Impact of E. muris infection on B. burgdorferi-induced joint pathology in mice.

Tick-borne infections are increasing in the United States and around the world. The most common tick-borne disease in the United States is Lyme disease caused by infection with the spirochete Borrelia burgdorferi (Bb), and pathogenesis varies from subclinical to severe. Bb infection is transmitted by Ixodes ticks, which can carry multiple other microbial pathogens, including Ehrlichia species. To address how the simultaneous inoculation of a distinct pathogen impacted the course of Bb-induced disease, we used C57BL/6 (B6) mice which are susceptible to Bb infection but develop only mild joint pathology. While infection of B6 mice with Bb alone resulted in minimal inflammatory responses, mice co-infected with both Bb and the obligate intracellular pathogen Ehrlichia muris (Em) displayed hematologic changes, inflammatory cytokine production, and emergency myelopoiesis similar to what was observed in mice infected only with Em. Moreover, infection of B6 mice with Bb alone resulted in no detectable joint inflammation, whereas mice co-infected with both Em and Bb exhibited significant inflammation of the ankle joint. Our findings support the concept that co-infection with Ehrlichia can exacerbate inflammation, resulting in more severe Bb-induced disease.

An Image-Based Prior Knowledge-Free Approach for a Multi-Material Decomposition in Photon-Counting Computed Tomography.

Photon-counting CT systems generally allow for acquiring multiple spectral datasets and thus for decomposing CT images into multiple materials. We introduce a prior knowledge-free deterministic material decomposition approach for quantifying three material concentrations on a commercial photon-counting CT system based on a single CT scan. We acquired two phantom measurement series: one to calibrate and one to test the algorithm. For evaluation, we used an anthropomorphic abdominal phantom with inserts of either aqueous iodine solution, aqueous tungsten solution, or water. Material CT numbers were predicted based on a polynomial in the following parameters: Water-equivalent object diameter, object center-to-isocenter distance, voxel-to-isocenter distance, voxel-to-object center distance, and X-ray tube current. The material decomposition was performed as a generalized least-squares estimation. The algorithm provided material maps of iodine, tungsten, and water with average estimation errors of 4% in the contrast agent maps and 1% in the water map with respect to the material concentrations in the inserts. The contrast-to-noise ratio in the iodine and tungsten map was 36% and 16% compared to the noise-minimal threshold image. We were able to decompose four spectral images into iodine, tungsten, and water.

Lizards and the enzootic cycle of Borrelia burgdorferi sensu lato.

Emerging and re-emerging pathogens often stem from zoonotic origins, cycling between humans and animals, and are frequently vectored and maintained by hematophagous arthropod vectors. The efficiency by which these disease agents are successfully transmitted between vertebrate hosts is influenced by many factors, including the host on which a vector feeds. The Lyme disease bacterium Borrelia burgdorferi sensu lato has adapted to survive in complex host environments, vectored by Ixodes ticks, and maintained in multiple vertebrate hosts. The versatility of Lyme borreliae in disparate host milieus is a compelling platform to investigate mechanisms dictating pathogen transmission through complex networks of vertebrates and ticks. Squamata, one of the most diverse clade of extant reptiles, is comprised primarily of lizards, many of which are readily fed upon by Ixodes ticks. Yet, lizards are one of the least studied taxa at risk of contributing to the transmission and life cycle maintenance of Lyme borreliae. In this review, we summarize the current evidence, spanning from field surveillance to laboratory infection studies, supporting their contributions to Lyme borreliae circulation. We also summarize the current understanding of divergent lizard immune responses that may explain the underlying molecular mechanisms to confer Lyme spirochete survival in vertebrate hosts. This review offers a critical perspective on potential enzootic cycles existing between lizard-tick-Borrelia interactions and highlights the importance of an eco-immunology lens for zoonotic pathogen transmission studies.

Tungsten-Based Contrast Agent for Photon-Counting Detector CT Angiography in Calcified Coronaries: Comparison to Iodine in a Cardiovascular Phantom.

