Fast deep learning reconstruction techniques for preclinical magnetic resonance fingerprinting.

We propose a deep learning (DL) model and a hyperparameter optimization strategy to reconstruct T1 and T2 maps acquired with the magnetic resonance fingerprinting (MRF) methodology. We applied two different MRF sequence routines to acquire images of ex vivo rat brain phantoms using a 7-T preclinical scanner. Subsequently, the DL model was trained using experimental data, completely excluding the use of any theoretical MRI signal simulator. The best combination of the DL parameters was implemented by an automatic hyperparameter optimization strategy, whose key aspect is to include all the parameters to the fit, allowing the simultaneous optimization of the neural network architecture, the structure of the DL model, and the supervised learning algorithm. By comparing the reconstruction performances of the DL technique with those achieved from the traditional dictionary-based method on an independent dataset, the DL approach was shown to reduce the mean percentage relative error by a factor of 3 for T1 and by a factor of 2 for T2 , and to improve the computational time by at least a factor of 37. Furthermore, the proposed DL method enables maintaining comparable reconstruction performance, even with a lower number of MRF images and a reduced k-space sampling percentage, with respect to the dictionary-based method. Our results suggest that the proposed DL methodology may offer an improvement in reconstruction accuracy, as well as speeding up MRF for preclinical, and in prospective clinical, investigations.

Longitudinal and transverse NMR relaxivities of Ln(III)-DOTA complexes: A comprehensive investigation.

Longitudinal and transverse 1H nuclear magnetic resonance relaxivities of Ln(III)-DOTA complexes (with Ln = Gd, Tb, Dy, Er; DOTA = 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid) and Mn(II) aqueous solutions were measured in a wide range of frequencies, 10 kHz to 700 MHz. The experimental data were interpreted by means of models derived from the Solomon-Bloembergen-Morgan theory. The data analysis was performed assuming the orbital angular momentum L = 0 for Gd-DOTA and the aqua ion [Mn(H2O)6]2+ and L ≠ 0 for Dy-, Tb-, and Er-DOTA. A refined estimation of the zero-field-splitting barrier Δ and of the modulation correlation time τv was obtained for [Mn(H2O)6]2+ by extending the fitting of nuclear magnetic relaxation dispersion profiles to the low-field regime. The Gd-DOTA fitting parameters resulted in good agreement with the literature, and the fit of transverse relaxivity data confirmed the negligibility of the scalar interaction in the nuclear relaxation mechanism. Larger transverse relaxivities of Dy-DOTA and Tb-DOTA (∼10 mM-1 s-1) with respect to Er-DOTA (∼1 mM-1 s-1) were observed at 16 T. Such higher values are suggested to be due to a shorter residence time τm that is possibly linked to the fluctuations of the hyperfine interaction and the different shape of the magnetic anisotropy. The possible employment of Dy-DOTA, Tb-DOTA, and Er-DOTA as negative magnetic resonance imaging contrast agents for high-field applications was envisaged by collecting spin-echo images at 7 T. Particularly in Dy- and Tb-derivatives, the transverse relaxivity at 16 T is of the order of the Gd-one at 1.5 T.

Calorimetric glass transition in a mean-field theory approach.

The study of the properties of glass-forming liquids is difficult for many reasons. Analytic solutions of mean-field models are usually available only for systems embedded in a space with an unphysically high number of spatial dimensions; on the experimental and numerical side, the study of the properties of metastable glassy states requires thermalizing the system in the supercooled liquid phase, where the thermalization time may be extremely large. We consider here a hard-sphere mean-field model that is solvable in any number of spatial dimensions; moreover, we easily obtain thermalized configurations even in the glass phase. We study the 3D version of this model and we perform Monte Carlo simulations that mimic heating and cooling experiments performed on ultrastable glasses. The numerical findings are in good agreement with the analytical results and qualitatively capture the features of ultrastable glasses observed in experiments.

Link Prediction in Bipartite Nested Networks.

Real networks typically studied in various research fields-ecology and economic complexity, for example-often exhibit a nested topology, which means that the neighborhoods of high-degree nodes tend to include the neighborhoods of low-degree nodes. Focusing on nested networks, we study the problem of link prediction in complex networks, which aims at identifying likely candidates for missing links. We find that a new method that takes network nestedness into account outperforms well-established link-prediction methods not only when the input networks are sufficiently nested, but also for networks where the nested structure is imperfect. Our study paves the way to search for optimal methods for link prediction in nested networks, which might be beneficial for World Trade and ecological network analysis.

