Citations

AbstractBackgroundThe feasibility of oral dark contrast media is under exploration in abdominal computed tomography (CT) applications. One of the experimental contrast media in this class is dark borosilicate contrast media (DBCM), which has a CT attenuation lower than that of intra‐abdominal fat.PurposeTo evaluate the performances of DBCM using single‐ and multi‐energy CT imaging on a clinical photon‐counting‐detector CT (PCD‐CT).MethodsFive vials, three with iodinated contrast agent (5, 10, and 20 mg/mL; Omnipaque 350) and two with DBCM (6% and 12%; Nextrast, Inc.), and one solid‐water rod (neutral contrast agent) were inserted into two multi‐energy CT phantoms, and scanned on a clinical PCD‐CT system (NAEOTOM Alpha) at 90, 120, 140, Sn100, and Sn140 kV (Sn: tin filter) in multi‐energy mode. CARE keV IQ level was 180 (CTDIvol: 3.0 and 12.0 mGy for the small and large phantoms, respectively). Low‐energy threshold images were reconstructed with a quantitative kernel (Qr40, iterative reconstruction strength 2) and slice thickness/increment of 2.0/2.0 mm. Virtual monoenergetic images (VMIs) were reconstructed from 40 to 140 keV at 10 keV increments. On all images, average CT numbers for each vial/rod were measured using circular region‐of‐interests and averaged over eight slices. The contrast‐to‐noise ratio (CNR) of iodine (5 mg/mL) against DBCM was calculated and plotted against tube potential and VMI energy level, and compared to the CNR of iodine against water. Similar analyses were performed on iodine maps and VNC images derived from the multi‐energy scan at 120 kV.ResultsWith increasing kV or VMI keV, the negative HU of DBCM decreased only slightly, whereas the positive HU of iodine decreased across all contrast concentrations and phantom sizes. CT numbers for DBCM decreased from −178.5 ± 9.6 to −194.4 ± 6.3 HU (small phantom) and from −181.7 ± 15.7 to −192.1 ± 11.9 HU (large phantom) for DBCM‐12% from 90 to Sn140 kV; on VMIs, the CT numbers for DBCM decreased minimally from −147.1 ± 15.7 to −185.1 ± 9.2 HU (small phantom) and −158.8 ± 28.6 to −188.9 ± 14.7 HU (large phantom) from 40 to 70 keV, but remained stable from 80 to 140 keV. The highest iodine CNR against DBCM in low‐energy threshold images was seen at 90 or Sn140 kV for the small phantom, whereas all CNR values from low‐energy threshold images for the large phantom were comparable. The CNR values of iodine against DBCM computed on VMIs were highest at 40 or 70 keV depending on iodine and DBCM concentrations. The CNR values of iodine against DBCM were consistently higher than iodine to water (up to 460% higher dependent on energy level). Further, the CNR of iodine compared to DBCM is less affected by VMI energy level than the identical comparison between iodine and water: CNR values at 140 keV were reduced by 46.6% (small phantom) or 42.6% (large phantom) compared to 40 keV; CNR values for iodine compared to water were reduced by 86.3% and 83.8% for similar phantom sizes, respectively. Compared to 70 keV VMI, the iodine CNR against DBCM was 13%–79% lower on iodine maps and VNC.ConclusionsWhen evaluated at different tube potentials and VMI energy levels using a clinical PCD‐CT system, DBCM showed consistently higher CNR compared to iodine versus water (a neutral contrast).

Abstract Objectives Fluorescence in situ hybridization (FISH) for plasma cell neoplasms (PCNs) requires plasma cell (PC) identification or purification strategies to optimize results. We compared the efficacy of cytoplasmic immunoglobulin FISH (cIg-FISH) and fluorescence-activated cell sorting FISH (FACS-FISH) in a clinical laboratory setting. Methods The FISH analysis results of 14,855 samples from individuals with a suspected PCN subjected to cytogenetic evaluation between 2019 and 2022 with cIg-FISH (n = 6917) or FACS-FISH (n = 7938) testing were analyzed. Results Fluorescence-activated cell sorting–FISH increased the detection rate of abnormalities in comparison with cIg-FISH, with abnormal results documented in 54% vs 50% of cases, respectively (P < .001). It improved the detection of IGH::CCND1 (P < .001), IGH::MAF (P < .001), IGH::MAFB (P < .001), other IGH rearrangements (P < .001), and gains/amplifications of 1q (P < .001), whereas the detection rates of IGH::FGFR3 fusions (P = .3), loss of 17p (P = .3), and other abnormalities, including hyperdiploidy (P = .5), were similar. Insufficient PC yield for FISH analysis was decreased between cIg-FISH and FACS-FISH (22% and 3% respectively, P < .001). Flow cytometry allowed establishment of ploidy status in 91% of cases. In addition, FACS-FISH decreased analysis times, workload efforts, and operating costs. Conclusions Fluorescence-activated cell sorting–FISH is an efficient PC purification strategy that affords significant improvement in diagnostic yield and decreases workflow requirements in comparison with cIg-FISH.