OBJECTIVES: Calcified plaques induce blooming artifacts in coronary computed tomography angiography (CCTA) potentially leading to inaccurate stenosis evaluation. Tungsten represents a high atomic number, experimental contrast agent with different physical properties than iodine. We explored the potential of a tungsten-based contrast agent for photon-counting detector (PCD) CCTA in heavily calcified coronary vessels. MATERIALS AND METHODS: A cardiovascular phantom exhibiting coronaries with calcified plaques was imaged on a first-generation dual-source PCD-CT. The coronaries with 3 different calcified plaques were filled with iodine and tungsten contrast media solutions equating to iodine and tungsten delivery rates (IDR and TDR) of 0.3, 0.5, 0.7, 1.0, 1.5, 2.0, 2.5, and 3.0 g/s, respectively. Electrocardiogram-triggered sequential acquisitions were performed in the spectral mode (QuantumPlus). Virtual monoenergetic images (VMIs) were reconstructed from 40 to 190 keV in 1 keV increments. Blooming artifacts and percentage error stenoses from calcified plaques were quantified, and attenuation characteristics of both contrast media were recorded. RESULTS: Blooming artifacts from calcified plaques were most pronounced at 40 keV (78%) and least pronounced at 190 keV (58%). Similarly, percentage error stenoses were highest at 40 keV (48%) and lowest at 190 keV (2%), respectively. Attenuation of iodine decreased monotonically in VMIs from low to high keV, with the strongest decrease from 40 keV to 100 keV (IDR of 2.5 g/s: 1279 HU at 40 keV, 187 HU at 100 kV, and 35 HU at 190 keV). The attenuation of tungsten, on the other hand, increased monotonically as a function of VMI energy, with the strongest increase between 40 and 100 keV (TDR of 2.5 g/s: 202 HU at 40 keV, 661 HU at 100 kV, and 717 HU at 190 keV). For each keV level, the relationship between attenuation and IDR/TDR could be described by linear regressions ( R2 ≥ 0.88, P < 0.001). Specifically, attenuation increased linearly when increasing the delivery rate irrespective of keV level or contrast medium. Iodine exhibited the highest relative increase in attenuation values at lower keV levels when increasing the IDR. Conversely, for tungsten, the greatest relative increase in attenuation values occurred at higher keV levels when increasing the TDR. When high keV imaging is desirable to reduce blooming artifacts from calcified plaques, IDR has to be increased at higher keV levels to maintain diagnostic vessel attenuation (ie, 300 HU), whereas for tungsten, TDR can be kept constant or can be even reduced at high keV energy levels. CONCLUSIONS: Tungsten's attenuation characteristics in relation to VMI energy levels are reversed to those of iodine, with tungsten exhibiting high attenuation values at high keV levels and vice versa. Thus, tungsten shows promise for high keV imaging CCTA with PCD-CT as-in distinction to iodine-both high vessel attenuation and low blooming artifacts from calcified plaques can be achieved.

Structural evolution of an immune evasion determinant shapes pathogen host tropism.

Modern infectious disease outbreaks often involve changes in host tropism, the preferential adaptation of pathogens to specific hosts. The Lyme disease-causing bacterium Borrelia burgdorferi (Bb) is an ideal model to investigate the molecular mechanisms of host tropism, because different variants of these tick-transmitted bacteria are distinctly maintained in rodents or bird reservoir hosts. To survive in hosts and escape complement-mediated immune clearance, Bb produces the outer surface protein CspZ that binds the complement inhibitor factor H (FH) to facilitate bacterial dissemination in vertebrates. Despite high sequence conservation, CspZ variants differ in human FH-binding ability. Together with the FH polymorphisms between vertebrate hosts, these findings suggest that minor sequence variation in this bacterial outer surface protein may confer dramatic differences in host-specific, FH-binding-mediated infectivity. We tested this hypothesis by determining the crystal structure of the CspZ-human FH complex, and identifying minor variation localized in the FH-binding interface yielding bird and rodent FH-specific binding activity that impacts infectivity. Swapping the divergent region in the FH-binding interface between rodent- and bird-associated CspZ variants alters the ability to promote rodent- and bird-specific early-onset dissemination. We further linked these loops and respective host-specific, complement-dependent phenotypes with distinct CspZ phylogenetic lineages, elucidating evolutionary mechanisms driving host tropism emergence. Our multidisciplinary work provides a novel molecular basis for how a single, short protein motif could greatly modulate pathogen host tropism.

New Contrast Media for K-Edge Imaging With Photon-Counting Detector CT.

ABSTRACT: The recent technological developments in photon-counting detector computed tomography (PCD-CT) and the introduction of the first commercially available clinical PCD-CT unit open up new exciting opportunities for contrast media research. With PCD-CT, the efficacy of available iodine-based contrast media improves, allowing for a reduction of iodine dosage or, on the other hand, an improvement of image quality in low contrast indications. Virtual monoenergetic image reconstructions are routinely available and enable the virtual monoenergetic image energy to be adapted to the diagnostic task.A key property of PCD-CT is the ability of spectral separation in combination with improved material decomposition. Thus, the discrimination of contrast media from intrinsic or pathological tissues and the discrimination of 2 or more contrasting elements that characterize different tissues are attractive fields for contrast media research. For these approaches, K-edge imaging in combination with high atomic number elements such as the lanthanides, tungsten, tantalum, or bismuth plays a central role.The purpose of this article is to present an overview of innovative contrast media concepts that use high atomic number elements. The emphasis is on improving contrast enhancement for cardiovascular plaque imaging, stent visualization, and exploring new approaches using 2 contrasting elements. Along with the published research, new experimental findings with a contrast medium that incorporates tungsten are included.Both the literature review and the new experimental data demonstrate the great potential and feasibility for new contrast media to significantly increase diagnostic performance and to enable new clinical fields and indications in combination with PCD-CT.

