Inflammatory risk and cardiovascular events in patients without obstructive coronary artery disease: the ORFAN multicentre, longitudinal cohort study.

BACKGROUND: Coronary computed tomography angiography (CCTA) is the first line investigation for chest pain, and it is used to guide revascularisation. However, the widespread adoption of CCTA has revealed a large group of individuals without obstructive coronary artery disease (CAD), with unclear prognosis and management. Measurement of coronary inflammation from CCTA using the perivascular fat attenuation index (FAI) Score could enable cardiovascular risk prediction and guide the management of individuals without obstructive CAD. The Oxford Risk Factors And Non-invasive imaging (ORFAN) study aimed to evaluate the risk profile and event rates among patients undergoing CCTA as part of routine clinical care in the UK National Health Service (NHS); to test the hypothesis that coronary arterial inflammation drives cardiac mortality or major adverse cardiac events (MACE) in patients with or without CAD; and to externally validate the performance of the previously trained artificial intelligence (AI)-Risk prognostic algorithm and the related AI-Risk classification system in a UK population. METHODS: This multicentre, longitudinal cohort study included 40 091 consecutive patients undergoing clinically indicated CCTA in eight UK hospitals, who were followed up for MACE (ie, myocardial infarction, new onset heart failure, or cardiac death) for a median of 2·7 years (IQR 1·4-5·3). The prognostic value of FAI Score in the presence and absence of obstructive CAD was evaluated in 3393 consecutive patients from the two hospitals with the longest follow-up (7·7 years [6·4-9·1]). An AI-enhanced cardiac risk prediction algorithm, which integrates FAI Score, coronary plaque metrics, and clinical risk factors, was then evaluated in this population. FINDINGS: In the 2·7 year median follow-up period, patients without obstructive CAD (32 533 [81·1%] of 40 091) accounted for 2857 (66·3%) of the 4307 total MACE and 1118 (63·7%) of the 1754 total cardiac deaths in the whole of Cohort A. Increased FAI Score in all the three coronary arteries had an additive impact on the risk for cardiac mortality (hazard ratio [HR] 29·8 [95% CI 13·9-63·9], p<0·001) or MACE (12·6 [8·5-18·6], p<0·001) comparing three vessels with an FAI Score in the top versus bottom quartile for each artery. FAI Score in any coronary artery predicted cardiac mortality and MACE independently from cardiovascular risk factors and the presence or extent of CAD. The AI-Risk classification was positively associated with cardiac mortality (6·75 [5·17-8·82], p<0·001, for very high risk vs low or medium risk) and MACE (4·68 [3·93-5·57], p<0·001 for very high risk vs low or medium risk). Finally, the AI-Risk model was well calibrated against true events. INTERPRETATION: The FAI Score captures inflammatory risk beyond the current clinical risk stratification and CCTA interpretation, particularly among patients without obstructive CAD. The AI-Risk integrates this information in a prognostic algorithm, which could be used as an alternative to traditional risk factor-based risk calculators. FUNDING: British Heart Foundation, NHS-AI award, Innovate UK, National Institute for Health and Care Research, and the Oxford Biomedical Research Centre.

Capmatinib is an effective treatment for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy.

BACKGROUND: Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGG and are associated with devastating morbidity and mortality. METHODS: To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion IHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy. RESULTS: Capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib in both models. The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy in two complementary mouse models. Capmatinib treatment increased radiation-induced DNA double-strand breaks and delayed their repair. CONCLUSIONS: We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials.

The FES Gene at the 15q26 Coronary-Artery-Disease Locus Inhibits Atherosclerosis.

