Countering Calcium Blooming With Personalized Contrast Media Injection Protocols: The 1-2-3 Rule for Photon-Counting Detector CCTA.

OBJECTIVE: Photon-counting detector computed tomography (PCD-CT) enables spectral data acquisition of CT angiographies allowing for reconstruction of virtual monoenergetic images (VMIs) in routine practice. Specifically, it has potential to reduce the blooming artifacts associated with densely calcified plaques. However, calcium blooming and iodine attenuation are inversely affected by energy level (keV) of the VMIs, creating a challenge for contrast media (CM) injection protocol optimization. A pragmatic and simple rule for calcium-dependent CM injection protocols is investigated and proposed for VMI-based coronary CT angiography with PCD-CT. MATERIALS AND METHODS: A physiological circulation phantom with coronary vessels including calcified lesions (maximum CT value >700 HU) with a 50% diameter stenosis was injected into at iodine delivery rates (IDRs) of 0.3, 0.5, 0.7, 1.0, 1.5, 2.0, 2.5, and 3.0 g I/s. Images were acquired using a first-generation dual-source PCD-CT and reconstructed at various VMI levels (between 45 and 190 keV). Iodine attenuation in the coronaries was measured at each IDR for each keV, and blooming artifacts from the calcified lesions were assessed including stenosis grading error (as % overestimation vs true lumen). The IDR to achieve 300 HU at each VMI level was then calculated and compared with stenosis grading accuracy to establish a general rule for CM injection protocols. RESULTS: Plaque blooming artifacts and intraluminal iodine attenuation decreased with increasing keV. Fixed windowing (representing absolute worst case) resulted in stenosis overestimation from 77% ± 4% at 45 keV to 5% ± 2% at 190 keV, whereas optimized windowing resulted in overestimation from 29% ± 3% at 45 keV to 4% ± 1% at 190 keV. The required IDR to achieve 300 HU showed a strong linear correlation to VMI energy (R2 = 0.98). Comparison of this linear plot versus stenosis grading error and blooming artifact demonstrated that multipliers of 1, 2, and 3 times the reference IDR for theoretical clinical regimes of no, moderate, and severe calcification density, respectively, can be proposed as a general rule. CONCLUSIONS: This study provides a proof-of-concept in an anthropomorphic phantom for a simple pragmatic adaptation of CM injection protocols in coronary CT angiography with PCD-CT. The 1-2-3 rule demonstrates the potential for reducing the effects of calcium blooming artifacts on overall image quality.

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.

Assessing adverse drug reaction reports for antidiabetic medications approved by the food and drug administration between 2012 and 2017: a pharmacovigilance study.

Objective: Between 2012 and 2017, the U.S. Food and Drug Administration (FDA) approved 10 antidiabetic indicated therapies. Due to the limited literature on voluntarily reported safety outcomes for recently approved antidiabetic drugs, this study investigated adverse drug reactions (ADRs) reported in the FDA Adverse Event Reporting System (FAERS). Research Design and Methods: A disproportionality analysis of spontaneously reported ADRs was conducted. FAERS reports from January 1, 2012 to March 31, 2022 were compiled, allowing a 5-year buffer following drug approval in 2017. Reporting odds ratios were calculated for the top 10 ADRs, comparing new diabetic agents to the other approved drugs in their therapeutic class. Results: 127,525 reports were identified for newly approved antidiabetic medications listed as the primary suspect (PS). For sodium-glucose co-transporter-2 (SGLT-2) inhibitors, the odds of blood glucose increased, nausea, and dizziness being reported was greater for empagliflozin. Dapagliflozin was associated with greater reports of weight decreased. Canagliflozin was found to have a disproportionally higher number of reports for diabetic ketoacidosis, toe amputation, acute kidney injury, fungal infections, and osteomyelitis. Assessing glucagon-like peptide-1 (GLP-1) receptor agonists, dulaglutide and semaglutide were associated with greater reports of gastrointestinal adverse drug reactions. Exenatide was disproportionally associated with injection site reactions and pancreatic carcinoma reports. Conclusion: Pharmacovigilance studies utilizing a large publicly available dataset allow an essential opportunity to evaluate the safety profile of antidiabetic drugs utilized in clinical practice. Additional research is needed to evaluate these reported safety concerns for recently approved antidiabetic medications to determine causality.

