scholarly journals Novel Morphological Features on CMR for the Prediction of Pathogenic Sarcomere Gene Variants in Subjects Without Hypertrophic Cardiomyopathy

2021 ◽  
Vol 8 ◽  
Author(s):  
Nikki van der Velde ◽  
Roy Huurman ◽  
H. Carlijne Hassing ◽  
Ricardo P. J. Budde ◽  
Marjon A. van Slegtenhorst ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Hypertrophic Cardiomyopathy ◽  
Wall Thickness ◽  
Area Under The Curve ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Morphological Features ◽  
Gene Variants ◽  
Healthy Controls ◽  
Score System

Background: Carriers of pathogenic DNA variants (G+) causing hypertrophic cardiomyopathy (HCM) can be identified by genetic testing. Several abnormalities have been brought forth as pre-clinical expressions of HCM, some of which can be identified by cardiovascular magnetic resonance (CMR). In this study, we assessed morphological differences between G+/left ventricular hypertrophy-negative (LVH-) subjects and healthy controls and examined whether CMR-derived variables are useful for the prediction of sarcomere gene variants.Methods: We studied 57 G+ subjects with a maximal wall thickness (MWT) < 13 mm, and compared them to 40 healthy controls matched for age and sex on a group level. Subjects underwent CMR including morphological, volumetric and function assessment. Logistic regression analysis was performed for the determination of predictive CMR characteristics, by which a scoring system for G+ status was constructed.Results: G+/LVH- subjects were subject to alterations in the myocardial architecture, resulting in a thinner posterior wall thickness (PWT), higher interventricular septal wall/PWT ratio and MWT/PWT ratio. Prominent hook-shaped configurations of the anterobasal segment were only observed in this group. A model consisting of the anterobasal hook, multiple myocardial crypts, right ventricular/left ventricular ratio, MWT/PWT ratio, and MWT/left ventricular mass ratio predicted G+ status with an area under the curve of 0.92 [0.87–0.97]. A score of ≥3 was present only in G+ subjects, identifying 56% of the G+/LVH- population.Conclusion: A score system incorporating CMR-derived variables correctly identified 56% of G+ subjects. Our results provide further insights into the wide phenotypic spectrum of G+/LVH- subjects and demonstrate the utility of several novel morphological features. If genetic testing for some reason cannot be performed, CMR and our purposed score system can be used to detect possible G+ carriers and to aid planning of the control intervals.

Layer-specific strain and the degree of left ventricular thickness in patients with hypertrophic cardiomyopathy

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Tsugu ◽  
Y Nagatomo ◽  
R Dulgheru ◽  
S Marchetta ◽  
A Postolache ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Wall Thickness ◽  
Myocardial Dysfunction ◽  
Interventricular Septum ◽  
Area Under The Curve ◽  
Cellular Level ◽  
Left Ventricular ◽  
Myocardial Tissue ◽  
Characteristic Analysis ◽  
Specific Strain

Abstract Background Left ventricular (LV) wall thickness is an important parameter for the diagnosis of hypertrophic cardiomyopathy (HCM) and is also associated with long-term clinical outcome in HCM patients. However, conventional tools have failed to analyze the mechanisms of structural and functional abnormalities that occur at the cellular level in hypertrophied myocardial tissue. Recently, technological progression of 2D-speckle tracking echocardiography (2D-STE) has enabled the estimation of layer-specific strain (LSS), such as epicardial, mid-myocardial, and endocardial longitudinal strain, respectively. LSS may have the potential to elucidate the detailed mechanisms of myocardial dysfunction. Purpose The aim of this study was (i) to clarify the detailed mechanisms of structural and functional abnormalities of myocardial tissue in HCM using LSS (ii) to investigate the diagnostic accuracy of LSS for HCM. Methods Forty-one patients with HCM and preserved LV ejection fraction (LVEF) (66% male, 52±18 years, LVEF 62.9±3.7%) and 41 controls matched for age and sex (66% male, 52±20 years, LVEF 63.5±8.2%) underwent 2D-STE (GE-Healthcare, Vivid-E9). Quantitative strain values of epicardial, mid-myocardial, and endocardial layers were measured. Results LV wall thickness including interventricular septum thickness (HCM vs. Controls; 18.9±5.0 vs. 9.1±1.8, p<0.001), posterior wall thickness (11.5±2.5 vs. 8.8±1.9, p<0.001), and maximum wall thickness (20.1±4.3 vs. 9.4±0.4, p<0.001) were significantly lower in HCM than in Controls. Absolute values of LSS for all layers were lower in HCM than in Controls (HCM vs. Controls; epicardial; −13.1±3.3 vs. −19.5±1.6, p<0.001; mid-myocardial; −15.8±3.3 vs. −21.4±1.7, p<0.001; endocardial; −18.9±3.9 vs. −23.6±1.9, p<0.001). End/Epi ratio was higher in HCM than in Controls (HCM vs. Controls; 1.5±0.2 vs. 1.2±0.0, p<0.001). Next, we investigated the echocardiographic parameters that correlated with LV maximal wall thickness (MWT). End/Epi ratio was an independent predictor of LV MWT (β=0.96, p<0.001). Receiver operating characteristic analysis revealed that a higher End/Epi ratio (≥1.3) was the strongest predictor of diagnostic criteria for HCM (LV wall thickness ≥15 mm) (area under the curve 0.99, p<0.001, sensitivity 98%, specificity 97%). Conclusions In HCM patients with preserved LVEF, (i) LSS was lower and End/Epi ratio was higher than in controls. (ii) End/Epi ratio (≥1.3) was the strongest predictor of abnormal wall thickness of HCM. The mechanism of higher End/Epi ratio in HCM might be attributable to the more common myofibrillar disarray in mid- and epicardial layers. Variations of LSS represented by End/Epi ratio might have the potential to accurately detect HCM and to elucidate the pathophysiology of impaired LV wall motion at cellular level in HCM. Funding Acknowledgement Type of funding source: None