Nestedness Maximization in Complex Networks through the Fitness-Complexity Algorithm.

Nestedness refers to the structural property of complex networks that the neighborhood of a given node is a subset of the neighborhoods of better-connected nodes. Following the seminal work by Patterson and Atmar (1986), ecologists have been long interested in revealing the configuration of maximal nestedness of spatial and interaction matrices of ecological communities. In ecology, the BINMATNEST genetic algorithm can be considered as the state-of-the-art approach for this task. On the other hand, the fitness-complexity ranking algorithm has been recently introduced in the economic complexity literature with the original goal to rank countries and products in World Trade export networks. Here, by bringing together quantitative methods from ecology and economic complexity, we show that the fitness-complexity algorithm is highly effective in the nestedness maximization task. More specifically, it generates matrices that are more nested than the optimal ones by BINMATNEST for 61.27% of the analyzed mutualistic networks. Our findings on ecological and World Trade data suggest that beyond its applications in economic complexity, the fitness-complexity algorithm has the potential to become a standard tool in nestedness analysis.

Nano and sub-nano multiscale porosity formation and other features revealed by 1H NMR relaxometry during cement hydration.

Cement hydration occurs when water is added to cement powder, leading to the formation of crystalline products like Portlandite and the quasi-amorphous, poorly crystalline, calcium silicate hydrate (C-S-H) gel. Despite its importance in determining the final properties of the cement, many models exist for the nano and sub-nano level organization of this "liquid stone." (1)H NMR relaxometry in White Portland Cement paste during hydration allowed us to monitor the formation and evolution of the multiscale porosity of the cement, with the formation of structures at nano and sub-nano levels of C-S-H gel (calcium silicate interlayer water, water in small and large gel pores) along with three low-mobility (1)H pools, identified as (1)H nuclei in C-S-H layers, likely belonging to OH groups, with (1)H nuclei in Portlandite, and in crystal water of Ettringite. By assuming these assignments, our data allowed us to compute the distances of pairs of (1)H nuclei in Portlandite and in crystal water ((1.9 ± 0.2) Å and (1.6 ± 0.1) Å, respectively), consistent with the known values of these distances. The picture of the porous structure at nano and sub-nano levels emerging from our results is consistent with the Jennings colloidal model for C-S-H gel. Moreover, the constant values observed during hydration of parameters extracted from our data analysis strongly support that model, being compatible with the picture of C-S-H gel developing in comparable-sized clumps of the same composition, but not easily interpretable by models proposing quasi continuous sheets of C-S-H layers.

Beyond network centrality: individual-level behavioral traits for predicting information superspreaders in social media.

Understanding the heterogeneous role of individuals in large-scale information spreading is essential to manage online behavior as well as its potential offline consequences. To this end, most existing studies from diverse research domains focus on the disproportionate role played by highly connected 'hub' individuals. However, we demonstrate here that information superspreaders in online social media are best understood and predicted by simultaneously considering two individual-level behavioral traits: influence and susceptibility. Specifically, we derive a nonlinear network-based algorithm to quantify individuals' influence and susceptibility from multiple spreading event data. By applying the algorithm to large-scale data from Twitter and Weibo, we demonstrate that individuals' estimated influence and susceptibility scores enable predictions of future superspreaders above and beyond network centrality, and reveal new insights into the network positions of the superspreaders.

CT and MRI radiomic features of lung cancer (NSCLC): comparison and software consistency.