Adverse drug reactions reported for antidiabetic medications Introduction: This study investigated the trends in voluntary reporting of adverse drug reactions for recently approved antidiabetic medications. Methods: Data from the FDA Adverse Events Reporting System were evaluated. The top 10 adverse drug reactions were compared between antidiabetic medications in the same therapeutic class. Results: We identified 127,525 adverse drug reaction reports for the newer approved antidiabetic medications. For SGLT-2 inhibitors, empagliflozin was associated with greater reports of blood glucose increase, nausea, and dizziness; weight decreased was reported more often for dapagliflozin; and diabetic ketoacidosis, toe amputation, acute kidney injury, fungal infections, and osteomyelitis were reported more commonly for canagliflozin. Assessing GLP-1 receptor agonists, the odds of gastrointestinal adverse drug reactions being reported was greater for dulaglutide and semaglutide. Exenatide was disproportionally associated with injection site reactions and pancreatic carcinoma reports. Conclusion: Medication safety studies using a large publicly available dataset allows an essential opportunity to evaluate the safety profile of antidiabetic drugs in the real-world setting. Additional research is needed to determine if the reported safety concerns for recently approved antidiabetic medications to determine causality.

Shaken or Stirred? The Inconsistencies of Manual Contrast Media Dilution in Endovascular Interventions.

MATERIALS AND METHODS: Phase I: Eleven radiological technologists were asked to fill a CM injector 3 times with 50% diluted CM (iopromide 300 mg I/mL). The dilution was injected (12 mL/s) through a Coriolis flowmeter, with CM concentration and total volume calculated. Interoperator, intraoperator, and intraprocedural variations were calculated as coefficients of variability. Contrast media dose reporting accuracy was determined. Phase II: The study was repeated after implementation of a standardized dilution protocol with 5 representative operators. RESULTS: Phase I: The average injected concentration among 11 operators was 68% ± 16% CM (n = 33; range, 43%-98%), as compared with the target of 50% CM. The interoperator variability was 16%, the intraoperator variability was 6% ± 3%, and the intraprocedural variability was 23% ± 19% (range, 5%-67%). This led to overdelivery of CM compared with intended patient dose by 36% on average. Phase II: After standardization, injections averaged 55% ± 4% CM (n = 15; range, 49%-62%), with interoperator variability of 8%, intraoperator variability of 5% ± 1%, and intraprocedural variability of 1.6% ± 0.5% (range, 0.4%-3.7%). CONCLUSIONS: Manual CM dilution can lead to substantial interoperator and intraoperator, as well as intraprocedural variability in injected concentration. This can result in underreporting of administered CM doses to patients. It is recommended that clinics assess their current standard of care regarding CM injections for endovascular interventions and evaluate potential corrective actions if appropriate.

Third-Generation Cardiovascular Phantom: The Next Generation of Preclinical Research in Diagnostic Imaging.

OBJECTIVE: Different types of preclinical research tools used in the field of diagnostic imaging such as dynamic flow circulation phantoms have built the foundation for optimization and advancement of clinical procedures including new imaging techniques. The objective was to introduce a third-generation phantom, building on the limitations of earlier versions and unlocking new opportunities for preclinical investigation. MATERIAL AND METHODS: A third-generation phantom was designed and constructed comprising physiological vascular models from head to toe, including a 4-chamber heart with embedded heart valves and a controllable electromechanical pump. The models include modular segments, allowing for interchangeability between healthy and diseased vessels. Clinical sanity checks were performed using the phantom in combination with a dual-head power injector on a third-generation dual-source computed tomography scanner. Contrast media was injected at 1.5 g I/s, and the phantom was configured with a cardiac output of 5.3 L/min. Measurements of mean transit times between key vascular landmarks and peak enhancement values in Hounsfield units (HUs) were measured to compare with expected in vivo results estimated from literature. RESULTS: Good agreement was obtained between literature reference values from physiology and measured results. Contrast arrival between antecubital vein and right ventricle was measured to be 13.1 ± 0.3 seconds. Transit time from right ventricle to left ventricle was 12.0 ± 0.2 seconds, from left internal carotid artery to left internal jugular vein 7.7 ± 0.4 seconds, and 2.9 ± 0.2 seconds from aortic arch to aortic bifurcation. The peak enhancement measured in the regions of interest was between 336 HU and 557 HU. CONCLUSIONS: The third-generation phantom demonstrated the capability of simulating physiologic in vivo conditions with accurate contrast media transport timing, good repeatability, and expected enhancement profiles. As a nearly complete cardiovascular system including a functioning 4-chamber heart and interchangeable disease states, the third-generation phantom presents new opportunities for the expansion of preclinical research in diagnostic imaging.