BACKGROUND: Genome-wide association studies have discovered a link between genetic variants on human chromosome 15q26.1 and increased coronary artery disease (CAD) susceptibility; however, the underlying pathobiological mechanism is unclear. This genetic locus contains the FES (FES proto-oncogene, tyrosine kinase) gene encoding a cytoplasmic protein-tyrosine kinase involved in the regulation of cell behavior. We investigated the effect of the 15q26.1 variants on FES expression and whether FES plays a role in atherosclerosis. METHODS AND RESULTS: Analyses of isogenic monocytic cell lines generated by CRISPR (clustered regularly interspaced short palindromic repeats)-mediated genome editing showed that monocytes with an engineered 15q26.1 CAD risk genotype had reduced FES expression. Small-interfering-RNA-mediated knockdown of FES promoted migration of monocytes and vascular smooth muscle cells. A phosphoproteomics analysis showed that FES knockdown altered phosphorylation of a number of proteins known to regulate cell migration. Single-cell RNA-sequencing revealed that in human atherosclerotic plaques, cells that expressed FES were predominately monocytes/macrophages, although several other cell types including smooth muscle cells also expressed FES. There was an association between the 15q26.1 CAD risk genotype and greater numbers of monocytes/macrophage in human atherosclerotic plaques. An animal model study demonstrated that Fes knockout increased atherosclerotic plaque size and within-plaque content of monocytes/macrophages and smooth muscle cells, in apolipoprotein E-deficient mice fed a high fat diet. CONCLUSIONS: We provide substantial evidence that the CAD risk variants at the 15q26.1 locus reduce FES expression in monocytes and that FES depletion results in larger atherosclerotic plaques with more monocytes/macrophages and smooth muscle cells. This study is the first demonstration that FES plays a protective role against atherosclerosis and suggests that enhancing FES activity could be a potentially novel therapeutic approach for CAD intervention.

Genomic regions controlling yield-related traits in spring wheat: a mini review and a case study for rainfed environments in Australia and China.

A genome-wide association study (GWAS) was performed in six environments to identify major or consistent alleles responsible for wheat yield traits in Australia and North China where rainfed farming system is adopted. A panel of 228 spring wheat varieties were genotyped by double digest restriction-site associated DNA genotyping-by-sequencing. A total of 223 significant marker-trait association (MTAs) and 46 candidate genes for large- or consistent-effect MTAs were identified. The results were compared with previous studies based on a mini-review of 23 GWAS analyses on wheat yield. A phenomenon seldom reported in previous studies was that MTAs responsible for the trait tended to cluster together at certain chromosome segments, and many candidate genes were in the form of gene clusters. Although linkage disequilibrium (LD) might contribute to the co-segregation of the regions, it also suggested that marker-assisted selection (MAS) or transgenic method targeting a single gene might not be as effective as MAS targeting a larger genomic region where all the genes or gene clusters underlying play important roles.

MoDALAS: addressing assurance for learning-enabled autonomous systems in the face of uncertainty.

Increasingly, safety-critical systems include artificial intelligence and machine learning components (i.e., learning-enabled components (LECs)). However, when behavior is learned in a training environment that fails to fully capture real-world phenomena, the response of an LEC to untrained phenomena is uncertain and therefore cannot be assured as safe. Automated methods are needed for self-assessment and adaptation to decide when learned behavior can be trusted. This work introduces a model-driven approach to manage self-adaptation of a learning-enabled system (LES) to account for run-time contexts for which the learned behavior of LECs cannot be trusted. The resulting framework enables an LES to monitor and evaluate goal models at run time to determine whether or not LECs can be expected to meet functional objectives and enables system adaptation accordingly. Using this framework enables stakeholders to have more confidence that LECs are used only in contexts comparable to those validated at design time.

Right ventricular function declines prior to left ventricular ejection fraction in hypertrophic cardiomyopathy.