BACKGROUND: Radiomics is a quantitative approach that allows the extraction of mineable data from medical images. Despite the growing clinical interest, radiomics studies are affected by variability stemming from analysis choices. We aimed to investigate the agreement between two open-source radiomics software for both contrast-enhanced computed tomography (CT) and contrast-enhanced magnetic resonance imaging (MRI) of lung cancers and to preliminarily evaluate the existence of radiomic features stable for both techniques. METHODS: Contrast-enhanced CT and MRI images of 35 patients affected with non-small cell lung cancer (NSCLC) were manually segmented and preprocessed using three different methods. Sixty-six Image Biomarker Standardisation Initiative-compliant features common to the considered platforms, PyRadiomics and LIFEx, were extracted. The correlation among features with the same mathematical definition was analyzed by comparing PyRadiomics and LIFEx (at fixed imaging technique), and MRI with CT results (for the same software). RESULTS: When assessing the agreement between LIFEx and PyRadiomics across the considered resampling, the maximum statistically significant correlations were observed to be 94% for CT features and 95% for MRI ones. When examining the correlation between features extracted from contrast-enhanced CT and MRI using the same software, higher significant correspondences were identified in 11% of features for both software. CONCLUSIONS: Considering NSCLC, (i) for both imaging techniques, LIFEx and PyRadiomics agreed on average for 90% of features, with MRI being more affected by resampling and (ii) CT and MRI contained mostly non-redundant information, but there are shape features and, more importantly, texture features that can be singled out by both techniques. RELEVANCE STATEMENT: Identifying and selecting features that are stable cross-modalities may be one of the strategies to pave the way for radiomics clinical translation. KEY POINTS: • More than 90% of LIFEx and PyRadiomics features contain the same information. • Ten percent of features (shape, texture) are stable among contrast-enhanced CT and MRI. • Software compliance and cross-modalities stability features are impacted by the resampling method.

Investigation on NMR relaxivity of nano-sized cyano-bridged coordination polymers.

We present the first comparative investigation of the Nuclear Magnetic Resonance (NMR) relaxivity of a series of nanosized cyano-bridged coordination networks stabilized in aqueous solution. These Ln(3+)/[Fe(CN)6](3-) (Ln = Gd, Tb, Y) and M(2+)/[Fe(CN)6](3-) (M = Ni, Cu, Fe) nanoparticles with sizes ranging from 1.4 to 5.5 nm are stabilized by polyethylene glycols (MW = 400 or 1000), polyethylene glycol functionalized with amine groups (MW = 1500), or by N-acetyl-D-glucosamine. The evaluation of NMR relaxivity allowed estimation of the Magnetic Resonance Imaging (MRI) contrast efficiency of our systems. The results demonstrate that Gd(3+)/[Fe(CN)6](3-) nanoparticles have r1p and r2p relaxivities about four times higher than the values observed in the same conditions for the commercial Contrast Agents (CAs) ProHance or Omniscan, regardless of the stabilizing agent used, while nanoparticles of Prussian blue and its analogues M(2+)/[Fe(CN)6](3-) (M = Ni, Cu, Fe) present relatively modest values. The influence of the chemical composition of the nanoparticles, their crystal structure, spin values of lanthanide and transition metal ions, and stabilizing agent on the relaxivity values are investigated and discussed.

A time-domain nuclear magnetic resonance study of Mediterranean scleractinian corals reveals skeletal-porosity sensitivity to environmental changes.

Mediterranean corals are a natural model for studying global warming, as the Mediterranean basin is expected to be one of the most affected regions and the increase in temperature is one of the greatest threats for coral survival. We have analyzed for the first time with time-domain nuclear magnetic resonance (TD-NMR) the porosity and pore-space structure, important aspects of coral skeletons, of two scleractinian corals, Balanophyllia europaea (zooxanthellate) and Leptopsammia pruvoti (nonzooxanthellate), taken from three different sites on the western Italian coast along a temperature gradient. Comparisons have been made with mercury intrusion porosimetry and scanning electron microscopy images. TD-NMR parameters are sensitive to changes in the pore structure of the two coral species. A parameter, related to the porosity, is larger for L. pruvoti than for B. europaea, confirming previous non-NMR results. Another parameter representing the fraction of the pore volume with pore sizes of less than 10-20 µm is inversely related, with a high degree of statistical significance, to the mass of the specimen and, for B. europaea, to the temperature of the growing site. This effect in the zooxanthellate species, which could reduce its resistance to mechanical stresses, may depend on an inhibition of the photosynthetic process at elevated temperatures and could have particular consequences in determining the effects of global warming on these species.

The effect of size, shape, coating and functionalization on nuclear relaxation properties in iron oxide core-shell nanoparticles: a brief review of the situation.

