Coronary artery calcium assessed with calibrated mass scoring in asymptomatic individuals: results from the Copenhagen General Population Study.

BACKGROUND: Coronary artery calcification (CAC) is commonly assessed with Agatston score (AS). A higher sensitivity and precision for the detection of CAC has been demonstrated with calibrated mass score (cMS). We hypothesized that cMS would detect low-level CAC not detectable with AS in a large asymptomatic background population. METHODS: Participants (N = 2985) from the Copenhagen General Population Study were evaluated for CAC using both conventional AS and cMS. The population was grouped according to number of traditional risk factors and heart score was used to assess the risk of event for those with no CAC, those with only cMS > 0 and those with both AS and cMS > 0. RESULTS: In participants with an AS = 0, 11% had cMS > 0. The risk profile of this cMS-only group was between that of the CAC-negative participants and those with AS > 0 and cMS > 0. Overall, 6% of the population belonged to the cMS-only group independent of the number of risk factors. CONCLUSION: In individuals with AS = 0, a fraction was found to have cMS > 0. Based on traditional risk factors, this group has a higher 10-year risk than individuals with both AS = 0 and cMS = 0; cMS might offer very early cardiovascular risk assessment in asymptomatic individuals. KEY POINTS: • In individuals with AS=0, a fraction has CAC with highly sensitive cMS. • This fraction has a higher 10-year risk of cardiovascular disease. • Regardless of risk factors, 6% has CAC detectable only with cMS. • cMS might offer very early cardiovascular risk assessment in asymptomatic individuals.

Steroids and Cross-Linking for Ulcer Treatment Trial II: Baseline Characteristics.

PURPOSE: The Steroids and Cross-linking for Ulcer Treatment Trial is an NIH-funded international, randomized, double-masked, sham and placebo-controlled clinical trial to determine the benefit of adjunctive corneal cross-linking with riboflavin and/or topical difluprednate in addition to topical antibiotic drops for treatment of smear-positive bacterial ulcers. The purpose of this study was to explore the baseline characteristics for infection of patients enrolled, and the ocular comorbidities of patients screened for inclusion. METHODS: Of the 2005 patients with smear-positive bacterial ulcers screened, 280 patients were enrolled. Descriptive statistics were used to summarize and characterize the data. RESULTS: Eligible patients in India had baseline factors associated with agricultural work (N = 132; 47%) and manual labor (N = 54; 19%), whereas patients in the United States were associated with contact lens wear (N = 11; 69%) (P <0.001). Nearly, 10% of patients with unilateral infectious keratitis are at risk of bilateral blindness because of preexisting visual disability in their other eye and thus ineligible for inclusion. India had higher rates of exclusionary factors for blindness in the other eye such as cataract (N = 48; 27%) and glaucoma (N = 24; 13) compared with the United States (N = 0; 0%) (P <0.001). CONCLUSIONS: While corneal ulceration is an important cause of disability in technologically advanced countries, it occurs more frequently in low and middle-income countries, and the implications on these populations should be considered. These baseline factors can be evaluated to address such health care disparities.

A double-masked, sham-controlled trial of rose bengal photodynamic therapy for the treatment of fungal and acanthameoba keratitis: Rose Bengal Electromagnetic Activation with Green Light for Infection Reduction (REAGIR) Study.

Background: Infectious keratitis secondary to fungus or acanthamoeba often has a poor outcome despite receiving the best available medical therapy. In vitro Rose Bengal Photodynamic therapy (RB-PDT) appears to be effective against fungal and acanthamoeba isolates.22,23 In one published series RB-PDT reduced the need for therapeutic penetrating keratoplasty in severe bacterial, fungal, and acanthameoba keratitis not responsive to medical therapy. Methods: This international, randomized, sham and placebo controlled 2-arm clinical trial, randomizes patients with smear positive fungal and acanthameoba and smear negative corneal ulcers in a 1:1 fashion to one of two treatment arms: 1) Topical antimicrobial plus sham RB-PDT or 2) Topical antimicrobial plus RB-PDT. Discussion: We anticipate that RB-PDT will improve best spectacle corrected visual acuity and also reduce complications such as corneal perforation and the need for therapeutic penetrating keratoplasty. This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. Our results will be disseminated via clinicaltrials.gov website, meetings, and journal publications. Our data will also be available upon reasonable request. Trial Registration: NCT, NCT05110001, Registered November 5, 2021. https://www.clinicaltrials.gov/study/NCT05110001.