BACKGROUND: The right ventricle (RV) in hypertrophic cardiomyopathy (HCM) tends to be neglected, as previous efforts have predominantly focused on examining the prognostic value of left ventricular (LV) abnormalities. The objectives of this study were to assess RV function in HCM, changes over time, and association with clinical outcomes. METHODS: Two hundred and ninety HCM patients with preserved LV ejection fraction (LVEF ≥ 55%) and 30 age- and sex-matched controls underwent cardiovascular magnetic resonance (CMR). All patients were followed up for clinical events for a median duration of 4.4 years. Sixty-three patients had a follow-up CMR undertaken at a median interval of 5.4 years. Main study measures and outcomes were RV function (RV ejection fraction (RVEF) and RV strain) at baseline, temporal changes in RV function over time and prognostic value of RV dysfunction for predicting cardiovascular outcomes in HCM. RESULTS: When compared to controls, HCM patients exhibited lower RV and LV peak global longitudinal systolic strains on feature-tracking analysis of cine images, while RVEF and LVEF were within the normal range. On follow-up CMR, both RV and LV strain parameters decreased over time. RVEF decreased at follow-up (65 ± 7% to 62 ± 7%, P < 0.001) but the change in LVEF was not significant (68 ± 10% to 66 ± 8%, P = 0.30). On clinical follow up, reduced RVEF was an independent predictor of non-sustained ventricular tachycardia (NSVT) [HR 1.10 (95% CI 1.06-1.15), P < 0.001] and composite cardiovascular events (NSVT, stroke, heart failure hospitalisation and cardiovascular death) [HR 1.07 (95% CI 1.03-1.10), P < 0.001]. RV longitudinal strain was an independent predictor of NSVT [HR 1.05 (95% CI 1.01-1.09), P = 0.029]. Patients with RVEF < 55% showed an increased risk of NSVT and composite cardiovascular events. In contrast, LVEF and LV global longitudinal strain were not predictive of such events on multivariable analysis. CONCLUSIONS: In HCM, RV function, including RV strain, and LV strain decrease over time despite preserved LVEF. Reduction in RV but not LV function is associated with adverse cardiovascular outcomes. Assessing RV function in early HCM disease might have a role in risk stratification to prevent future cardiovascular events.

Application of a Proposed Algorithm to Cesarean Deliveries for Nonreassuring Fetal Heart Rate Tracing.

OBJECTIVES: The aim of the study is to evaluate how current management of Category II fetal heart rate tracings compares with that suggested by a published algorithm and whether these differences lead to disparate neonatal outcomes. STUDY DESIGN: This is a retrospective observational study from the resident service at an academic-community tertiary care center from 2013 to 2018. We reviewed archived fetal heart rate tracings from patients with cesarean delivery performed for nonreassuring fetal heart rate tracing and interpreted tracings against the algorithm. We assigned tracings to one of three categories: Group A-consistent; Group B-inconsistent too early (algorithm permits the patient to labor longer); Group C-inconsistent too late (algorithm suggests performing the cesarean delivery sooner). Maternal demographics, features of labor, and neonatal outcomes were compared. RESULTS: Of the 110 cases, 27 (24.5%) had a cesarean delivery performed in group A, 49 (44.5%) in group B, and 34 (30.9%) in group C. Baseline characteristics were similar. Of the 49 in group B, 46 (93.9%) violated the algorithm at the same branchpoint. In group C, cesarean deliveries would have been performed on average 244 minutes earlier had the algorithm been used. Neonatal outcomes were not significantly different among the groups, including 5-minute Apgar <7, pH <7.1, and NICU admit. CONCLUSION: Our retrospective application of the algorithm showed that 44.5% of patients who have cesarean delivery for nonreassuring fetal heart rate tracing may be able to labor longer and that violation at a common decision point on the algorithm (moderate variability or accelerations, but a lack of recurrent decelerations) is responsible for nearly all such cesarean deliveries. More studies are needed to evaluate if cesarean delivery rates for nonreassuring fetal heart rate tracing can be reduced without impacting neonatal outcomes using the algorithm. KEY POINTS: · There is a potential to further standardize management of Category II fetal heart rate tracings.. · In our practice, 25% of cesareans performed for fetal distress were consistent with the algorithm.. · A subset of patients (45%) with cesarean for fetal distress may have been able to labor longer..

