrates the technical feasibility of generating volumetric ablation in pancreatic tissue using endoluminal ultrasound applicators positioned in the stomach lumen. MR guidance facilitates target identification, device tracking/positioning, and treatment monitoring through real-time multislice PRF-based thermometry. [ABSTRACT FROM AUTHOR]

Purpose A novel application of two-dimensional (2D) spatially selective radiofrequency (2DRF) excitation pulses in hyperpolarized [ABSTRACT FROM AUTHOR]

Urchin-like Ag nanowires were prepared by reacting AgNO3(aq) with Cu metal in the presence of cetyltrimethylammonium chloride and HNO3(aq) on a screen printed carbon electrode at room temperature. The diameters of the nanowires were about 100 nm, while the lengths were up to 10 μm. Cyclic voltammetric experiments using the Ag nanowires as the working electrode showed electrocatalytic H2O2 reduction. The electrode exhibited a high sensitivity of 4705 μA mM-1 mg-1 cm-2 from 50 μM to 10.35 mM and a measurable detection limit of 10 μM in amperometric detection. This is the first report on Ag NWs for non-enzymatic H2O2 sensing. [ABSTRACT FROM AUTHOR]

A case study of a 64-year-old woman is presented, who had a 50-mm lesion which was endoscopically diagnosed as a sessile serrated adenoma/polyp without dysplasia.

In this work, it is demonstrated that the negative capacitance effect of ferroelectric Hf1−xZrxO2 transistor is highly correlated with Zr doping concentration. A steep subthreshold swing of 40 mV/decade, a low off‐state leakage current of 190 fA μm−1, and a large on/off current ratio of >107 can be simultaneously achieved in optimized negative capacitance Hf1−xZrxO2 transistor. Besides, the Zr diffusion issue and non‐ferroelectric phases significantly affect the multi‐domain switching of polycrystalline Hf1−xZrxO2. Therefore, an appropriate amount of Zr substitution is more favorable for both boosting ferroelectric and implementing the negative capacitance switch. [ABSTRACT FROM AUTHOR]

MRI using hyperpolarized (HP) carbon‐13 pyruvate is being investigated in clinical trials to provide non‐invasive measurements of metabolism for cancer and cardiac imaging. In this project, we applied HP [1‐13C]pyruvate dynamic MRI in prostate cancer to measure the conversion from pyruvate to lactate, which is expected to increase in aggressive cancers. The goal of this work was to develop and test analysis methods for improved quantification of this metabolic conversion. In this work, we compared specialized kinetic modeling methods to estimate the pyruvate‐to‐lactate conversion rate, kPL, as well as the lactate‐to‐pyruvate area‐under‐curve (AUC) ratio. The kinetic modeling included an "inputless" method requiring no assumptions regarding the input function, as well as a method incorporating bolus characteristics in the fitting. These were first evaluated with simulated data designed to match human prostate data, where we examined the expected sensitivity of metabolism quantification to variations in kPL, signal‐to‐noise ratio (SNR), bolus characteristics, relaxation rates, and B1 variability. They were then applied to 17 prostate cancer patient datasets. The simulations indicated that the inputless method with fixed relaxation rates provided high expected accuracy with no sensitivity to bolus characteristics. The AUC ratio showed an undesired strong sensitivity to bolus variations. Fitting the input function as well did not improve accuracy over the inputless method. In vivo results showed qualitatively accurate kPL maps with inputless fitting. The AUC ratio was sensitive to bolus delivery variations. Fitting with the input function showed high variability in parameter maps. Overall, we found the inputless kPL fitting method to be a simple, robust approach for quantification of metabolic conversion following HP [1‐13C]pyruvate injection in human prostate cancer studies. This study also provided initial ranges of HP [1‐13C]pyruvate parameters (SNR, kPL, bolus characteristics) in the human prostate. Analysis methods, including kinetic models and area‐under‐curve (AUC) methods, for hyperpolarized (HP) 13C‐pyruvate MRI were investigated to provide robust and accurate quantifications of metabolism for patient studies of prostate cancer. Simulation and in vivo results showed that an inputless pyruvate‐to‐lactate rate (kPL) fitting method was relatively robust for low SNR data acquired with any flip‐angle scheme and across a range of bolus characteristics. Such robust analysis methods are essential as HP 13C‐pyruvate MRI enters more widespread clinical application. [ABSTRACT FROM AUTHOR]