Outer surface protein E (OspE) mediates Borrelia burgdorferi sensu stricto strain-specific complement evasion in the eastern fence lizard, Sceloporus undulatus.

In North America, Lyme disease is primarily caused by the spirochetal bacterium Borrelia burgdorferi sensu stricto (Bb), which is transmitted between multiple vertebrate hosts and ixodid ticks, and is a model commonly used to study host-pathogen interactions. While Bb is consistently observed in its mammalian and avian reservoirs, the bacterium is rarely isolated from North American reptiles. Two closely related lizard species, the eastern fence lizard (Sceloporus undulatus) and the western fence lizard (Sceloporus occidentalis), are examples of reptiles parasitized by Ixodes ticks. Vertebrates are known to generate complement as an innate defense mechanism, which can be activated before Bb disseminate to distal tissues. Complement from western fence lizards has proven lethal against one Bb strain, implying the role of complement in making those lizards unable to serve as hosts to Bb. However, Bb DNA is occasionally identified in distal tissues of field-collected eastern fence lizards, suggesting some Bb strains may overcome complement-mediated clearance in these lizards. These findings raise questions regarding the role of complement and its impact on Bb interactions with North American lizards. In this study, we found Bb seropositivity in a small population of wild-caught eastern fence lizards and observed Bb strain-specific survivability in lizard sera. We also found that a Bb outer surface protein, OspE, from Bb strains viable in sera, promotes lizard serum survivability and binds to a complement inhibitor, factor H, from eastern fence lizards. Our data thus identify bacterial and host determinants of eastern fence lizard complement evasion, providing insights into the role of complement influencing Bb interactions with North American lizards.

Phylogenomic Diversity Elucidates Mechanistic Insights into Lyme Borreliae-Host Association.

Host association-the selective adaptation of pathogens to specific host species-evolves through constant interactions between host and pathogens, leaving a lot yet to be discovered on immunological mechanisms and genomic determinants. The causative agents of Lyme disease (LD) are spirochete bacteria composed of multiple species of the Borrelia burgdorferi sensu lato complex, including B. burgdorferi (Bb), the main LD pathogen in North America-a useful model for the study of mechanisms underlying host-pathogen association. Host adaptation requires pathogens' ability to evade host immune responses, such as complement, the first-line innate immune defense mechanism. We tested the hypothesis that different host-adapted phenotypes among Bb strains are linked to polymorphic loci that confer complement evasion traits in a host-specific manner. We first examined the survivability of 20 Bb strains in sera in vitro and/or bloodstream and tissues in vivo from rodent and avian LD models. Three groups of complement-dependent host-association phenotypes emerged. We analyzed complement-evasion genes, identified a priori among all strains and sequenced and compared genomes for individual strains representing each phenotype. The evolutionary history of ospC loci is correlated with host-specific complement-evasion phenotypes, while comparative genomics suggests that several gene families and loci are potentially involved in host association. This multidisciplinary work provides novel insights into the functional evolution of host-adapted phenotypes, building a foundation for further investigation of the immunological and genomic determinants of host association. IMPORTANCE Host association is the phenotype that is commonly found in many pathogens that preferential survive in particular hosts. The Lyme disease (LD)-causing agent, B. burgdorferi (Bb), is an ideal model to study host association, as Bb is mainly maintained in nature through rodent and avian hosts. A widespread yet untested concept posits that host association in Bb strains is linked to Bb functional genetic variation conferring evasion to complement, an innate defense mechanism in vertebrate sera. Here, we tested this concept by grouping 20 Bb strains into three complement-dependent host-association phenotypes based on their survivability in sera and/or bloodstream and distal tissues in rodent and avian LD models. Phylogenomic analysis of these strains further correlated several gene families and loci, including ospC, with host-specific complement-evasion phenotypes. Such multifaceted studies thus pave the road to further identify the determinants of host association, providing mechanistic insights into host-pathogen interaction.

CspZ FH-Binding Sites as Epitopes Promote Antibody-Mediated Lyme Borreliae Clearance.