Incremental value of left atrial booster and reservoir strain in predicting atrial fibrillation in patients with hypertrophic cardiomyopathy: a cardiovascular magnetic resonance study.

BACKGROUND: Left atrial (LA) size and function are known predictors of new onset atrial fibrillation (AF) in hypertrophic cardiomyopathy (HCM) patients. Components of LA deformation including reservoir, conduit, and booster function provide additional information on atrial mechanics. Whether or not LA deformation can augment our ability to predict the risk of new onset AF in HCM patients beyond standard measurements is unknown. METHODS: We assessed LA size, function, and deformation on cardiovascular magnetic resonance (CMR) in 238 genotyped HCM patients and compared this with twenty age, sex, blood pressure and body mass index matched control subjects. We further evaluated the determinants of new onset AF in HCM patients. RESULTS: Compared to control subjects, HCM patients had higher LA antero-posterior diameter, lower LA ejection fraction and lower LA reservoir (19.9 [17.1, 22.2], 21.6 [19.9, 22.9], P = 0.047) and conduit strain (10.6 ± 4.4, 13.7 ± 3.3, P = 0.002). LA booster strain did not differ between healthy controls and HCM patients, but HCM patients who developed new onset AF (n = 33) had lower booster strain (7.6 ± 3.3, 9.5 ± 3.0, P = 0.001) than those that did not (n = 205). In separate multivariate models, age, LA ejection fraction, and LA booster and reservoir strain were each independent determinants of AF. Age ≥ 55 years was the strongest determinant (HR 6.62, 95% CI 2.79-15.70), followed by LA booster strain ≤ 8% (HR 3.69, 95% CI 1.81-7.52) and LA reservoir strain ≤ 18% (HR 2.56, 95% CI 1.24-5.27). Conventional markers of HCM phenotypic severity, age and sudden death risk factors were associated with LA strain components. CONCLUSIONS: LA strain components are impaired in HCM and, together with age, independently predicted the risk of new onset AF. Increasing age and phenotypic severity were associated with LA strain abnormalities. Our findings suggest that the routine assessment of LA strain components and consideration of age could augment LA size in predicting risk of AF, and potentially guide prophylactic anticoagulation use in HCM.

Comparison between velocity-specific exercise and isometric exercise on neck muscle functions and performance: a randomised clinical trial.

BACKGROUND: Evidence has shown that velocity-specific exercise results in additional benefits for peripheral joint muscles by promoting their functions, however, its effects on spinal muscles are yet to be investigated. This study aimed to examine the feasibility and effects of velocity-specific exercise compared to isometric exercise on cervical muscle functions and performance in healthy individuals. METHODS: Thirty healthy adults were randomised to practise either the velocity-specific exercise (VSE, n = 15) or isometric exercise (IE, n = 15) for 6 weeks. Functions and performance of the cervical extensors and flexors were assessed pre- and post-program, by analyzing the peak torque and electromyography during the isokinetic testing, and cross-sectional area of the deep cervical muscles at rest. The self-reported level of difficulty and post-exercise soreness during the exercise were recorded to evaluate the feasibility and safety of the two exercise programs. RESULTS: Both VSE and IE exercises resulted in significant improvement of the muscle functions and performance while there were no between-group differences at reassessment of the (a) cross-sectional area of longus colli and semispinalis capitis; (b) EMG amplitude in sternocleidomastoid and cervical erector spinae, and (c) peak torque values. Further analysis revealed that degree of correlation between extension torque and EMG amplitude of cervical erector spinae increased in both groups. However, significant correlation was found only in VSE group post-program. There were no significant differences for the level of difficulty and post-exercise soreness found between two groups. CONCLUSIONS: Both velocity-specific and isometric exercises significantly promoted cervical muscle functions and performance. The present study confirms that velocity-specific exercise can be practised safely and it also contributes to a greater enhancement in neuromuscular efficiency of the cervical extensors. These findings indicate that the velocity-specific exercise can be considered as a safe alternative for training of the cervical muscles. Further study is recommended to examine its benefit and application for promoting the muscle functions and recovery in symptomatic individuals.

