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Introduction: COVID-19 is a disease caused by the severe acute respiratory syndrome coronavirus 2 that has appeared as a global pandemic in recent times. Currently, the transmission rate has slowed down significantly, but the definite pathological reason behind this is still unknown. Therefore, the prevalence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody must be studied to establish the relation between the rate of transmission and antibody presence. Materials and Methods: A clinical assessment was performed to evaluate the seroprevalence of SARS-CoV-2 Immunoglobulin G (IgG) antibodies among 299 healthy volunteers in the period of February to May 2021. Serum samples were analyzed using chemiluminescent microparticle immunoassay (CMIA) technology to detect the presence of IgG antibodies. Result: It was observed that 21% of the participants were seropositive, and 78% of the population was seronegative across the different genders. This confirmed that the generation of antibodies is independent of gender. Simultaneously, a t-test was performed that further suggested no statistical correlation between gender and seroprevalence. Moreover, a comprehensive analysis was performed to establish the relation between age and blood group with the seroprevalence. However, there was no statistical relationship found among these parameters. Conclusion: This study assisted in examining the underlying causes of high or low seroprevalence among healthy volunteers.

Summary: Background: NVX-CoV2373, a Covid-19 vaccine was developed in the USA with ∼90% efficacy. The same vaccine is manufactured in India after technology transfer (called as SII-NVX-CoV2373), was evaluated in this phase 2/3 immuno-bridging study. Methods: This was an observer-blind, randomised, phase 2/3 study in 1600 adults. In phase 2, 200 participants were randomized 3:1 to SII-NVX-CoV2373 or placebo. In phase 3, 1400 participants were randomized 3:1 to SII-NVX-CoV2373 or NVX-CoV2373 (940 safety cohort and 460 immunogenicity cohort). Two doses of study products (SII-NVX-CoV2373, NVX-CoV2373 or placebo) were given 3 weeks apart. Primary objectives were to demonstrate non-inferiority of SII-NVX-CoV2373 to NVX-CoV2373 in terms of geometric mean ELISA units (GMEU) ratio of anti-S IgG antibodies 14 days after the second dose (day 36) and to determine the incidence of causally related serious adverse events (SAEs) through 180 days after the first dose. Anti-S IgG response was assessed using an Enzyme-Linked Immunosorbent Assay (ELISA) and neutralizing antibodies (nAb) were assessed by a microneutralization assay using wild type SARS CoV-2 in participants from the immunogenicity cohort at baseline, day 22, day 36 and day 180. Cell mediated immune (CMI) response was assessed in a subset of 28 participants from immunogenicity cohort by ELISpot assay at baseline, day 36 and day 180. The total follow-up was for 6 months. Trial registration: CTRI/2021/02/031554. Findings: Total 1596 participants (200 in Phase 2 and 1396 in Phase 3) received the first dose. SII-NVX-CoV2373 was found non-inferior to NVX-CoV2373 (anti-S IgG antibodies GMEU ratio 0.91; 95% CI: 0.79, 1.06). At day 36, there was more than 58-fold rise in anti-S IgG and nAb titers compared to baseline in both the groups. On day 180 visit, these antibody titers declined to levels slightly lower than those after the first dose (13–22 fold-rise above baseline). Incidence of unsolicited and solicited AEs was similar between the SII-NVX-CoV2373 and NVX-CoV2373 groups. No adverse event of special interest (AESI) was reported. No causally related SAE was reported. Interpretation: SII-NVX-CoV2373 induced a non-inferior immune response compared to NVX-CoV2373 and has acceptable safety profile. Funding: SIIPL, Indian Council of Medical Research, Novavax.