Transmitted by ticks, the bacterium Borrelia burgdorferi sensu lato is the causative agent of Lyme disease (LD), the most common vector-borne disease in the Northern hemisphere. No effective vaccines are currently available. B. burgdorferi sensu lato produces the CspZ protein that binds to the complement inhibitor, factor H (FH), promoting evasion of the host complement system. We previously showed that while vaccination with CspZ did not protect mice from B. burgdorferi infection, mice can be protected after immunization with CspZ-Y207A/Y211A (CspZ-YA), a CspZ mutant protein without FH-binding activity. To further study the mechanism of this protection, herein we evaluated both poly- and monoclonal antibodies recognizing CspZ FH-binding or non-FH-binding sites. We found that the anti-CspZ antibodies that recognize the FH-binding sites (i.e., block FH-binding activity) eliminate B. burgdorferi sensu lato in vitro more efficiently than those that bind to the non-FH-binding sites, and passive inoculation with anti-FH-binding site antibodies eradicated B. burgdorferi sensu lato in vivo. Antibodies against non-FH-binding sites did not have the same effect. These results emphasize the importance of CspZ FH-binding sites in triggering a protective antibody response against B. burgdorferi sensu lato in future LD vaccines.

Coronary Computed Tomography Angiography-Based Calcium Scoring: In Vitro and In Vivo Validation of a Novel Virtual Noniodine Reconstruction Algorithm on a Clinical, First-Generation Dual-Source Photon Counting-Detector System.

PURPOSE: The aim of this study was to evaluate coronary computed tomography angiography (CCTA)-based in vitro and in vivo coronary artery calcium scoring (CACS) using a novel virtual noniodine reconstruction (PureCalcium) on a clinical first-generation photon-counting detector-computed tomography system compared with virtual noncontrast (VNC) reconstructions and true noncontrast (TNC) acquisitions. MATERIALS AND METHODS: Although CACS and CCTA are well-established techniques for the assessment of coronary artery disease, they are complementary acquisitions, translating into increased scan time and patient radiation dose. Hence, accurate CACS derived from a single CCTA acquisition would be highly desirable. In this study, CACS based on PureCalcium, VNC, and TNC, reconstructions was evaluated in a CACS phantom and in 67 patients (70 [59/80] years, 58.2% male) undergoing CCTA on a first-generation photon counting detector-computed tomography system. Coronary artery calcium scores were quantified for the 3 reconstructions and compared using Wilcoxon test. Agreement was evaluated by Pearson and Spearman correlation and Bland-Altman analysis. Classification of coronary artery calcium score categories (0, 1-10, 11-100, 101-400, and >400) was compared using Cohen κ . RESULTS: Phantom studies demonstrated strong agreement between CACS PureCalcium and CACS TNC (60.7 ± 90.6 vs 67.3 ± 88.3, P = 0.01, r = 0.98, intraclass correlation [ICC] = 0.98; mean bias, 6.6; limits of agreement [LoA], -39.8/26.6), whereas CACS VNC showed a significant underestimation (42.4 ± 75.3 vs 67.3 ± 88.3, P < 0.001, r = 0.94, ICC = 0.89; mean bias, 24.9; LoA, -87.1/37.2). In vivo comparison confirmed a high correlation but revealed an underestimation of CACS PureCalcium (169.3 [0.7/969.4] vs 232.2 [26.5/1112.2], P < 0.001, r = 0.97, ICC = 0.98; mean bias, -113.5; LoA, -470.2/243.2). In comparison, CACS VNC showed a similarly high correlation, but a substantially larger underestimation (24.3 [0/272.3] vs 232.2 [26.5/1112.2], P < 0.001, r = 0.97, ICC = 0.54; mean bias, -551.6; LoA, -2037.5/934.4). CACS PureCalcium showed superior agreement of CACS classification ( κ = 0.88) than CACS VNC ( κ = 0.60). CONCLUSIONS: The accuracy of CACS quantification and classification based on PureCalcium reconstructions of CCTA outperforms CACS derived from VNC reconstructions.

Photon-Counting Detector CT-Based Vascular Calcium Removal Algorithm: Assessment Using a Cardiac Motion Phantom.