Clinical utility of serial analysis of circulating tumour cells for detection of minimal residual disease of metastatic nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is an important cancer in Hong Kong. We aim to utilise liquid biopsies for serial monitoring of disseminated NPC in patients to compare with PET-CT imaging in detection of minimal residual disease. METHOD: Prospective serial monitoring of liquid biopsies was performed for 21 metastatic patients. Circulating tumour cell (CTC) enrichment and characterisation was performed using a sized-based microfluidics CTC chip, enumerating by immunofluorescence staining, and using target-capture sequencing to determine blood mutation load. PET-CT scans were used to monitor NPC patients throughout their treatment according to EORTC guidelines. RESULTS: The longitudinal molecular analysis of CTCs by enumeration or NGS mutational profiling findings provide supplementary information to the plasma EBV assay for disease progression for good responders. Strikingly, post-treatment CTC findings detected positive findings in 75% (6/8) of metastatic NPC patients showing complete response by imaging, thereby demonstrating more sensitive CTC detection of minimal residual disease. Positive baseline, post-treatment CTC, and longitudinal change of CTCs significantly associated with poorer progression-free survival by the Kaplan-Meier analysis. CONCLUSIONS: We show the potential usefulness of application of serial analysis in metastatic NPC of liquid biopsy CTCs, as a novel more sensitive biomarker for minimal residual disease, when compared with imaging.

Chest ultrasonography versus supine chest radiography for diagnosis of pneumothorax in trauma patients in the emergency department.

BACKGROUND: Chest X-ray (CXR) is a longstanding method for the diagnosis of pneumothorax but chest ultrasonography (CUS) may be a safer, more rapid, and more accurate modality in trauma patients at the bedside that does not expose the patient to ionizing radiation. This may lead to improved and expedited management of traumatic pneumothorax and improved patient safety and clinical outcomes. OBJECTIVES: To compare the diagnostic accuracy of chest ultrasonography (CUS) by frontline non-radiologist physicians versus chest X-ray (CXR) for diagnosis of pneumothorax in trauma patients in the emergency department (ED). To investigate the effects of potential sources of heterogeneity such as type of CUS operator (frontline non-radiologist physicians), type of trauma (blunt vs penetrating), and type of US probe on test accuracy. SEARCH METHODS: We conducted a comprehensive search of the following electronic databases from database inception to 10 April 2020: Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus, Database of Abstracts of Reviews of Effects, Web of Science Core Collection and Clinicaltrials.gov. We handsearched reference lists of included articles and reviews retrieved via electronic searching; and we carried out forward citation searching of relevant articles in Google Scholar and looked at the "Related articles" on PubMed. SELECTION CRITERIA: We included prospective, paired comparative accuracy studies comparing CUS performed by frontline non-radiologist physicians to supine CXR in trauma patients in the emergency department (ED) suspected of having pneumothorax, and with computed tomography (CT) of the chest or tube thoracostomy as the reference standard. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from each included study using a data extraction form. We included studies using patients as the unit of analysis in the main analysis and we included those using lung fields in the secondary analysis. We performed meta-analyses by using a bivariate model to estimate and compare summary sensitivities and specificities. MAIN RESULTS: We included 13 studies of which nine (410 traumatic pneumothorax patients out of 1271 patients) used patients as the unit of analysis; we thus included them in the primary analysis. The remaining four studies used lung field as the unit of analysis and we included them in the secondary analysis. We judged all studies to be at high or unclear risk of bias in one or more domains, with most studies (11/13, 85%) being judged at high or unclear risk of bias in the patient selection domain. There was substantial heterogeneity in the sensitivity of supine CXR amongst the included studies. In the primary analysis, the summary sensitivity and specificity of CUS were 0.91 (95% confidence interval (CI) 0.85 to 0.94) and 0.99 (95% CI 0.97 to 1.00); and the summary sensitivity and specificity of supine CXR were 0.47 (95% CI 0.31 to 0.63) and 1.00 (95% CI 0.97 to 1.00). There was a significant difference in the sensitivity of CUS compared to CXR with an absolute difference in sensitivity of 0.44 (95% CI 0.27 to 0.61; P < 0.001). In contrast, CUS and CXR had similar specificities: comparing CUS to CXR, the absolute difference in specificity was -0.007 (95% CI -0.018 to 0.005, P = 0.35). The findings imply that in a hypothetical cohort of 100 patients if 30 patients have traumatic pneumothorax (i.e. prevalence of 30%), CUS would miss 3 (95% CI 2 to 4) cases (false negatives) and overdiagnose 1 (95% CI 0 to 2) of those without pneumothorax (false positives); while CXR would miss 16 (95% CI 11 to 21) cases with 0 (95% CI 0 to 2) overdiagnosis of those who do not have pneumothorax. AUTHORS' CONCLUSIONS: The diagnostic accuracy of CUS performed by frontline non-radiologist physicians for the diagnosis of pneumothorax in ED trauma patients is superior to supine CXR, independent of the type of trauma, type of CUS operator, or type of CUS probe used. These findings suggest that CUS for the diagnosis of traumatic pneumothorax should be incorporated into trauma protocols and algorithms in future medical training programmes; and that CUS may beneficially change routine management of trauma.

