Mucopolysaccharidosis IVA: Diagnosis, Treatment, and Management.

Mucopolysaccharidosis type IVA (MPS IVA, or Morquio syndrome type A) is an inherited metabolic lysosomal disease caused by the deficiency of the N-acetylglucosamine-6-sulfate sulfatase enzyme. The deficiency of this enzyme accumulates the specific glycosaminoglycans (GAG), keratan sulfate, and chondroitin-6-sulfate mainly in bone, cartilage, and its extracellular matrix. GAG accumulation in these lesions leads to unique skeletal dysplasia in MPS IVA patients. Clinical, radiographic, and biochemical tests are needed to complete the diagnosis of MPS IVA since some clinical characteristics in MPS IVA are overlapped with other disorders. Early and accurate diagnosis is vital to optimizing patient management, which provides a better quality of life and prolonged life-time in MPS IVA patients. Currently, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) are available for patients with MPS IVA. However, ERT and HSCT do not have enough impact on bone and cartilage lesions in patients with MPS IVA. Penetrating the deficient enzyme into an avascular lesion remains an unmet challenge, and several innovative therapies are under development in a preclinical study. In this review article, we comprehensively describe the current diagnosis, treatment, and management for MPS IVA. We also illustrate developing future therapies focused on the improvement of skeletal dysplasia in MPS IVA

Comparison of T1 mapping techniques for ECV quantification. histological validation and reproducibility of ShMOLLI versus multibreath-hold T1 quantification equilibrium contrast CMR

BACKGROUND: Myocardial extracellular volume (ECV) is elevated in fibrosis or infiltration and can be quantified by measuring the haematocrit with pre and post contrast T1 at sufficient contrast equilibrium. Equilibrium CMR (EQ-CMR), using a bolus-infusion protocol, has been shown to provide robust measurements of ECV using a multibreath-hold T1 pulse sequence. Newer, faster sequences for T1 mapping promise whole heart coverage and improved clinical utility, but have not been validated. METHODS: Multibreathhold T1 quantification with heart rate correction and single breath-hold T1 mapping using Shortened Modified Look-Locker Inversion recovery (ShMOLLI) were used in equilibrium contrast CMR to generate ECV values and compared in 3 ways.Firstly, both techniques were compared in a spectrum of disease with variable ECV expansion (n=100, 50 healthy volunteers, 12 patients with hypertrophic cardiomyopathy, 18 with severe aortic stenosis, 20 with amyloid). Secondly, both techniques were correlated to human histological collagen volume fraction (CVF%, n=18, severe aortic stenosis biopsies). Thirdly, an assessment of test:retest reproducibility of the 2 CMR techniques was performed 1 week apart in individuals with widely different ECVs (n=10 healthy volunteers, n=7 amyloid patients). RESULTS: More patients were able to perform ShMOLLI than the multibreath-hold technique (6% unable to breath-hold). ECV calculated by multibreath-hold T1 and ShMOLLI showed strong correlation (r(2)=0.892), little bias (bias -2.2%, 95%CI -8.9% to 4.6%) and good agreement (ICC 0.922, range 0.802 to 0.961, p<0.0001). ECV correlated with histological CVF% by multibreath-hold ECV (r(2)= 0.589) but better by ShMOLLI ECV (r(2)= 0.685). Inter-study reproducibility demonstrated that ShMOLLI ECV trended towards greater reproducibility than the multibreath-hold ECV, although this did not reach statistical significance (95%CI -4.9% to 5.4% versus 95%CI -6.4% to 7.3% respectively, p=0.21). CONCLUSIONS: ECV quantification by single breath-hold ShMOLLI T1 mapping can measure ECV by EQ-CMR across the spectrum of interstitial expansion. It is procedurally better tolerated, slightly more reproducible and better correlates with histology compared to the older multibreath-hold FLASH techniques

Experimental study of a R290 variable geometry ejector

Ejectors are classified as fluid-dynamics controlled devices where the "component-scale"performances are imposed by the local-scale fluid dynamic phenomena. For this reason, ejector performances (measured by the pressure-entrainment ratio coordinate of the critical point) are determined by the connection of operation conditions, working fluid and geometrical parameters. Given such a connection, variable geometry ejector represents a promising solution to increase the flexibility of ejector-based systems. The present study aims to extend knowledge on variable geometry systems, evaluating the local and global performances of the R290 ejector equipped with a spindle. The prototype ejector was installed at the R290 vapour compression test rig adapted and modified for the required experimental campaign. The test campaign considered global parameter measurements, such as the pressure and the temperature at inlets and outlet ports together with the mass flow rates at both inlet nozzles, and the local pressure drop measurements inside the ejector. In addition, the experimental data were gathered for different spindle positions starting from fully open position the spindle position limited by the mass flow rate inside the test rig with the step of 1.0 mm

Fully Automated Myocardial Strain Estimation from Cardiovascular MRI–tagged Images Using a Deep Learning Framework in the UK Biobank