Purpose: This study is to investigate time-resolved 13 C MR spectroscopy (MRS) as an alternative to imaging for assessing pyruvate metabolism using hyperpolarized (HP) [1- 13 C]pyruvate in the human brain., Methods: Time-resolved 13 C spectra were acquired from four axial brain slices of healthy human participants (n = 4) after a bolus injection of HP [1- 13 C]pyruvate. 13 C MRS with low flip-angle excitations and a multichannel 13 C/ 1 H dual-frequency radiofrequency (RF) coil were exploited for reliable and unperturbed assessment of HP pyruvate metabolism. Slice-wise areas under the curve (AUCs) of 13 C-metabolites were measured and kinetic analysis was performed to estimate the production rates of lactate and HCO 3 - . Linear regression analysis between brain volumes and HP signals was performed. Region-focused pyruvate metabolism was estimated using coil-wise 13 C reconstruction. Reproducibility of HP pyruvate exams was presented by performing two consecutive injections with a 45-minutes interval., Results: [1- 13 C]Lactate relative to the total 13 C signal (tC) was 0.21-0.24 in all slices. [ 13 C] HCO 3 - /tC was 0.065-0.091. Apparent conversion rate constants from pyruvate to lactate and HCO 3 - were calculated as 0.014-0.018 s -1 and 0.0043-0.0056 s -1 , respectively. Pyruvate/tC and lactate/tC were in moderate linear relationships with fractional gray matter volume within each slice. White matter presented poor linear regression fit with HP signals, and moderate correlations of the fractional cerebrospinal fluid volume with pyruvate/tC and lactate/tC were measured. Measured HP signals were comparable between two consecutive exams with HP [1- 13 C]pyruvate., Conclusions: Dynamic MRS in combination with multichannel RF coils is an affordable and reliable alternative to imaging methods in investigating cerebral metabolism using HP [1- 13 C]pyruvate., (© 2021 International Society for Magnetic Resonance in Medicine.)

Purpose: Previous cardiac imaging studies using hyperpolarized (HP) [1- 13 C]pyruvate were acquired at end-diastole (ED). Little is known about the interaction between cardiac cycle and metabolite content in the myocardium. In this study, we compared images of HP pyruvate and products at end-systole (ES) and ED., Methods: A dual-phase 13 C MRI sequence was implemented to acquire two sequential HP images within a single cardiac cycle at ES and ED during successive R-R intervals in an interleaved manner. Each healthy volunteer (N = 3) received two injections of HP [1- 13 C]pyruvate for the dual-phase imaging on the short-axis and the vertical long-axis planes. Spatial distribution of HP 13 C metabolites at each cardiac phase was correlated to multiphase 1 H MRI to confirm the mechanical changes. Ratios of myocardial HP metabolites were compared between ES and ED. Segmental analysis was performed on the midcavity short-axis plane., Results: In addition to mechanical changes, metabolic profiles of the heart detected by HP [1- 13 C]pyruvate differed between ES and ED. The myocardial signal of [ 13 C]bicarbonate relative to [1- 13 C]lactate was significantly smaller at ED than the ratio at ES (p < .05), particularly in mid-anterior and mid-inferoseptal segments. The distinct metabolic profiles in the myocardium likely reflect the technical aspects of the imaging approach such as the coronary flow in addition to the cyclical changes in metabolism., Conclusion: The study demonstrates that metabolic profiles of the heart, measured by HP [1- 13 C]pyruvate, are affected by the cardiac cycle in which that the data are acquired., (© 2021 International Society for Magnetic Resonance in Medicine.)

Background Pyruvate dehydrogenase (PDH) and lactate dehydrogenase are essential for adenosine triphosphate production in skeletal muscle. At the onset of exercise, oxidation of glucose and glycogen is quickly enabled by dephosphorylation of PDH. However, direct measurement of PDH flux in exercising human muscle is daunting, and the net effect of covalent modification and other control mechanisms on PDH flux has not been assessed. Purpose To demonstrate the feasibility of assessing PDH activation and changes in pyruvate metabolism in human skeletal muscle after the onset of exercise using carbon 13 ( 13 C) MRI with hyperpolarized (HP) [1- 13 C]-pyruvate. Materials and Methods For this prospective study, sedentary adults in good general health (mean age, 42 years ± 18 [standard deviation]; six men) were recruited from August 2019 to September 2020. Subgroups of the participants were injected with HP [1- 13 C]-pyruvate at resting, during plantar flexion exercise, or 5 minutes after exercise during recovery. In parallel, hydrogen 1 arterial spin labeling MRI was performed to estimate muscle tissue perfusion. An unpaired t test was used for comparing 13 C data among the states. Results At rest, HP [1- 13 C]-lactate and [1- 13 C]-alanine were detected in calf muscle, but [ 13 C]-bicarbonate was negligible. During moderate flexion-extension exercise, total HP 13 C signals (tC) increased 2.8-fold because of increased muscle perfusion ( P = .005), and HP [1- 13 C]-lactate-to-tC ratio increased 1.7-fold ( P = .04). HP [ 13 C]-bicarbonate-to-tC ratio increased 8.4-fold ( P = .002) and returned to the resting level 5 minutes after exercise, whereas the lactate-to-tC ratio continued to increase to 2.3-fold as compared with resting ( P = .008). Conclusion Lactate and bicarbonate production from hyperpolarized (HP) [1-carbon 13 { 13 C}]-pyruvate in skeletal muscle rapidly reflected the onset and the termination of exercise. These results demonstrate the feasibility of imaging skeletal muscle metabolism using HP [1- 13 C]-pyruvate MRI and the sensitivity of in vivo pyruvate metabolism to exercise states. © RSNA, 2021 Online supplemental material is available for this article.