Image-Guided Ablation of Dental Calculus From Root Surfaces Using a DPSS Er:YAG Laser.

BACKGROUND AND OBJECTIVES: Recent studies have demonstrated that near-infrared (IR) imaging can be used to acquire high-contrast images of root caries and calculus on the root surfaces of extracted teeth at wavelengths longer than 1450 nm. The purpose of this study was to determine if image-guided laser ablation can be used to selectively remove calculus from tooth surfaces with minimal damage to the underlying sound cementum and dentin. MATERIALS AND METHODS: In this study, sequential near-IR images at 1500-1700 nm were used to guide a diode-pumped (DPSS) Er:YAG laser for the removal of calculus from the root surfaces of 10 extracted teeth. The selectivity of removal was assessed using digital microscopy, optical coherence tomography, and surface profilometry. RESULTS: Calculus was removed rapidly with minimal damage to the underlying sound cementum and dentin. Image-guided ablation achieved high-selectivity, the mean volume of calculus removal was more than 27 times higher than the mean loss of cementum. CONCLUSIONS: We have demonstrated that near-IR image-guided laser ablation can be used for the selective removal of calculus from root surfaces ex vivo. Additionally, we have demonstrated that a diode-pumped solid-state Er:YAG laser is well suited for selective removal. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Selective ablation of dental caries using coaxial Co2 (9.3-µm) and near-IR (1880-nm) lasers.

OBJECTIVE: The purpose of this study was to determine the feasibility of image-guided laser ablation of demineralization from tooth occlusal surfaces using coaxial near-infrared (NIR) and CO2 lasers. MATERIALS AND METHODS: A CO2 laser operating at a wavelength of 9.3-µm was combined with a thulium-doped fiber laser operating at 1880-nm for the selective removal of simulated occlusal caries lesions from 10 tooth samples. Serial NIR reflectance images at 1880-nm were used to guide the CO2 laser for image-guided laser ablation. Polarization-sensitive optical coherence tomography (PS-OCT) was used to assess the initial depth of the lesions before removal and assess the volume of sound and demineralized tissue removed by the CO2 laser. RESULTS: PS-OCT scans indicated that roughly ∼99% of the lesion was removed by image-guided laser ablation. A mean volume of 0.191-mm3 or 11.9-µm/voxel of excess enamel was removed during lesion removal. CONCLUSION: A co-aligned NIR/CO2 laser scanning system has great potential for the highly selective removal of dental decay (demineralization). Lasers Surg. Med. 51:176-184, 2019. © 2018 Wiley Periodicals, Inc.