In this perspective article, we present a short selection of some of the most significant case studies on magnetic nanoparticles for potential applications in nanomedicine, mainly magnetic resonance. For almost 10 years, our research activity focused on the comprehension of the physical mechanisms on the basis of the nuclear relaxation of magnetic nanoparticles in the presence of magnetic fields; taking advantage of the insights gathered over this time span, we report on the dependence of the relaxation behaviour on the chemico-physical properties of magnetic nanoparticles and discuss them in full detail. In particular, a critical review is carried out on the correlations between their efficiency as contrast agents in magnetic resonance imaging and the magnetic core of magnetic nanoparticles (mainly iron oxides), their size and shape, and the coating and solvent used for making them biocompatible and well dispersible in physiological media. Finally, the heuristic model proposed by Roch and coworkers is presented, as it was extensively adopted to describe most of the experimental data sets. The large amount of data analyzed allowed us to highlight both the advantages and limitations of the model.

1H-NMR Relaxation of Ferrite Core-Shell Nanoparticles: Evaluation of the Coating Effect.

We investigated the effect of different organic coatings on the 1H-NMR relaxation properties of ultra-small iron-oxide-based magnetic nanoparticles. The first set of nanoparticles, with a magnetic core diameter ds1 = 4.4 ± 0.7 nm, was coated with polyacrylic acid (PAA) and dimercaptosuccinic acid (DMSA), while the second set, ds2 = 8.9 ± 0.9 nm, was coated with aminopropylphosphonic acid (APPA) and DMSA. At fixed core diameters but different coatings, magnetization measurements revealed a similar behavior as a function of temperature and field. On the other hand, the 1H-NMR longitudinal r1 nuclear relaxivity in the frequency range ν = 10 kHz ÷ 300 MHz displayed, for the smallest particles (diameter ds1), an intensity and a frequency behavior dependent on the kind of coating, thus indicating different electronic spin dynamics. Conversely, no differences were found in the r1 relaxivity of the biggest particles (ds2) when the coating was changed. It is concluded that, when the surface to volume ratio, i.e., the surface to bulk spins ratio, increases (smallest nanoparticles), the spin dynamics change significantly, possibly due to the contribution of surface spin dynamics/topology.

Proton Therapy, Magnetic Nanoparticles and Hyperthermia as Combined Treatment for Pancreatic BxPC3 Tumor Cells.

We present an investigation of the effects on BxPC3 pancreatic cancer cells of proton therapy combined with hyperthermia, assisted by magnetic fluid hyperthermia performed with the use of magnetic nanoparticles. The cells' response to the combined treatment has been evaluated by means of the clonogenic survival assay and the estimation of DNA Double Strand Breaks (DSBs). The Reactive Oxygen Species (ROS) production, the tumor cell invasion and the cell cycle variations have also been studied. The experimental results have shown that the combination of proton therapy, MNPs administration and hyperthermia gives a clonogenic survival that is much smaller than the single irradiation treatment at all doses, thus suggesting a new effective combined therapy for the pancreatic tumor. Importantly, the effect of the therapies used here is synergistic. Moreover, after proton irradiation, the hyperthermia treatment was able to increase the number of DSBs, even though just at 6 h after the treatment. Noticeably, the magnetic nanoparticles' presence induces radiosensitization effects, and hyperthermia increases the production of ROS, which contributes to cytotoxic cellular effects and to a wide variety of lesions including DNA damage. The present study indicates a new way for clinical translation of combined therapies, also in the vision of an increasing number of hospitals that will use the proton therapy technique in the near future for different kinds of radio-resistant cancers.

The simple regularities in the dynamics of online news impact.

Online news can quickly reach and affect millions of people, yet we do not know yet whether there exist potential dynamical regularities that govern their impact on the public. We use data from two major news outlets, BBC and New York Times, where the number of user comments can be used as a proxy of news impact. We find that the impact dynamics of online news articles does not exhibit popularity patterns found in many other social and information systems. In particular, we find that a simple exponential distribution yields a better fit to the empirical news impact distributions than a power-law distribution. This observation is explained by the lack or limited influence of the otherwise omnipresent rich-get-richer mechanism in the analyzed data. The temporal dynamics of the news impact exhibits a universal exponential decay which allows us to collapse individual news trajectories into an elementary single curve. We also show how daily variations of user activity directly influence the dynamics of the article impact. Our findings challenge the universal applicability of popularity dynamics patterns found in other social contexts. Supplementary Information: The online version contains supplementary material available at 10.1007/s42001-021-00140-w.

Toward Detecting Previously Undiscovered Interaction Types in Networked Systems.