Purpose: Noninvasive imaging with hyperpolarized (HP) pyruvate can capture in vivo cardiac metabolism. For proper quantification of the metabolites and optimization of imaging parameters, understanding MR characteristics such as T 2 ∗ s of the HP signals is critical. This study is to measure in vivo cardiac T 2 ∗ s of HP [1- 13 C]pyruvate and the products in rodents and humans., Methods: A dynamic 13 C multi-echo spiral imaging sequence that acquires [ 13 C]bicarbonate, [1- 13 C]lactate, and [1- 13 C]pyruvate images in an interleaved manner was implemented for a clinical 3 Tesla system. T 2 ∗ of each metabolite was calculated from the multi-echo images by fitting the signal decay of each region of interest mono-exponentially. The performance of measuring T 2 ∗ using the sequence was first validated using a 13 C phantom and then with rodents following a bolus injection of HP [1- 13 C]pyruvate. In humans, T 2 ∗ of each metabolite was calculated for left ventricle, right ventricle, and myocardium., Results: Cardiac T 2 ∗ s of HP [1- 13 C]pyruvate, [1- 13 C]lactate, and [ 13 C]bicarbonate in rodents were measured as 24.9 ± 5.0, 16.4 ± 4.7, and 16.9 ± 3.4 ms, respectively. In humans, T 2 ∗ of [1- 13 C]pyruvate was 108.7 ± 22.6 ms in left ventricle and 129.4 ± 8.9 ms in right ventricle. T 2 ∗ of [1- 13 C]lactate was 40.9 ± 8.3, 44.2 ± 5.5, and 43.7 ± 9.0 ms in left ventricle, right ventricle, and myocardium, respectively. T 2 ∗ of [ 13 C]bicarbonate in myocardium was 64.4 ± 2.5 ms. The measurements were reproducible and consistent over time after the pyruvate injection., Conclusion: The proposed metabolite-selective multi-echo spiral imaging sequence reliably measures in vivo cardiac T 2 ∗ s of HP [1- 13 C]pyruvate and products., (© 2021 International Society for Magnetic Resonance in Medicine.)