Reporting diarrhoea through a vernacular term in Quechua-speaking settings of rural Bolivia.

Field studies often use caregiver-reported diarrhoea and related symptoms to measure child morbidity. There are various vernacular terms to define diarrhoea that vary across the local cultural contexts. The relationship between vernacular definitions of diarrhoea and symptoms-based definitions is not well-documented. This paper describes the association of the vernacular Quechua term k'echalera with the symptoms-based standard definition of diarrhoea in rural Bolivian settings. During a cluster randomized trial in rural Bolivia, both signs and symptoms of diarrhoea and reports of k'echalera were collected for children aged less than five years. Reported k'echalera were found to be associated with important changes in stool frequency, consistency, and presence of blood and mucus. Reported k'echalera were highly related to three of four recorded categories of watery stool. The intermediate (milk-rice) stool consistency, which fits into the definition of watery stool, was not strongly related to k'echalera. Mucus in the stool was also associated with k'echalera; however, its presence in k'echalera-free days accounted for at least 50% of the possible false negatives. The sensitivity and specificity of the term k'echalera were estimated by Bayesian methods, allowing for both symptoms of diarrhoea and reports of k'echalera to be subject to diagnosis error. An average specificity of at least 97% and the sensitivity of at least 50% were obtained. The findings suggest that the use of k'echalera would identify fewer cases of diarrhoea than a symptom-based definition in rural Bolivia.

Peak SNR in automated coronary calcium scoring: selecting CT scan parameters and statistically defined scoring thresholds.

PURPOSE: Development and verification of peak signal-to-noise ratio (SNR(P)) equations for determining optimum CT scanning and scoring parameters for a new automated coronary calcium scoring program (N-vivo). Experimental evaluation of the new program for scoring small calcium hydroxyapatite (CaHA) microspheres with small voxel CT images. METHODS: Theoretical SNR(P) equations were developed using measures of noise, resolution, contrast, scatter, and x-ray photon energy. A coronary calcium scoring test phantom containing very small CaHA microspheres was scanned simultaneously with a calibration phantom at three kVps, three voxel sizes, and three phantom sizes. Agatston and calibrated mass scores, noise standard deviations, peak noise, and peak signal voxel intensities were measured by the N-vivo method for individual microspheres and in patient CT scans. RESULTS: The SNR(P) equation was predictive of the optimum voxel size, kVp, and phantom size, and allowed automated computation of mass scoring thresholds specific to each patient and CT scan. The smallest microcalcification scored in the full sized phantom with the N-vivo method by calibrated mass score (volume 0.075 mm3, mass 0.17 mg) was approximately four times smaller than that scored with the Agatston method (0.27 mm3, mass 0.63 mg). CONCLUSIONS: The SNR(P) equation can be used to model and optimize calcium scoring and CT scan parameters. The common assumptions that noise is too high in thin slice CT or requires high radiation dose for CAC scoring are shown to be misleading. The N-vivo method showed higher detection sensitivity for small microspheres and more consistent mass scores at different beam energies than the conventional Agatston method. Advanced calcium scoring methods with higher sensitivity may allow improved monitoring of plaque changes and provide earlier detection of atherosclerosis.

Assessment of coronary calcification using calibrated mass score with two different multidetector computed tomography scanners in the Copenhagen General Population Study.