scholarly journals Echocardiography assessment of the left ventricle apical morphology and dynamics in patients with unexplainable deep T-wave inversion and apical wall thickness<15 mm

2020 ◽  
Author(s):  
Shengnan Lin ◽  
Qinyun Ruan ◽  
Chunyan Huang ◽  
Lei Yan ◽  
Liyun Fu ◽  
...  
Keyword(s):  
Wall Thickness ◽  
Early Stage ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Healthy Controls ◽  
Dynamic Features ◽  
Apical Angle ◽  
Mild Phenotype ◽  
T Wave ◽  
Wave Inversion

Abstract Background: There exists a group of patients with the same ECG characteristics as typical apical hypertrophic cardiomyopathy (AHCM) but fails to reach the diagnostic criteria. The objective of this study was to evaluate the apical morphological and dynamical features of this type of patients using echocardiography.Methods:A total of 30 subjects with unexplainable T-wave inversion (TWI) on ECG and apical myocardium thickness <15 mm by echocardiography were recruited. The apical morphological and dynamic features included the left ventricular (LV) apical-to-basal posterior wall thickness ratio (ABR), apical angle (apA) and its percentage change in cardiac cycle, peak blood flow velocity at the apical cavity (Vap) and its ratio to the velocity at LV outflow tract (Vap/VLVOT). The results were compared to those from 32 patients with typical AHCM, 44 with essential hypertension and 43 healthy controls.Results: Compared to healthy controls and hypertension patients, the suspected AHCM group had a significantly higher ABR (1.37±0.23 vs. 0.75±0.08 and 0.75±0.11, P<0.001), lower apAs, higher percent change of apA (74±23% vs. 16±8% and 28±13%, P<0.001) and higher Vap/VLVOT (0.5±0.3 vs. 0.3±0.1 and 0.3±0.1, P<0.05). Patients with typical AHCM had similar apAs and its change and significantly higher ABR (1.85±0.42, P<0.001) and Vap/VLVOT (0.8±0.5, p=0.009) than the suspected AHCM group.Conclusion: Apical morphology and dynamic features of subjects with TWI and LV apical thickness <15 mm were significantly different from healthy controls and hypertension patients, but shared similarities with typical AHCM patients. The results suggest this suspected group may be in an early stage or exhibit a mild phenotype of AHCM. With careful assessment and additional quantitative measurements, it is possible to detect this suspected AHCM group using echocardiography.

Combination of Huangqi Granule and Rosuvastatin Improves the Cardiac Function in Heart Failure

2020 ◽  
Vol 19 (2) ◽  
pp. 181-187
Author(s):  
Jing Li ◽  
Yun Zhang ◽  
Weizhong Huangfu ◽  
Yuhong Ma
Keyword(s):  
Heart Failure ◽  
Left Ventricular Ejection Fraction ◽  
Ejection Fraction ◽  
Wall Thickness ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Model Group ◽  
Ventricular Ejection Fraction ◽  
Posterior Wall Thickness