OBJECTIVES: The diagnostic performance of coronary computed tomography angiography is known to be negatively affected by the presence of severely calcified plaques in the coronary arteries. In this article, the performance of a novel image reconstruction algorithm (PureLumen) based on spectral CT data of a first-generation dual-source photon-counting detector computed tomography (PCD-CT) system was assessed in a phantom study. PureLumen tries to remove only the calcified contributions from the image while leaving the rest unmodified. MATERIALS AND METHODS: The study uses 2 iodine contrast filled vessel phantoms (diameter 4 mm) filled with different concentrations of iodine and equipped with calcified stenosis inserts. Each phantom features 2 separate calcified lesions of 25% and 50% percentage diameter stenosis (PDS) size. The vessel phantoms were mounted inside an anthropomorphic thorax phantom attached to an artificial motion device, simulating realistic cardiac motion at heart rates between 50 beats per minute and 100 beats per minute. Acquisitions were performed using a prospectively electrocardiogram triggered dual-source sequence mode on a PCD-CT system (NAEOTOM Alpha, Siemens Healthineers). Images were reconstructed at 80% of the RR interval with virtual monoenergetic images (Mono) and with additional calcium-removal (PureLumen), both at 65 keV. PureLumen is based on a spectral base material decomposition into iodine and calcium, which aims to reconstruct images without calcium contributions, while leaving all other material contribution unchanged. Stenosis grade was assessed individually for each vessel insert in all reconstructed image series by 2 readers. RESULTS: The measured median PDS values for the 50% lesion were 56.0% (52.0%, 57.0%) for the Mono case and 50.0% (48.5%, 51.0%) for PureLumen. The 25% lesion median PDS values were 36.0% (29.5%, 39.5%) for Mono and 31.5% (30.5%, 34.0%) for PureLumen. Both lesion sizes demonstrate a significant difference between Mono and PureLumen in their result (P < 0.05) with PureLumen median values being closer to the actual true stenosis size for the 50% and 25% lesion. A visual assessment of the image quality depending on the heart rate yielded good image quality up to a heart rate of 80 beats per minute in the PureLumen case. CONCLUSIONS: This phantom study shows that a novel calcium-removal image reconstruction algorithm (PureLumen) using a first-generation dual-source PCD-CT effectively decreases blooming artifacts caused by heavily calcified plaques and improves image interpretability. It also shows that PureLumen retains its performance in the presence of motion with simulated heart rates up to 80 beats per minute. Future in vivo clinical studies are needed to confirm the benefits of this type of reconstruction in terms of coronary computed tomography angiography quality and accuracy.

Utilizing Two Borrelia bavariensis Isolates Naturally Lacking the PFam54 Gene Array To Elucidate the Roles of PFam54-Encoded Proteins.

Lyme borreliosis is the most common vector-borne disease in the Northern Hemisphere, caused by spirochetes belonging to the Borrelia burgdorferi sensu lato species complex, which are transmitted by ixodid ticks. B. burgdorferi sensu lato species produce a family of proteins on the linear plasmid 54 (PFam54), some of which confer the functions of cell adhesion and inactivation of complement, the first line of host defense. However, the impact of PFam54 in promoting B. burgdorferi sensu lato pathogenesis remains unclear because of the hurdles to simultaneously knock out all PFam54 proteins in a spirochete. Here, we describe two Borrelia bavariensis strains, PBN and PNi, isolated from patients naturally lacking PFam54 but maintaining the rest of the genome with greater than 95% identity to the reference B. bavariensis strain, PBi. We found that PBN and PNi less efficiently survive in human serum than PBi. Such defects were restored by introducing two B. bavariensis PFam54 recombinant proteins, BGA66 and BGA71, confirming the role of these proteins in providing complement evasion of B. bavariensis. Further, we found that all three strains remain detectable in various murine tissues 21 days post-subcutaneous infection, supporting the nonessential role of B. bavariensis PFam54 in promoting spirochete persistence. This study identified and utilized isolates deficient in PFam54 to associate the defects with the absence of these proteins, building the foundation to further study the role of each PFam54 protein in contributing to B. burgdorferi sensu lato pathogenesis. IMPORTANCE To establish infections, Lyme borreliae utilize various means to overcome the host's immune system. Proteins encoded by the PFam54 gene array play a role in spirochete survival in vitro and in vivo. Moreover, this gene array has been described in all currently available Lyme borreliae genomes. By investigating the first two Borrelia bavariensis isolates naturally lacking the entire PFam54 gene array, we showed that both patient isolates display an increased susceptibility to human serum, which can be rescued in the presence of two PFam54 recombinant proteins. However, both isolates remain infectious to mice after intradermal inoculation, suggesting the nonessential role of PFam54 during the long-term, but may differ slightly in the colonization of specific tissues. Furthermore, these isolates show high genomic similarity to type strain PBi (>95%) and could be used in future studies investigating the role of each PFam54 protein in Lyme borreliosis pathogenesis.

Assessment of Bone Mineral Density From a Computed Tomography Topogram of Photon-Counting Detector Computed Tomography-Effect of Phantom Size and Tube Voltage.