Performance of Centargo: A Novel Piston-Based Injection System for High Throughput in CE CT.

Purpose: To compare an investigational device (MEDRAD® Centargo CT Injection System, "Centargo") to the currently available MEDRAD® Stellant CT Injection System ("Stellant"), in terms of efficiency, injector performance, and user satisfaction. Patients and Methods: A total of 425 patients at two sites were enrolled; 198 patients in phase one, a randomized study (98 Stellant and 100 Centargo). The second observational phase included 227 patients who were injected with Centargo. Phase one recorded times for setup, disassembly, and patient changeovers. Demographic data, subjective image quality, and injection parameters were collected. Phase two assessed usability via a questionnaire provided to all end-users of both systems (radiographers). Results: Patient changeover times were statistically significantly faster with Centargo (15.4s ± 8.7s vs 53.7s ± 19.6s, p < 0.001). Centargo day-setup times were similar to Stellant (138.1s ± 92s vs 151.8s ± 30.6s, p = 0.33) and end-of-day-disassembly times were significantly slower (60.6s ± 27s vs 17.1s ± 12.9s, p < 0.001). Based on four different scenarios modelling patient throughput, the projected time savings with Centargo over Stellant was 40-63%, with the highest efficiency improvements for higher throughputs and the use of larger contrast medium bottles. Both Centargo and Stellant usability averaged between "Very Easy" and "Easy" in all responses to the questionnaire. There were no instances of interrupted injections due to communication loss or detected air and no insufficient images due to injector performance. No safety issues were identified. Conclusion: Centargo was able to demonstrate improved efficiency as compared to Stellant while maintaining injector performance and high usability scores.

Proactive Air Management in CT Power Injections: A Comprehensive Approach to Reducing Air Embolization.

OBJECTIVE: Venous air embolism as a complication of contrast media administration from power injection systems in CT is found to occur in 7%-55% of patients, impacting patient safety, diagnostic image quality, workflow efficiency, and patient and radiographer satisfaction. This study reviews the challenges associated with reactive air management approaches employed on contemporary systems, proposes a novel air management approach using proactive methods, and compares the impact of reactive and proactive approaches on injected air volumes under simulated clinical use. METHODS: Injected air volumes from three power injection systems were measured under simulated clinical use via custom air trap fixture. Two of the systems employed reactive air management approaches, while a new system implemented the proposed proactive air management approach. RESULTS: The proactive system injected significantly less air (average of 0.005 mL ± 0.006 mL with a maximum of 0.017 mL) when compared to two systems with reactive approaches (averages of 0.130 mL ± 0.082 mL and 0.106 mL ± 0.094 mL with maximums of 0.259 mL and 0.311 mL, respectively) (p < 0.05). CT images were taken of static and dynamic 0.1 mL air bubbles inside of a vascular phantom, both of which were clearly visible. Additionally, the dynamic bubble was shown to introduce image artifacts similar to those observed clinically. CONCLUSION: Comparison of the injected air volumes show that a system with a proactive air management approach injected significantly less air compared to tested systems employing reactive approaches. SIGNIFICANCE: The results indicate that the use of a proactive approach could significantly reduce the prevalence of observable, and potentially artifact-inducing, venous air embolism in contrast-enhanced CT procedures.

Nanogel-Mediated RNAi Against Runx2 and Osx Inhibits Osteogenic Differentiation in Constitutively Active BMPR1A Osteoblasts.