Coronary-Heart-Disease-Associated Genetic Variant at the COL4A1/COL4A2 Locus Affects COL4A1/COL4A2 Expression, Vascular Cell Survival, Atherosclerotic Plaque Stability and Risk of Myocardial Infarction.

Genome-wide association studies have revealed an association between coronary heart disease (CHD) and genetic variation on chromosome 13q34, with the lead single nucleotide polymorphism rs4773144 residing in the COL4A2 gene in this genomic region. We investigated the functional effects of this genetic variant. Analyses of primary cultures of vascular smooth muscle cells (SMCs) and endothelial cells (ECs) from different individuals showed a difference between rs4773144 genotypes in COL4A2 and COL4A1 expression levels, being lowest in the G/G genotype, intermediate in A/G and highest in A/A. Chromatin immunoprecipitation followed by allelic imbalance assays of primary cultures of SMCs and ECs that were of the A/G genotype revealed that the G allele had lower transcriptional activity than the A allele. Electrophoretic mobility shift assays and luciferase reporter gene assays showed that a short DNA sequence encompassing the rs4773144 site interacted with a nuclear protein, with lower efficiency for the G allele, and that the G allele sequence had lower activity in driving reporter gene expression. Analyses of cultured SMCs from different individuals demonstrated that cells of the G/G genotype had higher apoptosis rates. Immunohistochemical and histological examinations of ex vivo atherosclerotic coronary arteries from different individuals disclosed that atherosclerotic plaques with the G/G genotype had lower collagen IV abundance and thinner fibrous cap, a hallmark of unstable, rupture-prone plaques. A study of a cohort of patients with angiographically documented coronary artery disease showed that patients of the G/G genotype had higher rates of myocardial infarction, a phenotype often caused by plaque rupture. These results indicate that the CHD-related genetic variant at the COL4A2 locus affects COL4A2/COL4A1 expression, SMC survival, and atherosclerotic plaque stability, providing a mechanistic explanation for the association between the genetic variant and CHD risk.

Aspiration Thrombectomy versus Conventional Catheter-Directed Thrombolysis as First-Line Treatment for Noniatrogenic Acute Lower Limb Ischemia.

PURPOSE: To examine the efficacy, safety, and procedural costs of percutaneous aspiration thrombectomy (PAT) as a first-line treatment for noniatrogenic acute lower limb ischemia (ALI) compared with conventional catheter-directed thrombolysis (CDT). MATERIALS AND METHODS: All patients who underwent endovascular intervention for ALI from January 2015 to August 2017 were included. Fifteen patients were treated with the use of primary PAT and 27 patients were treated with the use of primary CDT. The primary end point was complete thrombus clearance with improvement in Thrombolysis in Myocardial Infarction (TIMI) score. Adjunctive treatment for thrombus removal was considered to indicate technical failure. Treatment of underlying chronic disease was not considered to indicate technical failure. Procedural costs for each patient were calculated by itemizing all disposable equipment, facility overheads, and staff costs. RESULTS: Of the 15 primary PAT patients, technical success was achieved in 8 (53%); the remaining 7 (47%) required adjunctive CDT. Of the 27 primary CDT patients, technical success was achieved in 25 (89%); the remaining 2 (11%) required adjunctive PAT. There were 4 complications in the primary PAT group: 2 were procedure related and of a minor grade. There were 8 complications in the primary CDT group: All were procedure-related, including 2 major groin/retroperitoneal hemorrhage and 1 death from intracranial hemorrhage. Limb salvage was attained in all patients. There were no significant differences in average procedural costs per patient between the 2 groups. CONCLUSIONS: First-line use of PAT for endovascular treatment of ALI can reduce the need for CDT, with no significant cost difference.

Grossly Abnormal Ventilation/Perfusion SPECT Study in Idiopathic Pulmonary Arterial Hypertension Without Thromboembolism.