Purpose: To demonstrate the feasibility and performance of a fully automated deep learning framework to estimate myocardial strain from short-axis cardiac magnetic resonance tagged images. Methods and Materials: In this retrospective cross-sectional study, 4508 cases from the UK Biobank were split randomly into 3244 training and 812 validation cases, and 452 test cases. Ground truth myocardial landmarks were defined and tracked by manual initialization and correction of deformable image registration using previously validated software with five readers. The fully automatic framework consisted of 1) a convolutional neural network (CNN) for localization, and 2) a combination of a recurrent neural network (RNN) and a CNN to detect and track the myocardial landmarks through the image sequence for each slice. Radial and circumferential strain were then calculated from the motion of the landmarks and averaged on a slice basis. Results: Within the test set, myocardial end-systolic circumferential Green strain errors were -0.001 +/- 0.025, -0.001 +/- 0.021, and 0.004 +/- 0.035 in basal, mid, and apical slices respectively (mean +/- std. dev. of differences between predicted and manual strain). The framework reproduced significant reductions in circumferential strain in diabetics, hypertensives, and participants with previous heart attack. Typical processing time was ~260 frames (~13 slices) per second on an NVIDIA Tesla K40 with 12GB RAM, compared with 6-8 minutes per slice for the manual analysis. Conclusions: The fully automated RNNCNN framework for analysis of myocardial strain enabled unbiased strain evaluation in a high-throughput workflow, with similar ability to distinguish impairment due to diabetes, hypertension, and previous heart attack.Comment: accepted in Radiology Cardiothoracic Imagin

Characterizing the hypertensive cardiovascular phenotype in the UK Biobank

Aims: To describe hypertension-related cardiovascular magnetic resonance (CMR) phenotypes in the UK Biobank considering variations across patient populations. Methods and results: We studied 39 095 (51.5% women, mean age: 63.9 ± 7.7 years, 38.6% hypertensive) participants with CMR data available. Hypertension status was ascertained through health record linkage. Associations between hypertension and CMR metrics were estimated using multivariable linear regression adjusting for major vascular risk factors. Stratified analyses were performed by sex, ethnicity, time since hypertension diagnosis, and blood pressure (BP) control. Results are standardized beta coefficients, 95% confidence intervals, and P-values corrected for multiple testing. Hypertension was associated with concentric left ventricular (LV) hypertrophy (increased LV mass, wall thickness, concentricity index), poorer LV function (lower global function index, worse global longitudinal strain), larger left atrial (LA) volumes, lower LA ejection fraction, and lower aortic distensibility. Hypertension was linked to significantly lower myocardial native T1 and increased LV ejection fraction. Women had greater hypertension-related reduction in aortic compliance than men. The degree of hypertension-related LV hypertrophy was greatest in Black ethnicities. Increasing time since diagnosis of hypertension was linked to adverse remodelling. Hypertension-related remodelling was substantially attenuated in hypertensives with good BP control. Conclusion: Hypertension was associated with concentric LV hypertrophy, reduced LV function, dilated poorer functioning LA, and reduced aortic compliance. Whilst the overall pattern of remodelling was consistent across populations, women had greater hypertension-related reduction in aortic compliance and Black ethnicities showed the greatest LV mass increase. Importantly, adverse cardiovascular remodelling was markedly attenuated in hypertensives with good BP control

Adverse cardiovascular magnetic resonance phenotypes are associated with greater likelihood of incident coronavirus disease 2019: findings from the UK Biobank.

BACKGROUND: Coronavirus disease 2019 (COVID-19) disproportionately affects older people. Observational studies suggest indolent cardiovascular involvement after recovery from acute COVID-19. However, these findings may reflect pre-existing cardiac phenotypes. AIMS: We tested the association of baseline cardiovascular magnetic resonance (CMR) phenotypes with incident COVID-19. METHODS: We studied UK Biobank participants with CMR imaging and COVID-19 testing. We considered left and right ventricular (LV, RV) volumes, ejection fractions, and stroke volumes, LV mass, LV strain, native T1, aortic distensibility, and arterial stiffness index. COVID-19 test results were obtained from Public Health England. Co-morbidities were ascertained from self-report and hospital episode statistics (HES). Critical care admission and death were from HES and death register records. We investigated the association of each cardiovascular measure with COVID-19 test result in multivariable logistic regression models adjusting for age, sex, ethnicity, deprivation, body mass index, smoking, diabetes, hypertension, high cholesterol, and prior myocardial infarction. RESULTS: We studied 310 participants (n = 70 positive). Median age was 63.8 [57.5, 72.1] years; 51.0% (n = 158) were male. 78.7% (n = 244) were tested in hospital, 3.5% (n = 11) required critical care admission, and 6.1% (n = 19) died. In fully adjusted models, smaller LV/RV end-diastolic volumes, smaller LV stroke volume, and poorer global longitudinal strain were associated with significantly higher odds of COVID-19 positivity. DISCUSSION: We demonstrate association of pre-existing adverse CMR phenotypes with greater odds of COVID-19 positivity independent of classical cardiovascular risk factors. CONCLUSIONS: Observational reports of cardiovascular involvement after COVID-19 may, at least partly, reflect pre-existing cardiac status rather than COVID-19 induced alterations