AbstractBackgroundCoronary calcification is a strong indicator of coronary artery disease, and patients with a “zero” coronary calcification score have a much lower risk of future cardiac events than those with even small amounts of calcium. However, false‐negative (incorrect zero scores) may occur if small calcifications are missed at CT due to limited spatial resolution.PurposeTo demonstrate lower limits of detection for coronary calcification using an ultra‐high‐resolution (UHR) mode on a clinical photon‐counting‐detector CT (PCD‐CT), compared to a conventional energy‐integrating‐detector CT (EID‐CT).MethodsChicken eggshell fragments (0.4–0.8 mm) mimicking coronary calcifications were scanned on a clinical PCD‐CT (NAEOTOM Alpha) in UHR mode and a conventional EID‐CT (SOMATOM Force) with matched tube potential and radiation dose levels to the PCD‐CT. PCD‐CT images were reconstructed with a sharp kernel (Qr68) and a quantum iterative algorithm (QIR‐3). Two sets of EID‐CT images were reconstructed: routine clinical kernel (Qr36, ADMIRE‐3) and a sharper kernel (Qr54) with similar noise to PCD‐CT images. With institutional review board approval, in vivo exams performed with the PCD‐CT in UHR mode were compared against patients’ clinical EID‐CT exams. The visibility of calcifications on PCD‐CT and EID‐CT images was assessed and compared qualitatively.ResultsPCD‐CT images visualized all calcified fragments, while EID‐CT failed to detect those below 0.6 mm using a routine protocol. EID‐CT with Qr54 improved visibility but distorted boundaries. Calcifications were less visible on EID‐CT than PCD‐CT as phantom sizes increased. 0.6‐ and 0.7‐mm calcified fragments were barely visible on 35‐ and 40‐cm phantom EID‐CT images. Patient cases showed small calcifications missed on EID‐CT but detected on PCD‐CT.ConclusionAt matched radiation dose, PCD‐CT in UHR mode provided higher spatial resolution and improved the detectability of small calcified fragments for different phantom/patient sizes in comparison to EID‐CT.

To investigate downstream molecular changes caused by mitogen-activated protein kinase (MEK) inhibitor treatment and further explore the impact of direct knockdown of early growth response-1 (EGR1) in melanoma cell culture. RNA-sequencing (RNA-Seq) was performed to determine gene expression changes with MEK inhibitor treatment. Treatment with MEK inhibitor (trametinib) was then assessed in two cutaneous (MEL888, MEL624) and one conjunctival (YUARGE 13-3064) melanoma cell line. Direct knockdown of EGR1 was accomplished using lentiviral vectors containing shRNA. Cell viability was measured using PrestoBlueHS Cell Viability Reagent. Total RNA and protein were assessed by qPCR and SimpleWestern. RNA-Seq demonstrated a profound reduction in EGR1 with MEK inhibitor treatment, prompting further study of melanoma cell lines. Following trametinib treatment of melanoma cells, viability was reduced in both cutaneous (MEL888 26%, P < 0.01; MEL624 27%, P < 0.001) and conjunctival (YUARGE 13-3064 33%, P < 0.01) melanoma compared with DMSO control, with confirmed EGR1 knockdown to 0.04-, 0.01-, and 0.16-fold DMSO-treated levels (all P < 0.05) in MEL888, MEL624, and YUARGE 13-3064, respectively. Targeted EGR1 knockdown using shRNA reduced viability in both cutaneous (MEL624 78%, P = 0.05) and conjunctival melanoma (YUARGE-13-3064 67%, P = 0.02). RNA-Sequencing in MEK inhibitor-treated cells identified EGR1 as a candidate effector molecule of interest. In a malignant melanoma cell population, MEK inhibition reduced viability in both cutaneous and conjunctival melanoma with a profound downstream reduction in EGR1 expression. Targeted knockdown of EGR1 reduced both cutaneous and conjunctival melanoma cell viability independent of MEK inhibition, suggesting a key role for EGR1 in melanoma pathobiology.

