Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Non-emphysematous chronic obstructive pulmonary disease is associated with diabetes mellitus

Background: Chronic obstructive pulmonary disease (COPD) has been classically divided into blue bloaters and pink puffers. The utility of these clinical subtypes is unclear. However, the broader distinction between airway-predominant and emphysema-predominant COPD may be clinically relevant. The objective was to define clinical features of emphysema-predominant and non-emphysematous COPD patients. Methods: Current and former smokers from the Genetic Epidemiology of COPD Study (COPDGene) had chest computed tomography (CT) scans with quantitative image analysis. Emphysema-predominant COPD was defined by low attenuation area at -950 Hounsfield Units (LAA-950) ≥10%. Non-emphysematous COPD was defined by airflow obstruction with minimal to no emphysema (LAA-950 < 5%). Results: Out of 4197 COPD subjects, 1687 were classified as emphysema-predominant and 1817 as non-emphysematous; 693 had LAA-950 between 5-10% and were not categorized. Subjects with emphysema-predominant COPD were older (65.6 vs 60.6 years, p < 0.0001) with more severe COPD based on airflow obstruction (FEV1 44.5 vs 68.4%, p < 0.0001), greater exercise limitation (6-minute walk distance 1138 vs 1331 ft, p < 0.0001) and reduced quality of life (St. George's Respiratory Questionnaire score 43 vs 31, p < 0.0001). Self-reported diabetes was more frequent in non-emphysematous COPD (OR 2.13, p < 0.001), which was also confirmed using a strict definition of diabetes based on medication use. The association between diabetes and non-emphysematous COPD was replicated in the ECLIPSE study. Conclusions: Non-emphysematous COPD, defined by airflow obstruction with a paucity of emphysema on chest CT scan, is associated with an increased risk of diabetes. COPD patients without emphysema may warrant closer monitoring for diabetes, hypertension, and hyperlipidemia and vice versa

Real-time myocardium segmentation for the assessment of cardiac function variation

Recent developments in MRI enable the acquisition of image sequences with high spatio-temporal resolution. Cardiac motion can be captured without gating and triggering. Image size and contrast relations differ from conventional cardiac MRI cine sequences requiring new adapted analysis methods. We suggest a novel segmentation approach utilizing contrast invariant polar scanning techniques. It has been tested with 20 datasets of arrhythmia patients. The results do not differ significantly more between automatic and manual segmentations than between observers. This indicates that the presented solution could enable clinical applications of real-time MRI for the examination of arrhythmic cardiac motion in the future

Accuracy of registration techniques and vascular imaging modalities in fusion imaging for aortic endovascular interventions: a phantom study

Abstract Background This study aimed to assess the error of different registration techniques and imaging modalities for fusion imaging of the aorta in a standardized setting using a anthropomorphic body phantom. Materials and methods A phantom with the 3D printed vasculature of a patient suffering from an infrarenal aortic aneurysm was constructed. Pulsatile flow was generated via an external pump. CTA/MRA of the phantom was performed, and a virtual 3D vascular model was computed. Subsequently, fusion imaging was performed employing 3D-3D and 2D-3D registration techniques. Accuracy of the registration was evaluated from 7 right/left anterior oblique c-arm angulations using the agreement of centerlines and landmarks between the phantom vessels and the virtual 3D virtual vascular model. Differences between imaging modalities were assessed in a head-to-head comparison based on centerline deviation. Statistics included the comparison of means ± standard deviations, student’s t-test, Bland-Altman analysis, and intraclass correlation coefficient for intra- and inter-reader analysis. Results 3D-3D registration was superior to 2D-3D registration, with the highest mean centerline deviation being 1.67 ± 0.24 mm compared to 4.47 ± 0.92 mm. The highest absolute deviation was 3.25 mm for 3D-3D and 6.25 mm for 2D-3D registration. Differences for all angulations between registration techniques reached statistical significance. A decrease in registration accuracy was observed for c-arm angulations beyond 30° right anterior oblique/left anterior oblique. All landmarks (100%) were correctly positioned using 3D-3D registration compared to 81% using 2D-3D registration. Differences in accuracy between CT and MRI were acceptably small. Intra- and inter-reader reliability was excellent. Conclusion In the realm of registration techniques, the 3D-3D method proved more accurate than did the 2D-3D method. Based on our data, the use of 2D-3D registration for interventions with high registration quality requirements (e.g., fenestrated aortic repair procedures) cannot be fully recommended. Regarding imaging modalities, CTA and MRA can be used equivalently

Rapid study assessment in follow-up whole-body computed tomography in patients with multiple myeloma using a dedicated bone subtraction software

Objectives: The diagnostic reading of follow-up low-dose whole-body computed tomography (WBCT) examinations in patients with multiple myeloma (MM) is a demanding process. This study aimed to evaluate the diagnostic accuracy and benefit of a novel software program providing rapid-subtraction maps for bone lesion change detection. Methods: Sixty patients (66 years ± 10 years) receiving 120 WBCT examinations for follow-up evaluation of MM bone disease were identified from our imaging archive. The median follow-up time was 292 days (range 200–641 days). Subtraction maps were calculated from 2-mm CT images using a nonlinear deformation algorithm. Reading time, correctly assessed lesions, and disease classification were compared to a standard reading software program. De novo clinical reading by a senior radiologist served as the reference standard. Statistics included Wilcoxon rank-sum test, Cohen’s kappa coefficient, and calculation of sensitivity, specificity, positive/negative predictive value, and accuracy. Results: Calculation time for subtraction maps was 84 s ± 24 s. Both readers reported exams faster using subtraction maps (reader A, 438 s ± 133 s; reader B, 1049 s ± 438 s) compared to PACS software (reader A, 534 s ± 156 s; reader B, 1486 s ± 587 s; p < 0.01). The course of disease was correctly classified by both methods in all patients. Sensitivity for lesion detection in subtraction maps/conventional reading was 92%/80% for reader A and 88%/76% for reader B. Specificity was 98%/100% for reader A and 95%/96% for reader B. Conclusion: A software program for the rapid-subtraction map calculation of follow-up WBCT scans has been successfully tested and seems suited for application in clinical routine. Subtraction maps significantly facilitated reading of WBCTs by reducing reading time and increasing sensitivity. Key Points: A novel algorithm has been successfully applied to generate motion-corrected bone subtraction maps of whole-body low-dose CT scans in less than 2 min. Motion-corrected bone subtraction maps significantly facilitate the reading of follow-up whole-body low-dose CT scans in multiple myeloma by reducing reading time and increasing sensitivity