Studying networked systems in a variety of domains, including biology, social science, and Internet of Things, has recently received a surge of attention. For a networked system, there are usually multiple types of interactions between its components, and such interaction-type information is crucial since it always associated with important features. However, some interaction types that actually exist in the network may not be observed in the metadata collected in practice. This article proposes an approach aiming to detect previously undiscovered interaction types (PUITs) in networked systems. The first step in our proposed PUIT detection approach is to answer the following fundamental question: is it possible to effectively detect PUITs without utilizing metadata other than the existing incomplete interaction-type information and the connection information of the system? Here, we first propose a temporal network model which can be used to mimic any real network and then discover that some special networks which fit the model shall a common topological property. Supported by this discovery, we finally develop a PUIT detection method for networks which fit the proposed model. Both analytical and numerical results show this detection method is more effective than the baseline method, demonstrating that effectively detecting PUITs in networks is achievable. More studies on PUIT detection are of significance and in great need since this approach should be as essential as the previously undiscovered node-type detection which has gained great success in the field of biology.

A method for T1 and T2 relaxation times validation and harmonization as a support to MRI mapping.

We present a proof-of-concept study focusing on a method for the intra- and inter-center validation and harmonization of data obtained from MRI T1 and T2 maps. The method is based on a set of MnCl2 samples that provide in-scan ground-truth reference values regardless of the details of the MRI protocol. The relaxation times of MnCl2 aqueous solutions were first measured by means of an NMR laboratory relaxometer, as a function of concentration and temperature. The obtained T1 and T2 values, once renormalized at the scanner temperature, were used as reference values for the MRI mapping measurements of the MnCl2 relaxation times. By using different clinical MRI scanners and sequences, we found a good agreement for standard and turbo sequences (limits of agreement: 5% for IR, SE, IR-TSE; 10% for TSE), while an under-estimation and an over-estimation were found respectively for MOLLI and T2-prep TrueFISP, as already reported in the literature. The linearity of the relaxation rates with the concentration predicted by the Solomon-Bloembergen-Morgan theory was observed for every dataset at all temperatures, except for T2-prep TrueFISP maps results. Some preliminary results of an in vivo experiment are also presented.

HeLLePhant: A phantom mimicking non-small cell lung cancer for texture analysis in CT images.

PURPOSE: Phantoms mimicking human tissue heterogeneity and intensity are required to establish radiomic features robustness in Computed Tomography (CT) images. We developed inserts with two different techniques for the radiomic study of Non-Small Cell Lung Cancer (NSCLC) lesions. METHODS: We developed two insert prototypes: two 3D-printed made of glycol-modified polyethylene terephthalate (PET-G), and nine with sodium polyacrylate plus iodinated contrast medium. The inserts were put in a handcraft phantom (HeLLePhant). We also analysed four materials of a commercial homogeneous phantom (Catphan® 424) and collected 29 NSCLC patients for comparison. All the CT acquisitions were performed with the same clinical protocol and scanner at 120kVp. The HeLLePhant phantom was scanned ten times in fixed condition at 120kVp and 100kVp for repeatability investigation. We extracted 153 radiomic features using Pyradiomics. To compare the features between phantoms and patients, we computed how many phantom features fell in the range between 10th and 90th percentile of the corresponding patient values. We deemed repeatable the features with a coefficient of variation (CV) less than or equal to 0.10. RESULTS: The best similarity with the patients was obtained with the polyacrylate inserts (55.6-90.2%), the worst with Catphan (15.7-19.0%). For the PET-G inserts 35.3% and 36.6% of the features match the patient range. We found high repeatability for all the inserts of the HeLLePhant phantom (74.3-100% at 120kVp, 75.7-97.9% at 100kVp), and observed a texture dependency in repeatability. CONCLUSIONS: Our study shows a promising way to construct heterogeneous inserts mimicking a target tissue for radiomic studies.

Tailoring the Magnetic and Structural Properties of Manganese/Zinc Doped Iron Oxide Nanoparticles through Microwaves-Assisted Polyol Synthesis.