Abstract Objectives Multimorbidity is burdensome for people with RA. We investigated differences in multimorbidity and comorbidities by sex and age in the RA population. Methods This cross-sectional analysis used national administrative claims (OptumLabs® Data Warehouse) from people with RA and non-RA comparators (matched on age, sex, race, census region, index year and length of baseline insurance coverage) from 2010–2019. RA was determined using a validated algorithm. Multimorbidity was defined as ≥2 (MM2+) or ≥5 (MM5+) comorbidities from a validated set of 44 chronic conditions. We used logistic regression to assess associations between characteristics and multimorbidity. Results The sample included 154 391 RA patients and 154 391 non-RA comparators. For people aged 18–50 years, RA women (vs RA men) had 7.5 and 4.4 (vs 3.2 and 0.9 in non-RA women vs non-RA men) percentage point increases for MM2+ and MM5+, respectively. For people aged 51+ years, RA women (vs RA men) had 2.1 and 2.5 (vs 1.2 and 0.3 in non-RA women vs non-RA men) percentage point increases for MM2+ and MM5+, respectively. Interactions revealed that differences in multimorbidity between women and men were exacerbated by RA (vs non-RA) (P &lt; 0.05), with more pronounced effects in people aged 18–50. Men had more cardiovascular-related conditions, whereas RA women had more psychological, neurological and general musculoskeletal conditions. Other comorbidities varied by sex and age. Conclusion Multimorbidity disproportionately impacts women with RA. Research, clinical and policy agendas for rheumatic diseases should acknowledge and support the variation in care needs by sex and gender across the lifespan.

AbstractYoung adults have increasing genomic testing opportunities; however, little is known about how equipped they feel about making decisions to learn personal genomic information. We conducted qualitative interviews with 19 young adults, ages 18–21 years old, enrolled in a research study where they made decisions about learning personal genomic risk for developing preventable, treatable, and adult‐onset conditions and carrier status for autosomal recessive conditions. Participants had the option to include a parent in their study visit and the decision‐making process. The goal of this project was to explore young adults' reasons for involving or not involving a parent in the study and to assess young adults' perspectives about parental roles in their healthcare. Nine participants included a parent in the study and ten did not include a parent. Eleven participants received genomic test results before the interview, while eight participants had not yet received their results at the time of the interview. The study team developed a coding guide and coded interview transcripts inductively and deductively using an interpretive descriptive‐analytic approach. Logistical issues dominated solo participants' reasons for not involving a parent in the study, whereas those who involved a parent often cited a close relationship with the parent and the parent's previous involvement in the participant's healthcare as reasons for involving them. Both groups of participants described gradually transitioning to independent healthcare decision‐making with age and felt their comfort in medical decision‐making depends on the severity of and their familiarity with the situation. Participants recommended that future genomic researchers or clinicians give young adults the option to involve a parent or friend as a support person in research or clinical visits. Although young adults may have different journeys toward independent healthcare decision‐making, some may benefit from continued parental or peer involvement after reaching the age of legal adulthood.

Importance Radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS) punctuated by incidental magnetic resonance imaging (MRI) white matter anomalies within the central nervous system. Objective To determine the time to onset of symptoms consistent with MS. Design, Setting, and Participants From September 2017 to October 2022, this multicenter, double-blind, phase 3, randomized clinical trial investigated the efficacy of teriflunomide in delaying MS in individuals with RIS, with a 3-year follow-up. The setting included referral centers in France, Switzerland, and Turkey. Participants older than 18 years meeting 2009 RIS criteria were randomly assigned (1:1) to oral teriflunomide, 14 mg daily, or placebo up to week 96 or, optionally, to week 144. Interventions Clinical, MRI, and patient-reported outcomes (PROs) were collected at baseline and yearly until week 96, with an optional third year in the allocated arm if no symptoms have occurred. Main outcomes Primary analysis was performed in the intention-to-treat population, and safety was assessed accordingly. Secondary end points included MRI outcomes and PROs. Results Among 124 individuals assessed for eligibility, 35 were excluded for declining to participate, not meeting inclusion criteria, or loss of follow-up. Eighty-nine participants (mean [SD] age, 37.8 [12.1] years; 63 female [70.8%]) were enrolled (placebo, 45 [50.6%]; teriflunomide, 44 [49.4%]). Eighteen participants (placebo, 9 [50.0%]; teriflunomide, 9 [50.0%]) discontinued the study, resulting in a dropout rate of 20% for adverse events (3 [16.7%]), consent withdrawal (4 [22.2%]), loss to follow-up (5 [27.8%]), voluntary withdrawal (4 [22.2%]), pregnancy (1 [5.6%]), and study termination (1 [5.6%]). The time to the first clinical event was significantly extended in the teriflunomide arm compared with placebo, in both the unadjusted (hazard ratio [HR], 0.37; 95% CI, 0.16-0.84; P = .02) and adjusted (HR, 0.28; 95% CI, 0.11-0.71; P = .007) analysis. Secondary imaging end point outcomes including the comparison of the cumulative number of new or newly enlarging T2 lesions (rate ratio [RR], 0.57; 95% CI, 0.27-1.20; P = .14), new gadolinium-enhancing lesions (RR, 0.33; 95% CI, 0.09-1.17; P = .09), and the proportion of participants with new lesions (odds ratio, 0.72; 95% CI, 0.25-2.06; P = .54) were not significant. Conclusion and Relevance Treatment with teriflunomide resulted in an unadjusted risk reduction of 63% and an adjusted risk reduction of 72%, relative to placebo, in preventing a first clinical demyelinating event. These data suggest a benefit to early treatment in the MS disease spectrum. Trial Registration ClinicalTrials.gov Identifier: NCT03122652