OBJECTIVE: Population studies have shown coronary calcium score to improve risk stratification in subjects suspected for cardiovascular disease. The aim of this work was to assess the validity of multidetector computed tomography (MDCT) for measurement of calibrated mass scores (MS) in a phantom study, and to investigate inter-scanner variability for MS and Agaston score (AS) recorded in a population study on two different high-end MDCT scanners. MATERIALS AND METHODS: A calcium phantom was scanned by a first (A) and second (B) generation 320-MDCT. MS was measured for each calcium deposit from repeated measurements in each scanner and compared to known physical phantom mass. Random samples of human subjects from the Copenhagen General Population Study were scanned with scanner A (N=254) and scanner B (N=253) where MS and AS distributions of these two groups were compared. RESULTS: The mean total MS of the phantom was 32.9±0.8mg and 33.1±0.9mg (p=0.43) assessed by scanner A and B respectively - the physical calcium mass was 34.0mg. Correlation between measured MS and physical calcium mass was R2=0.99 in both scanners. In the population study the median total MS was 16.8mg (interquartile range (IQR): 3.5-81.1) and 15.8mg (IQR: 3.8-63.4) in scanner A and B (p=0.88). The corresponding median total AS were 92 (IQR: 23-471) and 89 (IQR: 40-384) (p=0.64). CONCLUSION: Calibrated calcium mass score may be assessed with very high accuracy in a calcium phantom by different generations of 320-MDCT scanners. In population studies, it appears acceptable to pool calcium scores acquired on different 320-MDCT scanners.

Reduced Bone Density and Vertebral Fractures in Smokers. Men and COPD Patients at Increased Risk.

RATIONALE: Former smoking history and chronic obstructive pulmonary disease (COPD) are potential risk factors for osteoporosis and fractures. Under existing guidelines for osteoporosis screening, women are included but men are not, and only current smoking is considered. OBJECTIVES: To demonstrate the impact of COPD and smoking history on the risk of osteoporosis and vertebral fracture in men and women. METHODS: Characteristics of participants with low volumetric bone mineral density (vBMD) were identified and related to COPD and other risk factors. We tested associations of sex and COPD with both vBMD and fractures adjusting for age, race, body mass index (BMI), smoking, and glucocorticoid use. MEASUREMENTS AND MAIN RESULTS: vBMD by calibrated quantitative computed tomography (QCT), visually scored vertebral fractures, and severity of lung disease were determined from chest CT scans of 3,321 current and ex-smokers in the COPDGene study. Low vBMD as a surrogate for osteoporosis was calculated from young adult normal values. Male smokers had a small but significantly greater risk of low vBMD (2.5 SD below young adult mean by calibrated QCT) and more fractures than female smokers. Low vBMD was present in 58% of all subjects, was more frequent in those with worse COPD, and rose to 84% among subjects with very severe COPD. Vertebral fractures were present in 37% of all subjects and were associated with lower vBMD at each Global Initiative for Chronic Obstructive Lung Disease stage of severity. Vertebral fractures were most common in the midthoracic region. COPD and especially emphysema were associated with both low vBMD and vertebral fractures after adjustment for steroid use, age, pack-years of smoking, current smoking, and exacerbations. Airway disease was associated with higher bone density after adjustment for other variables. Calibrated QCT identified more subjects with abnormal values than the standard dual-energy X-ray absorptiometry in a subset of subjects and correlated well with prevalent fractures. CONCLUSIONS: Male smokers, with or without COPD, have a significant risk of low vBMD and vertebral fractures. COPD was associated with low vBMD after adjusting for race, sex, BMI, smoking, steroid use, exacerbations, and age. Screening for low vBMD by using QCT in men and women who are smokers will increase opportunities to identify and treat osteoporosis in this at-risk population.

Very small calcifications are detected and scored in the coronary arteries from small voxel MDCT images using a new automated/calibrated scoring method with statistical and patient specific plaque definitions.