PURPOSE: The aim of this study was to assess the accuracy and impact of different sizes and tube voltages on bone mineral density (BMD) assessment using a computed tomography (CT) topogram acquired with photon-counting detector CT in an osteopenic ex vivo animal spine. MATERIALS AND METHODS: The lumbar back of a piglet was used to simulate osteopenia of the lumbar spine. Five fat layers (each with a thickness of 3 cm) were consecutively placed on top of the excised spine to emulate a total of 5 different sizes. Each size was repeatedly imaged on (A) a conventional dual-energy x-ray absorptiometry scanner as the reference standard, (B) a prototype photon-counting detector CT system at 120 kVp with energy thresholds at 20 and 70 keV, and (C) the same prototype system at 140 kVp with thresholds at 20 and 75 keV. Material-specific data were reconstructed from spectral topograms for B and C. Bone mineral density was measured for 3 lumbar vertebrae (L2-L4). A linear mixed-effects model was used to estimate the impact of vertebra, imaging setup, size, and their interaction term on BMD. RESULTS: The BMD of the lumbar spine corresponded to a T score in humans between -4.2 and -4.8, which is seen in osteoporosis. Averaged across the 3 vertebrae and 5 sizes, mean BMD was 0.56 ± 0.03, 0.55 ± 0.02, and 0.55 ± 0.02 g/cm2 for setup A, B, and C, respectively. There was no significant influence of imaging setup (P = 0.7), simulated size (P = 0.67), and their interaction term (both P > 0.2) on BMD. Bone mineral density decreased significantly from L2 to L4 for all 3 setups (all P < 0.0001). Bone mineral density was 0.59 ± 0.01, 0.57 ± 0.01, and 0.52 ± 0.02 g/cm2 for L2, L3, and L4, respectively, for setup A; 0.57 ± 0.02, 0.55 ± 0.01, and 0.53 ± 0.01 g/cm2 for setup B; and 0.57 ± 0.01, 0.55 ± 0.01, and 0.53 ± 0.01 g/cm2 for setup C. CONCLUSION: A single CT topogram acquired on photon-counting detector CT with 2 energy thresholds enabled BMD quantification with similar accuracy compared with dual-energy x-ray absorptiometry over a range of simulated sizes and tube voltages in an osteopenic ex vivo animal spine.

Photon-Counting Multienergy Computed Tomography With Spectrally Optimized Contrast Media for Plaque Removal and Stenosis Assessment.

PURPOSE: The aim of this study was to systematically evaluate the potential to combine investigational contrast media with spectrally optimized energy-thresholding of photon-counting detector computed tomography (PCCT) for subtraction of calcified plaques in a coronary artery stenosis phantom. METHODS: A small vessel phantom containing 3 fillable tubes (diameter, 3 mm each) with calcified plaques was placed into an anthropomorphic chest phantom. The plaques had incremental thicknesses ranging from 0.3 to 2.7 mm, simulating vessel stenoses ranging from 10% to 90% of the lumen diameter. The phantom was filled with 5 different investigational contrast media (iodine, bismuth, hafnium, holmium, and tungsten) at equal mass concentrations (15 mg/mL) and was imaged on a prototype PCCT at 140 kVp using optimized, contrast media-dependent energy thresholds. Contrast maps (CMs) were reconstructed for each contrast medium by applying a linear 2-material decomposition algorithm. Image noise magnitude and noise texture of CM were compared among the contrast media using the noise power spectrum. Two blinded readers independently rated the vessel lumen visualization on short-axis and the overall subjective image quality on long-axis CM relative to iodine as the reference standard. Four readers determined the highest degree of stenosis that could be assessed with high diagnostic confidence on long-axis CM. RESULTS: Average image noise on CM was lower for tungsten (49 HU) and hafnium (62 HU) and higher for bismuth (81 HU) and holmium (165 HU) compared with iodine (78 HU). Noise texture of CM was similar among the contrast media. Interreader agreement for vessel lumen visualization on short-axis CM ranged from moderate to excellent (k = 0.567-0.814). Compared with iodine, lumen visualization of each reader was improved using tungsten (P < 0.001 for both readers), similar to improved using hafnium (P = 0.008, P = 0.29), similar using bismuth (P = 0.38, P = 0.69), and decreased using holmium (both, P < 0.001). Overall subjective image quality was similar for holmium and superior for tungsten, hafnium, and bismuth as compared with iodine. Higher-degree stenoses were evaluable with high confidence using tungsten (mean, 70%; interquartile range, 70%-70%), bismuth (70%; 60%-70%), and hafnium (75%; 70%-80%) compared with iodine (50%; 50%-60%) and holmium (50%; 50%-60%). CONCLUSIONS: Spectral optimization in PCCT combined with investigational contrast media can improve calcium subtraction and stenosis assessment in small vessels. Contrast maps of tungsten and, to a lesser extent, hafnium as contrast media yielded superior image noise properties and improved vessel lumen visualization, along with a higher subjective image quality compared with the reference standard iodine.

Bone Mineral Density Quantification from Localizer Radiographs: Accuracy and Precision of Energy-integrating Detector CT and Photon-counting Detector CT.