Objectives: To evaluate if dual-energy CT (DECT) pulmonary angiography (CTPA) can detect anemia with the aid of machine learning. Methods: Inclusion of 100 patients (mean age ± SD, 51.3 ± 14.8 years; male-to-female ratio, 42/58) who underwent DECT CTPA and hemoglobin (Hb) analysis within 24 h, including 50 cases with Hb below and 50 controls with Hb ≥ 12 g/dL. Blood pool attenuation was assessed on virtual noncontrast (VNC) images at eight locations. A classification model using extreme gradient-boosted trees was developed on a training set (n = 76) for differentiating cases from controls. The best model was evaluated in a separate test set (n = 24). Results: Blood pool attenuation was significantly lower in cases than controls (p-values < 0.01), except in the right atrium (p = 0.06). The machine learning model had sensitivity, specificity, and accuracy of 83%, 92%, and 88%, respectively. Measurements at the descending aorta had the highest relative importance among all features; a threshold of 43 HU yielded sensitivity, specificity, and accuracy of 68%, 76%, and 72%, respectively. Conclusion: VNC imaging and machine learning shows good diagnostic performance for detecting anemia on DECT CTPA.

ImportanceSystematic data on the association between anticancer therapies and thromboembolic events (TEEs) in patients with COVID-19 are lacking.ObjectiveTo assess the association between anticancer therapy exposure within 3 months prior to COVID-19 and TEEs following COVID-19 diagnosis in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included patients who were hospitalized and had active cancer and laboratory-confirmed SARS-CoV-2 infection. Data were accrued from March 2020 to December 2021 and analyzed from December 2021 to October 2022.ExposureTreatments of interest (TOIs) (endocrine therapy, vascular endothelial growth factor inhibitors/tyrosine kinase inhibitors [VEGFis/TKIs], immunomodulators [IMiDs], immune checkpoint inhibitors [ICIs], chemotherapy) vs reference (no systemic therapy) in 3 months prior to COVID-19.Main Outcomes and MeasuresMain outcomes were (1) venous thromboembolism (VTE) and (2) arterial thromboembolism (ATE). Secondary outcome was severity of COVID-19 (rates of intensive care unit admission, mechanical ventilation, 30-day all-cause mortality following TEEs in TOI vs reference group) at 30-day follow-up.ResultsOf 4988 hospitalized patients with cancer (median [IQR] age, 69 [59-78] years; 2608 [52%] male), 1869 had received 1 or more TOIs. Incidence of VTE was higher in all TOI groups: endocrine therapy, 7%; VEGFis/TKIs, 10%; IMiDs, 8%; ICIs, 12%; and chemotherapy, 10%, compared with patients not receiving systemic therapies (6%). In multivariable log-binomial regression analyses, relative risk of VTE (adjusted risk ratio [aRR], 1.33; 95% CI, 1.04-1.69) but not ATE (aRR, 0.81; 95% CI, 0.56-1.16) was significantly higher in those exposed to all TOIs pooled together vs those with no exposure. Among individual drugs, ICIs were significantly associated with VTE (aRR, 1.45; 95% CI, 1.01-2.07). Also noted were significant associations between VTE and active and progressing cancer (aRR, 1.43; 95% CI, 1.01-2.03), history of VTE (aRR, 3.10; 95% CI, 2.38-4.04), and high-risk site of cancer (aRR, 1.42; 95% CI, 1.14-1.75). Black patients had a higher risk of TEEs (aRR, 1.24; 95% CI, 1.03-1.50) than White patients. Patients with TEEs had high intensive care unit admission (46%) and mechanical ventilation (31%) rates. Relative risk of death in patients with TEEs was higher in those exposed to TOIs vs not (aRR, 1.12; 95% CI, 0.91-1.38) and was significantly associated with poor performance status (aRR, 1.77; 95% CI, 1.30-2.40) and active/progressing cancer (aRR, 1.55; 95% CI, 1.13-2.13).Conclusions and RelevanceIn this cohort study, relative risk of developing VTE was high among patients receiving TOIs and varied by the type of therapy, underlying risk factors, and demographics, such as race and ethnicity. These findings highlight the need for close monitoring and perhaps personalized thromboprophylaxis to prevent morbidity and mortality associated with COVID-19–related thromboembolism in patients with cancer.