Light to moderate coffee consumption is associated with lower risk of death: a UK Biobank study

Aims: To study the association of daily coffee consumption with all-cause and cardiovascular (CV) mortality and major CV outcomes. In a subgroup of participants who underwent cardiovascular magnetic resonance (CMR) imaging, we evaluated the association between regular coffee intake and cardiac structure and function.Methods: UK Biobank participants without clinically manifested heart disease at the time of recruitment were included. Regular coffee intake was categorized into 3 groups: zero, light-to-moderate (0.5-3 cups/day) and high (>3 cups/day). In the multivariate analysis, we adjusted for the main CV risk factors.Results: We included 468,629 individuals (56.2 ± 8.1 years, 44.2% male), 22.1% did not consume coffee on a regular basis, 58.4% had 0.5-3 cups per day and 19.5% had >3 cups per day. Compared to non-coffee drinkers, light-to-moderate (0.5-3 cups per day) coffee drinking was associated with lower risk of all-cause mortality (multivariate HR = 0.88, 95%CI : 0.83-0.92; p < 0.001) and CV mortality (multivariate HR = 0.83, 95%CI : 0.74-0.94; p = 0.006), and incident stroke (multivariate HR = 0.79, 95%CI : 0.63-0.99 p = 0.037) after a median follow-up of 11 years. CMR data were available in 30,650 participants. Both light-to-moderate and high coffee consuming categories were associated with dose-dependent increased left and right ventricular end-diastolic, end-systolic and stroke volumes, as well as greater left ventricular mass. Conclusion: Coffee consumption of up to 3 cups per day was associated with favorable CV outcomes. Regular coffee consumption was also associated with a likely healthy pattern of CMR metrics in keeping with the reverse of age-related cardiac alterations

Development of the natural working fluid‐based refrigeration system for domestic scale freeze‐dryer

In this work, the analysis of the refrigeration system designed for the FrostX 10 freeze‐dryer is presented. The main goal of this study was to experimentally investigate the reference R452a freeze‐dryer and prepare recommendations for a machine based on the R290 refrigeration unit. In order to guarantee the temperature requirements and efficient operation of that unit, the analysis of suitable natural refrigerants was performed. Consequently, propane (R290) was selected. In addition, a number of modifications were introduced for the prototype system. System analysis showed that the replacement of the refrigerant in the existing system improves the system energy efficiency by approximately 18%. During the experimental campaign of the basic refrigeration unit, an unstable operation of the evaporator was found. The concept of a new cooling system for a prototype device was presented. The configuration and type of heat exchanger to maximise the performance of the ice trap of the freeze‐dryer were proposed.Development of the natural working fluid‐based refrigeration system for domestic scale freeze‐dryeracceptedVersio

Calibration of myocardial T2 and T1 against iron concentration.

BACKGROUND: The assessment of myocardial iron using T2* cardiovascular magnetic resonance (CMR) has been validated and calibrated, and is in clinical use. However, there is very limited data assessing the relaxation parameters T1 and T2 for measurement of human myocardial iron. METHODS: Twelve hearts were examined from transfusion-dependent patients: 11 with end-stage heart failure, either following death (n=7) or cardiac transplantation (n=4), and 1 heart from a patient who died from a stroke with no cardiac iron loading. Ex-vivo R1 and R2 measurements (R1=1/T1 and R2=1/T2) at 1.5 Tesla were compared with myocardial iron concentration measured using inductively coupled plasma atomic emission spectroscopy. RESULTS: From a single myocardial slice in formalin which was repeatedly examined, a modest decrease in T2 was observed with time, from mean (± SD) 23.7 ± 0.93 ms at baseline (13 days after death and formalin fixation) to 18.5 ± 1.41 ms at day 566 (p<0.001). Raw T2 values were therefore adjusted to correct for this fall over time. Myocardial R2 was correlated with iron concentration [Fe] (R2 0.566, p<0.001), but the correlation was stronger between LnR2 and Ln[Fe] (R2 0.790, p<0.001). The relation was [Fe] = 5081•(T2)-2.22 between T2 (ms) and myocardial iron (mg/g dry weight). Analysis of T1 proved challenging with a dichotomous distribution of T1, with very short T1 (mean 72.3 ± 25.8 ms) that was independent of iron concentration in all hearts stored in formalin for greater than 12 months. In the remaining hearts stored for <10 weeks prior to scanning, LnR1 and iron concentration were correlated but with marked scatter (R2 0.517, p<0.001). A linear relationship was present between T1 and T2 in the hearts stored for a short period (R2 0.657, p<0.001). CONCLUSION: Myocardial T2 correlates well with myocardial iron concentration, which raises the possibility that T2 may provide additive information to T2* for patients with myocardial siderosis. However, ex-vivo T1 measurements are less reliable due to the severe chemical effects of formalin on T1 shortening, and therefore T1 calibration may only be practical from in-vivo human studies