Background Bone mineral density (BMD) could be derived from CT localizer radiographs and could potentially enable opportunistic osteoporosis screening. Purpose To assess the accuracy and precision of BMD measurement using two localizer radiographs obtained with energy-integrating detector CT and a single localizer radiograph obtained with photon-counting detector CT. Materials and Methods A calibration phantom and a porcine phantom with lumbar vertebrae were imaged with a dual-energy x-ray absorptiometry (DXA) scanner, a clinical energy-integrating detector CT scanner, and a prototype photon-counting detector CT scanner. Two localizer radiographs at different combinations of tube voltages were obtained with energy-integrating detector CT, and one localizer radiograph was obtained with photon-counting detector CT using different energy thresholds. BMD was calculated for all three approaches and compared with the known specifications in the calibration phantom. In the animal phantom, BMDs from both CT systems were compared with those from the DXA scanner (the reference standard). Accuracy was defined as the measurement error of BMD (ΔBMD), and precision was defined as the coefficient of variation (in percentage). Radiation doses were estimated. Nonparametric tests were applied. Results In the calibration phantom, ΔBMD was smaller with both CT systems compared with the DXA scanner (both P < .05). ΔBMD ranged from -5% to -1.8% for DXA, from -2.3% to -1.7% for energy-integrating detector CT, and from -1.6% to 1.6% for photon-counting detector CT. Precision (range, 0.3%-2.8%) was high for both CT systems. In the animal phantom, ΔBMD ranged from -0.6% to 0.1% for energy-integrating detector CT and from -0.1% to 0.6% for photon-counting detector CT, with no significant differences between CT systems (P = .65). The dose-area product in the animal phantom was 4.6 cGy ∙ cm2 for DXA, 3.5-11.5 cGy ∙ cm2 for energy-integrating detector CT, and 7.2-11.2 cGy ∙ cm2 for photon-counting detector CT, depending on tube voltage and energy threshold combination. Conclusion Experimental evidence suggests that bone mineral density measurements are accurate and precise using two localizer radiographs at different tube voltages from energy-integrating detector CT and a single localizer radiograph with different energy thresholds from photon-counting detector CT. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Pourmorteza in this issue.

Photon-counting CT with tungsten as contrast medium: Experimental evidence of vessel lumen and plaque visualization.

BACKGROUND AND AIMS: We aimed to investigate the potential of a preclinical photon-counting detector CT (PCT) scanner with an experimental tungsten-based contrast medium for carotid artery imaging. METHODS: A carotid artery specimen was imaged on a PCT system using the multi-energy bin option (pixel size 0.5 × 0.5 mm2; tube voltage 140 kVp, contrast media-dependent energy thresholds: iodine 20, 75 keV; tungsten 20, 68 keV) at two radiation doses (CTDIvol of 100 mGy and 10 mGy) with iodine and tungsten as contrast media at equal mass-concentrations. Standard CT, virtual non-calcium (VNCa) and calcium-only images were reconstructed. Subjective image quality (4-point Likert scale) was rated using histology as reference. Noise and attenuation measurements were performed. Simulations were conducted to assess the material-decomposition efficiency for different object diameters. RESULTS: Image quality on VNCa images was significantly higher for tungsten at lower dose (reader 1/reader 2: 2, [2,2]/2, [2,2] vs 1.5, [2,1]/1, [1,1.75], p < 0.05). Noise was significantly lower at both dose levels for tungsten VNCa images as compared to iodine images (higher dose: tungsten 24 vs iodine 31; lower dose: tungsten 60 vs iodine 82; both p < 0.01). Simulations indicated improved material-decomposition efficiency for tungsten than for iodine pronounced at smaller object diameters. CONCLUSIONS: PCT employing the multi-energy bin option in combination with tungsten as contrast media enables improved carotid artery imaging with respect to lumen and plaque visualization and image noise.

New Insights Into CRASP-Mediated Complement Evasion in the Lyme Disease Enzootic Cycle.

Lyme disease (LD), which is caused by genospecies of the Borrelia burgdorferi sensu lato complex, is the most common vector-borne disease in the Northern hemisphere. Spirochetes are transmitted by Ixodes ticks and maintained in diverse vertebrate animal hosts. Following tick bite, spirochetes initially establish a localized infection in the skin. However, they may also disseminate hematogenously to several distal sites, including heart, joints, or the CNS. Because they need to survive in diverse microenvironments, from tick vector to mammalian hosts, spirochetes have developed multiple strategies to combat the numerous host defense mechanisms. One of these strategies includes the production of a number of complement-regulator acquiring surface proteins (CRASPs) which encompass CspA, CspZ, and OspE paralogs to blunt the complement pathway. These proteins are capable of preventing complement activation on the spirochete surface by binding to complement regulator Factor H. The genes encoding these CRASPs differ in their expression patterns during the tick-to-host infection cycle, implying that these proteins may exhibit different functions during infection. This review summarizes the recent published reports which investigated the roles that each of these molecules plays in conferring tick-borne transmission and dissemination in vertebrate hosts. These findings offer novel mechanistic insights into LD pathobiology and may facilitate the identification of new targets for preventive strategies against Lyme borreliosis.