A negative (zero) Agatston coronary calcium score (CCS) by current methods confers a very low risk for hard coronary events during the next years. However, controversy remains on how to use a negative score since some hard events still occur. We report on a new method with improved detection sensitivity for very small calcifications with the potential to more confidently rule out early atherosclerotic disease. Seventy-eight (78) patients with negative Agatston scores by conventional methods with 2.5 mm slices were selected from routine GE 64 MDCT scans. Each scan was reconstructed a second time from the same data to create 0.625 mm isotropic voxels. The 2.5 mm images were manually scored by the usual Agatston method using the GE SmartScore™ software. Both the 2.5 and 0.625 mm image sets were scored with a new automated and calibrated method (N-vivo™, Image Analysis). The software automatically computes dual scoring thresholds that are statistically defined and specific for each patient, scanner, and scan. The images were hybrid calibrated by simultaneous scanned phantoms in combination with in vivo blood/muscle references. The output reported the calibrated mass scores along with the number of plaques using 18 pt, 3-D connectivity criteria. A CCS Test phantom with known CaHA microspheres was used to validate the method. Twenty-three percent (18 of 78) of the patients with negative Agatston scores by the conventional method scored positive for coronary calcifications by the N-vivo method. The number of small plaques scored per patient varied from 1 to 4. One patient with a single small calcification suffered a hard coronary event during the CT scan. All of the detected plaques were located in the proximal heart. The conventional CCS method misclassified 23% of these patients as having negative coronary calcium scores. The N-vivo automated scoring method with small voxel CT images increased the detection sensitivity of small calcifications with no increase in radiation dose. Detection of small coronary calcified plaques occult to conventional scoring methods may increase the negative predictive power of calcium scoring and may improve plaque composition analysis.

Coronary calcium test phantom containing true CaHA microspheres for evaluation of advanced CT calcium scoring methods.

BACKGROUND: Test phantoms with simulated micro-calcifications of true calcium hydroxyapatite (CaHA) density were not available to validate advanced calcium scoring methods or plaque density measurements. OBJECTIVES: We evaluated a coronary calcium scoring (CCS) test phantom containing very small CaHA microspheres and validated a new scoring method for measurements of plaque densities. METHODS: The semianthropomorphic CCS phantom was constructed with CaHA microspheres (volumes, 0.05-3.1 mm(3)) with the approximate density of biologic calcifications. QRM and CCS phantoms were scored with a new calibrated and automated calcium scoring method (N-vivo; Image Analysis). The densities of the microspheres and 609 individual patient plaques were measured. RESULTS: The range of measured densities of the CaHA microspheres was approximately equivalent to that measured in the patient coronary calcifications. The smallest microspheres scored with the calibrated/automated and the Agatston methods had volumes of 0.075 mm(3) and 0.27 mm(3), respectively. The standard deviations of the mass scores of the microspheres ranged from 0.02 to 0.17 mg with regression slope of 0.962 and R(2) = 0.997. The relationship of measured density to measured mass of the patient plaques was similar to that of the microspheres, suggesting that vascular calcifications are CaHA density. CONCLUSIONS: The CaHA microspheres of the CCS test phantom were found to be representative in density and size of coronary calcifications. The measurements show that CT calcium scoring underestimates plaque density and greatly overestimates volume. The heterogeneity of calcium concentration densities measured in the patient plaques was due largely to CT scanner measurement errors.

Systematic spatial analysis of gene expression during wheat caryopsis development.

The cereal caryopsis is a complex tissue in which maternal and endosperm tissues follow distinct but coordinated developmental programs. Because of the hexaploid genome in wheat (Triticum aestivum), the identification of genes involved in key developmental processes by genetic approaches has been difficult. To bypass this limitation, we surveyed 888 genes that are expressed during caryopsis development using a novel high-throughput mRNA in situ hybridization method. This survey revealed novel distinct spatial expression patterns that either reflected the ontogeny of the developing caryopsis or indicated specialized cellular functions. We have identified both known and novel genes whose expression is cell cycle-dependent. We have identified the crease region as important in setting up the developmental patterning, because the transition from proliferation to differentiation spreads from this region to the rest of the endosperm. A comparison of this set of genes with the rice (Oryza sativa) genome shows that approximately two-thirds have rice counterparts but also suggests considerable divergence with regard to proteins involved in grain filling. We found that the wheat genes had significant homology with 350 Arabidopsis thaliana genes. At least 25 of these are already known to be essential for seed development in Arabidopsis, but many others remain to be characterized.