Yttrium (III) complexes are interesting due to the similarity of their chemistry with gadolinium complexes that are used as contrast agents in nuclear magnetic resonance (NMR) spectroscopy or imaging (MRI). While most of the paramagnetic Gd 3+ -based MRI contrast agents are T 1 or T 2 relaxation-based sensors such as Gd 3+ -complexes for zinc or pH detection, a number of diamagnetic Y 3+ -complexes rely on changes in the chemical shift for potential quantitative MRI in biological milieu. 89 Y, however, is a challenging nucleus to work with in conventional NMR or MRI due to its inherently low sensitivity and relatively long T 1 relaxation time. This insensitivity problem in 89 Y-based complexes can be circumvented with the use of dissolution dynamic nuclear polarization (DNP) which allows for several thousand-fold enhancement of the NMR or MRI signal relative to thermal equilibrium signal. Herein, we report on the feasibility of using hyperpolarized 89 Y-complexes with phosphonated open-chain ligands, 89 Y-EDTMP and 89 Y-DTPMP, as potential chemical shift-based pH NMR sensors. Our DNP-NMR data show that hyperpolarized 89 Y-DTPMP has an apparent pK a  ~ 7.01 with a 4 ppm-wide chemical shift dispersion with the signal disappearing at pH below 6.2. On the other hand, pH titration data on hyperpolarized 89 Y-EDTMP show that it has an apparent pK a of pH 6.7 and a 16-ppm wide chemical shift dispersion at pH 5-9 range. In comparison, the previously reported hyperpolarized pH NMR sensor 89 Y-DOTP has a pK a of 7.64 and ~ 10-ppm wide chemical shift dispersion at pH 4-9 range. Overall, our data suggest that hyperpolarized 89 Y-EDTMP is better than hyperpolarized 89 Y-DOTP in terms of pH sensing capability at the physiological range., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Low-density lipoprotein nanoparticles reconstituted with unesterified docosahexaenoic acid (LDL-DHA) is promising nanomedicine with enhanced physicochemical stability and selective anticancer cytotoxic activity. The unique functionality of LDL-DHA ultimately relates to the structure of this nanoparticle. To date, however, little is known about the structural organization of this nanoparticle. In this study chemical, spectroscopic and electron microscopy analyses were undertaken to elucidate the structural and molecular organization of LDL-DHA nanoparticles. Unesterified DHA preferentially incorporates into the outer surface layer of LDL, where in this orientation the anionic carboxyl end of DHA is exposed to the LDL surface and imparts an electronegative charge to the nanoparticles surface. This negative surface charge promotes the monodisperse and homogeneous distribution of LDL-DHA nanoparticles in solution. Further structural analyses with cryo-electron microscopy revealed that the LDL-DHA nanostructure consist of a phospholipid bilayer surrounding an aqueous core, which is distinctly different from the phospholipid monolayer/apolar core organization of plasma LDL. Lastly, apolipoprotein B-100 remains strongly associated with this complex and maintains a discrete size and shape of the LDL-DHA nanoparticles similar to plasma LDL. This preliminary structural assessment of LDL-DHA now affords the opportunity to understand the important structure-function relationships of this novel nanoparticle., (Copyright © 2017 Elsevier B.V. All rights reserved.)

(13)C-enriched compounds are readily metabolized in human malignancies. Fragments of the tumor, acquired by biopsy or surgical resection, may be acid-extracted and (13)C NMR spectroscopy of metabolites such as glutamate, glutamine, 2-hydroxyglutarate, lactate and others provide a rich source of information about tumor metabolism in situ. Recently we observed (13)C-(13)C spin-spin coupling in (13)C NMR spectra of lactate in brain tumors removed from patients who were infused with [1,2-(13)C]acetate prior to the surgery. We found, in four patients, that infusion of (13)C-enriched acetate was associated with synthesis of (13)C-enriched glucose, detectable in plasma. (13)C labeled glucose derived from [1,2-(13)C]acetate metabolism in the liver and the brain pyruvate recycling in the tumor together lead to the production of the (13)C labeled lactate pool in the brain tumor. Their combined contribution to acetate metabolism in the brain tumors was less than 4.0%, significantly lower than the direct oxidation of acetate in the citric acid cycle in tumors., (Copyright © 2016. Published by Elsevier Ltd.)