Pulmonary hypertension is a serious condition with multiple underlying aetiologies which require different treatment strategies. We present a case of severe idiopathic pulmonary arterial hypertension in a 20-year-old patient with ongoing breathlessness. She was initially diagnosed with asthma and panic attacks in community care. As the symptoms became progressively worse, she was referred for pulmonary hypertension clinic assessment. Ventilation/perfusion single-photon emission computed tomography (V/Q SPECT) showed grossly abnormal perfusion defects which were mismatched to the ventilation scan, suggestive of chronic thromboembolic disease. However, corroborating computed tomographic (CT) pulmonary angiogram and invasive pulmonary angiography showed no thromboembolic disease. Histological examination of the pulmonary arteries post-mortem showed changes consistent with idiopathic pulmonary arterial hypertension. This case highlighted the clinical challenges in interpreting the investigation results and phenotyping pulmonary hypertension. V/Q SPECT might have a role in visualising the extent of vasculopathies in pulmonary arterial hypertension.

Automated ablation of dental composite using an IR pulsed laser coupled to a plume emission spectral feedback system.

OBJECTIVE: The purpose of this study is to assemble a laser system for the selective removal of dental composite from tooth surfaces, that is feasible for clinical use incorporating a spectral feedback system, a scanning system, articulating arm and a clinical hand-piece, and evaluate the performance of that system on extracted teeth. METHODS: Ten extracted teeth were collected and small fillings were placed on the occlusal surface of each tooth. A clinical system featuring a CO2 laser operating at 50 Hz and spectral optical feedback was used to remove the composite. Removal was confirmed using a cross polarized optical coherence tomography (CP-OCT) system designed for clinical use. RESULTS: The system was capable of rapidly removing composite from small preparations on tooth occlusal surfaces with a mean loss of enamel of less than 20 µm. CONCLUSION: We have demonstrated that spectral feedback can be successfully employed in an automated system for composite removal by incorporating dual photodiodes and a galvanometer controlled CO2 laser. Additionally, the use of registered OCT images presents as a viable method for volumetric benchmarking. Overall, this study represents the first implementation of spectral feedback into a clinical hand-piece and serves as a benchmark for a future clinical study. Lasers Surg. Med. 49:658-665, 2017. © 2017 Wiley Periodicals, Inc.

Near-IR and CP-OCT imaging of suspected occlusal caries lesions.

INTRODUCTION: Radiographic methods have poor sensitivity for occlusal lesions and by the time the lesions are radiolucent they have typically progressed deep into the dentin. New more sensitive imaging methods are needed to detect occlusal lesions. In this study, cross-polarization optical coherence tomography (CP-OCT) and near-IR imaging were used to image questionable occlusal lesions (QOC's) that were not visible on radiographs but had been scheduled for restoration on 30 test subjects. METHODS: Near-IR reflectance and transillumination probes incorporating a high definition InGaAs camera and near-IR broadband light sources were used to acquire images of the lesions before restoration. The reflectance probe utilized cross-polarization and operated at wavelengths from 1,500 to 1,700 nm where there is an increase in water absorption for higher contrast. The transillumination probe was operated at 1,300 nm where the transparency of enamel is highest. Tomographic images (6 × 6 × 7 mm3 ) of the lesions were acquired using a high-speed swept-source CP-OCT system operating at 1,300 nm before and after removal of the suspected lesion. RESULTS: Near-IR reflectance imaging at 1,500-1,700 nm yielded significantly higher contrast (P < 0.05) of the demineralization in the occlusal grooves compared with visible reflectance imaging. Stains in the occlusal grooves greatly reduced the lesion contrast in the visible range yielding negative values. Only half of the 26 lesions analyzed showed the characteristic surface demineralization and increased reflectivity below the dentinal-enamel junction (DEJ) in 3D OCT images indicative of penetration of the lesion into the dentin. CONCLUSION: This study demonstrates that near-IR imaging methods have great potential for improving the early diagnosis of occlusal lesions. Lasers Surg. Med. 49:215-224, 2017. © 2017 Wiley Periodicals, Inc.