Tuning the fundamental properties of iron oxide magnetic nanoparticles (MNPs) according to the required biomedical application is an unsolved challenge, as the MNPs' properties are affected by their composition, their size, the synthesis process, and so on. In this work, we studied the effect of zinc and manganese doping on the magnetic and structural properties of MNPs synthesized by the microwave-assisted polyol process, using diethylene glycol (DEG) and tetraethylene glycol (TEG) as polyols. The detailed morpho-structural and magnetic characterization showed a correspondence between the higher amounts of Mn and smaller crystal sizes of the MNPs. Such size reduction was compensated by an increase in the global magnetic moment so that it resulted in an increase of the saturation magnetization. Saturation magnetization MS values up to 91.5 emu/g and NMR transverse relaxivities r2 of 294 s-1mM-1 were obtained for Zn and Mn- doped ferrites having diameters around 10 nm, whereas Zn ferrites with diameters around 15 nm reached values of MS∼ 97.2 emu/g and of r2∼ 467 s-1mM-1, respectively. Both kinds of nanoparticles were synthesized by a simple, reproducible, and more sustainable method that makes them very interesting for diagnostic applications as MRI contrast agents.

Reproducibility of radiomic features in CT images of NSCLC patients: an integrative analysis on the impact of acquisition and reconstruction parameters.

BACKGROUND: We investigated to what extent tube voltage, scanner model, and reconstruction algorithm affect radiomic feature reproducibility in a single-institution retrospective database of computed tomography images of non-small-cell lung cancer patients. METHODS: This study was approved by the Institutional Review Board (UID 2412). Images of 103 patients were considered, being acquired on either among two scanners, at 100 or 120 kVp. For each patient, images were reconstructed with six iterative blending levels, and 1414 features were extracted from each reconstruction. At univariate analysis, Wilcoxon-Mann-Whitney test was applied to evaluate feature differences within scanners and voltages, whereas the impact of the reconstruction was established with the overall concordance correlation coefficient (OCCC). A multivariable mixed model was also applied to investigate the independent contribution of each acquisition/reconstruction parameter. Univariate and multivariable analyses were combined to analyse feature behaviour. RESULTS: Scanner model and voltage did not affect features significantly. The reconstruction blending level showed a significant impact at both univariate analysis (154/1414 features yielding an OCCC < 0.85) and multivariable analysis, with most features (1042/1414) revealing a systematic trend with the blending level (multiple comparisons adjusted p < 0.05). Reproducibility increased in association to image processing with smooth filters, nonetheless specific investigation in relation to clinical endpoints should be performed to ensure that textural information is not removed. CONCLUSIONS: Combining univariate and multivariable models is allowed to identify features for which corrections may be applied to reduce the trend with the algorithm and increase reproducibility. Subsequent clustering may be applied to eliminate residual redundancy.

Preliminary report on harmonization of features extraction process using the ComBat tool in the multi-center "Blue Sky Radiomics" study on stage III unresectable NSCLC.

BACKGROUND AND PURPOSE: In the retrospective-prospective multi-center "Blue Sky Radiomics" study (NCT04364776), we plan to test a pre-defined radiomic signature in a series of stage III unresectable NSCLC patients undergoing chemoradiotherapy and maintenance immunotherapy. As a necessary preliminary step, we explore the influence of different image-acquisition parameters on radiomic features' reproducibility and apply methods for harmonization. MATERIAL AND METHODS: We identified the primary lung tumor on two computed tomography (CT) series for each patient, acquired before and after chemoradiation with i.v. contrast medium and with different scanners. Tumor segmentation was performed by two oncological imaging specialists (thoracic radiologist and radio-oncologist) using the Oncentra Masterplan® software. We extracted 42 radiomic features from the specific ROIs (LIFEx). To assess the impact of different acquisition parameters on features extraction, we used the Combat tool with nonparametric adjustment and the longitudinal version (LongComBat). RESULTS: We defined 14 CT acquisition protocols for the harmonization process. Before harmonization, 76% of the features were significantly influenced by these protocols. After, all extracted features resulted in being independent of the acquisition parameters. In contrast, 5% of the LongComBat harmonized features still depended on acquisition protocols. CONCLUSIONS: We reduced the impact of different CT acquisition protocols on radiomic features extraction in a group of patients enrolled in a radiomic study on stage III NSCLC. The harmonization process appears essential for the quality of radiomic data and for their reproducibility. ClinicalTrials.gov Identifier: NCT04364776, First Posted:April 28, 2020, Actual Study Start Date: April 15, 2020, https://clinicaltrials.gov/ct2/show/NCT04364776 .