Spectral optimization for micro-CT.

PURPOSE: To optimize micro-CT protocols with respect to x-ray spectra and thereby reduce radiation dose at unimpaired image quality. METHODS: Simulations were performed to assess image contrast, noise, and radiation dose for different imaging tasks. The figure of merit used to determine the optimal spectrum was the dose-weighted contrast-to-noise ratio (CNRD). Both optimal photon energy and tube voltage were considered. Three different types of filtration were investigated for polychromatic x-ray spectra: 0.5 mm Al, 3.0 mm Al, and 0.2 mm Cu. Phantoms consisted of water cylinders of 20, 32, and 50 mm in diameter with a central insert of 9 mm which was filled with different contrast materials: an iodine-based contrast medium (CM) to mimic contrast-enhanced (CE) imaging, hydroxyapatite to mimic bone structures, and water with reduced density to mimic soft tissue contrast. Validation measurements were conducted on a commercially available micro-CT scanner using phantoms consisting of water-equivalent plastics. Measurements on a mouse cadaver were performed to assess potential artifacts like beam hardening and to further validate simulation results. RESULTS: The optimal photon energy for CE imaging was found at 34 keV. For bone imaging, optimal energies were 17, 20, and 23 keV for the 20, 32, and 50 mm phantom, respectively. For density differences, optimal energies varied between 18 and 50 keV for the 20 and 50 mm phantom, respectively. For the 32 mm phantom and density differences, CNRD was found to be constant within 2.5% for the energy range of 21-60 keV. For polychromatic spectra and CMs, optimal settings were 50 kV with 0.2 mm Cu filtration, allowing for a dose reduction of 58% compared to the optimal setting for 0.5 mm Al filtration. For bone imaging, optimal tube voltages were below 35 kV. For soft tissue imaging, optimal tube settings strongly depended on phantom size. For 20 mm, low voltages were preferred. For 32 mm, CNRD was found to be almost independent of tube voltage. For 50 mm, voltages larger than 50 kV were preferred. For all three phantom sizes stronger filtration led to notable dose reduction for soft tissue imaging. Validation measurements were found to match simulations well, with deviations being less than 10%. Mouse measurements confirmed simulation results. CONCLUSIONS: Optimal photon energies and tube settings strongly depend on both phantom size and imaging task at hand. For in vivo CE imaging and density differences, strong filtration and voltages of 50-65 kV showed good overall results. For soft tissue imaging of animals the size of a rat or larger, voltages higher than 65 kV allow to greatly reduce scan times while maintaining dose efficiency. For imaging of bone structures, usage of only minimum filtration and low tube voltages of 40 kV and below allow exploiting the high contrast of bone at very low energies. Therefore, a combination of two filtrations could prove beneficial for micro-CT: a soft filtration allowing for bone imaging at low voltages, and a variable stronger filtration (e.g., 0.2 mm Cu) for soft tissue and contrast-enhanced imaging.

Development and evaluation of a phantom for dynamic contrast-enhanced imaging.

OBJECTIVES: Dynamic contrast-enhanced imaging allows assessing functional information in addition to morphology using various modalities. Several applications have been established in clinical practice; however, there is no standard with respect to injection protocols or postprocessing algorithms. The purpose of this study was to develop a phantom for generating reproducible contrast-enhancement curves and providing a standard for comparison of different protocols and modalities in dynamic imaging. MATERIALS AND METHODS: Our experimental setup consists of a peristaltic pump to generate a water flow through the phantom and a contrast injection pump. The phantom holds a sequence of layers allowing for assessment of perfusion, signal-to-noise ratio, and spatiotemporal resolution; the latter is the spatial resolution of structures with temporally changing contrast. Reproducibility was evaluated by the functional parameters time to peak, mean transit time, and peak enhancement by 24 scans over 4 weeks on a clinical computed tomography scanner. In addition, the area under the curve was evaluated for different injection durations at constant injection volume. Spatiotemporal resolution was assessed by spatial profiles on perfused bore patterns and compared for standard reconstructions, smooth reconstructions, and highly constrained backprojection for local reconstruction (HYPR LR). RESULTS: The phantom showed good reproducibility in repeated measurements, with maximal deviations of 4% for time to peak, 9% for mean transit time, and 8% for peak enhancement. Area under the curve was constant within 3.5% for different injection protocols. For the static case, HYPR LR maintained spatial resolution. For dynamic objects, however, HYPR LR reduced spatial resolution dependent on temporal dynamics by up to 19% for highest dynamics, which was still superior to smooth reconstructions (27%). CONCLUSIONS: The proposed phantom showed good reproducibility and therefore allows for comparing injection protocols or modalities in dynamic imaging. Assessment of spatiotemporal resolution under measurement conditions provides means for assessing postprocessing methods and reconstruction techniques in dynamic imaging.