Trauma-induced heterotopic ossification (HO) and fibrodysplasia ossificans progressiva (FOP) are acquired and genetic variants of pathological bone formation occurring in soft tissues. Conventional treatment modalities target the inflammatory processes preceding bone formation. We investigated the development of a prophylaxis for heterotopic bone formation by addressing the biological basis for HO - dysregulation in the bone morphogenetic protein (BMP) signaling pathway. We previously reported the synthesis of cationic nanogel nanostructured polymers (NSPs) for efficient delivery of short interfering ribonucleic acids (siRNAs) and targeted gene silencing. Results suggested that nanogel:siRNA weight ratios of 1:1 and 5:1 silenced Runx2 and Osx gene expression in primary mouse osteoblasts with a constitutively active (ca) BMP Receptor 1A (BMPR1A) by the Q233D mutation. Repeated RNAi treatments over 14 days significantly inhibited alkaline phosphatase activity in caBMPR1A osteoblasts. Hydroxyapatite (HA) deposition was diminished over 28 days in culture, though complete suppression of HA deposition was not achieved. Outcome data suggested minimal cytotoxicity of nanogel-based RNAi therapeutics, and the multistage disruption of BMP-induced bone formation processes. This RNAi based approach to impeding osteoblastic differentiation and subsequent bone formation may form the basis of a clinical therapy for heterotopic bone formation.

Synthesis of poly(meth)acrylates with thioether and tertiary sulfonium groups by ARGET ATRP and their use as siRNA delivery agents.

The field of RNA interference depends on the development of safe and efficient carriers for short interfering ribonucleic acid (siRNA) delivery. Conventional cationic monomers for siRNA delivery have utilized the nitrogen heteroatom to produce cationic charges. Here, we polymerized cationic sulfonium (meth)acrylate by activators regenerated by electron transfer (ARGET) atom transfer radical polymerization (ATRP) to form polymers with narrow molecular weight distributions for siRNA delivery. The tertiary sulfonium species was stable toward dealkylation in water but less stable in the polar aprotic solvent dimethyl sulfoxide. Block copolymers poly(ethylene oxide) with poly(meth)acrylate containing sulfonium moieties were prepared as an siRNA delivery platform. Results suggested block copolymers were biocompatible up to 50 µg/mL in vitro and formed polyplexes with siRNA. Additionally, block copolymers protected siRNAs against endonuclease digestion and facilitated knockdown of glyceraldehyde 3-phosphate dehydrogenase (Gapdh) mRNA expression in murine calvarial preosteoblasts. The versatility, biocompatibility, and cationic nature of these tertiary sulfonium groups are expected to find widespread biological applications.

Bone tissue engineering: state of the union.

The quest to surpass the clinical efficacy of the allogeneic bone graft has had limited success, an outcome that is symbolic of tissue engineering as a whole. In this 'State of the Union'-type review, we highlight recent advances in the design of bone regenerative therapeutics using the primary elements of stem cells, growth factors and scaffolds, and identify major obstacles in their paths to the clinic. We underscore the need for rigorous performance criteria in the design of holistic tissue regenerative therapeutics, and an increased emphasis on the product production, storage and handling issues that will ultimately influence clinical success.

(2E)-N-(2-iodo-4,6-dimethylphenyl)-2-methylbut-2-enamide.

The title compound, C14H18INO, crystallizes as +sc/+sp/+sc 2-iodoanilide molecules (and racemic opposites) and shows significant intermolecular I...O interactions in the solid state, forming dimeric pairs about centres of symmetry. Under asymmetric Heck conditions, the S enantiomer of the dihydroindol-2-one was obtained using (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [(R)-BINAP], suggesting a mechanism that proceeds by oxidative addition to give the title (P) enantiomer of the compound and pro-S coordination of the Re face of the alkene in a conformation similar to that defined crystallographically, except that rotation about the C-C bond of the butenyl group is required.

Intramolecular asymmetric Heck reactions: evidence for dynamic kinetic resolution effects.

[reaction: see text] Enantioselectivity of the cyclization of 1 varies at different stages in the reaction. X-ray crystallography has shown that 1 exists as enantiomerically pure (M) and (P) chiral helical structures defined by the relative orientations of the arene, amide, and alkene. The relative rates of interconversion of the rotamers of 1 have been established, leading to mechanistic proposals to account for the variation of ee based on kinetic resolution effects.