(13)C NMR (nuclear magnetic resonance) spectroscopy of extracts from patient tumor samples provides rich information about metabolism. However, in isocitrate dehydrogenase (IDH)-mutant gliomas, (13)C labeling is obscured in oncometabolite 2-hydroxyglutaric acid (2 HG) by glutamate and glutamine, prompting development of a simple method to resolve the metabolites. J-coupled multiplets in 2 HG were similar to glutamate and glutamine and could be clearly resolved at pH 6. A cryogenically cooled (13)C probe, but not J-resolved heteronuclear single quantum coherence spectroscopy, significantly improved detection of 2 HG. These methods enable the monitoring of (13)C-(13)C spin-spin couplings in 2 HG expressing IDH-mutant gliomas., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: A main obstacle to in vivo applications of paramagnetic chemical exchange saturation transfer (paraCEST) is interference from endogenous tissue magnetization transfer contrast (MTC). The suitability of excitation-based frequency labeled exchange transfer (FLEX) to separate out such MTC effects in vivo was tested., Methods: The FLEX sequence measures modulation of the water signal based on the chemical shift evolution of solute proton magnetization as a function of evolution time. Time-domain analysis of this water signal allows identification of different solute components and provides a mechanism to separate out the rapidly decaying MTC components with short effective transverse relaxation time ( T2*) values., Results: FLEX imaging of paraCEST agents was possible in vitro in phantoms and in vivo in mouse kidneys and bladder. The results demonstrated that FLEX is capable of separating out the MTC signal from tissues in vivo while providing a quantitative exchange rate for the rapidly exchanging paraCEST water protons by fitting the FLEX time-domain signal to FLEX theory., Conclusions: The first in vivo FLEX images of a paraCEST agent were acquired, which allowed separation of the tissue MTC components. These results show that FLEX imaging has potential for imaging the distribution of functional paraCEST agents in biological tissues., (Copyright © 2013 Wiley Periodicals, Inc.)

Paramagnetic chemical exchange saturation transfer agents combine the benefits of a large chemical shift difference and a fast exchange rate for sensitive MRI detection. However, the in vivo detection of these agents is hampered by the need for high B(1) fields to allow sufficiently fast saturation before exchange occurs, thus causing interference of large magnetization transfer effects from semisolid macromolecules. A recently developed approach named frequency-labeled exchange transfer utilizes excitation pulses instead of saturation pulses for detecting the exchanging protons. Using solutions and gel phantoms containing the europium (III) complex of DOTA tetraglycinate (EuDOTA-(gly)(-) (4) ), it is shown that frequency-labeled exchange transfer allows the separation of chemical exchange effects and magnetization transfer (MT) effects in the time domain, therefore allowing the study of the individual resonance of rapidly exchanging water molecules (k(ex) >10(4) s(-1) ) without interference from conventional broad-band MT., (Copyright © 2012 Wiley Periodicals, Inc.)

The efficiency of chemical exchange dependent saturation transfer (CEST) agents is largely determined by their water or proton exchange kinetics, yet methods to measure such exchange rates are variable and many are not applicable to in vivo measurements. In this work, the water exchange kinetics of two prototype paramagnetic agents (PARACEST) are compared by using data from classic NMR line-width measurements, by fitting CEST spectra to the Bloch equations modified for chemical exchange, and by a method where CEST intensity is measured as a function of applied amplitude of radiofrequency field. A relationship is derived that provides the water exchange rate from the X-intercept of a plot of steady-state CEST intensity divided by reduction in signal caused by CEST irradiation versus 1/omega(1)(2), referred to here as an omega plot. Furthermore, it is shown that this relationship is independent of agent concentration. Exchange rates derived from omega plots using either high-resolution CEST NMR data or CEST data obtained by imaging agree favorably with exchange rates measured by the more commonly used Bloch fitting and line-width methods. Thus, this new method potentially allows access to a direct measure of exchange rates in vivo, where the agent concentration is typically unknown., ((c) 2010 Wiley-Liss, Inc.)

The properties of a novel Gd(3+)-based MRI zinc sensor are reported. Unlike previously reported Gd(3+)-based MRI contrast agents, this agent (GdL) differs in that the agent alone binds only weakly with human serum albumin (HSA), while the 1:2 GdL:Zn(2+) ternary complex binds strongly to HSA resulting in a substantial, 3-fold increase in water proton relaxivity. The GdL complex is shown to have a relatively strong binding affinity for Zn(2+) (K(D) = 33.6 nM), similar to the affinity of the Zn(2+) ion with HSA alone. The agent detects as little as 30 microM Zn(2+) in the presence of HSA by MRI in vitro, a value slightly more than the total Zn(2+) concentration in blood (approximately 20 microM). This combination of binding affinity constants and the high relaxivity of the agent when bound to HSA suggests that this new agent may be useful for detection of free Zn(2+) ions in vivo without disrupting other important biological processes involving Zn(2+).