Using rat models of heart failure, we evaluated the effects of rosuvastatin and Huangqi granule alone and in combination on left ventricular end-diastolic dimension, left ventricular end-systolic dimension, left ventricular ejection fraction, left ventricular posterior wall thickness at end-diastole, and left ventricular posterior wall thickness at end-systole. Results showed that left ventricular end-diastolic dimension, left ventricular end-systolic dimension in the rosuvastatin + Huangqi granule group were significantly decreased (P ‹ 0.01), while left ventricular ejection fraction, left ventricular posterior wall thickness at end-diastole and left ventricular posterior wall thickness at end-systole were significantly increased (P ‹ 0.05). The serum IL-2, IFN-β, and TNF-α in rosuvastatin + Huangqi granule group were significantly lower than those in model group (P ‹ 0.05). However, the levels of S-methylglutathione and superoxide dismutase in rosuvastatin + Huangqi granule group were significantly higher, while nitric oxide was significantly lower than that in the model group (P ‹ 0.05). Also, compared to the model group, the apoptosis rate, and the autophagy protein LC3-II in the cardiomyocytes of rosuvastatin + Huangqi granule group was significantly decreased (P ‹ 0.01), while the level of p62 protein was significantly increased (P ‹ 0.01). The levels of AMPK and p-AMPK in cardiomyocytes were significantly lower in rosuvastatin + Huangqi granule group; however, the levels of mTOR and p-mTOR showed an opposite trend (P ‹ 0.05). To sum up, rosuvastatin + Huangqi granule could improve the cardiac function, decrease the level of oxidative stress, and inflammatory cytokines in rats with HF. The possible underlying mechanism might be inhibition of autophagy and reduced apoptosis in cardiomyocytes by regulating AMPK-mTOR signaling pathway.

scholarly journals Aetiology-discriminative multimodality imaging of hypertrophic cardiomyopathy: deformation patterns relate to synchrotron-based assessment of microstructural tissue remodelling

2021 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
F Loncaric ◽  
A Garcia-Alvarez ◽  
P Garcia-Canadilla ◽  
L Sanchiz ◽  
H Dejea ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Wall Thickness ◽  
Multimodality Imaging ◽  
Global Longitudinal Strain ◽  
Microstructural Analysis ◽  
Left Ventricular ◽  
Doppler Imaging ◽  
Deformation Analysis ◽  
Septal Myectomy ◽  
Regional Deformation

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Horizon 2020 European Commission Project H2020-MSCA-ITN-2016 (764738) and the Clinical Research in Cardiology grant from the Spanish Cardiac Society. Background The aetiology of left ventricular hypertrophy (LVH) is a relevant clinical challenge with consequences for patient management. Phenotypes resulting from hypertensive remodelling and sarcomere mutation often overlap. Synchrotron X-ray phase-contrast imaging (X-PCI) is a technique that can provide 3-dimensional detailed information on myocardial micro-structure non-destructively. The aim is to relate macrostructural/functional, non-invasive, imaging phenotypes of hypertrophic cardiomyopathy (HCM) to the underlying myocardial microstructure assessed with X-PCI. Methods Myocardial tissue samples were obtained from three patients (P1-3) with obstructive myocardial hypertrophy undergoing septal myectomy. Medical history and the 5-year HCM risk scores were evaluated. The patients were imaged with magnetic resonance imaging and echocardiography prior to procedure. Myocardial structure was assessed with wall thickness, late gadolinium enhancement (LGE), whereas function with speckle-tracking deformation (STE) and tissue Doppler imaging (TDI). Myectomy tissue was imaged with X-PCI in the TOMCAT beamline, using a multiscale propagation-based protocol combining a low-resolution (LR) and a high-resolution (HR) setup (5.8 and 0.7 um pixel size, respectively). Results The clinical and imaging data are shown in Fig 1. On initial assessment, wall thickness, LGE distribution, global longitudinal strain and septal TDI demonstrated a similar macrostructural and functional phenotype of P1 and P2, whereas P3 stood out with more severe hypertrophy, scarring and dysfunction. Additional regional deformation analysis with STE revealed reduced deformation in the basal and mid septum in P1, paired with a hypertensive pattern of post-systolic shortening (PSS) (yellow arrows). In comparison, in P2 and P3, deformation was more heterogeneous regionally, with regions of almost complete absence of deformation (orange arrows). Upon further exploration with TDI, areas with abnormal deformation were identified on the transition from basal to mid septum in both P2 and P3, whereas deformation was normal, but reduced in P1, and paired with PSS. LR X-PCI defined regions of interest to scan with HR (yellow frame), where HR revealed extensive interstitial fibrosis (orange arrow) with normal myocyte size and organisation in P1, compatible with severe hypertensive remodelling. However, in P2 and P3, patches of fibrosis (yellow arrow) paired with enlarged myocytes organized in visible disarray, considerably more prominent in P3, were both compatible with sarcomere-mutation HCM. Conclusion The results demonstrate multiscale phenotyping of HCM - relating micro- and macrostructural findings to function, and integrating multimodality data. In-depth regional deformation analysis, validated by synchrotron-based microstructural analysis, showed potential to identify distinct imaging phenotypes in HCM, distinguishing between overlapping presentations in different aetiologies. Abstract Figure 1

scholarly journals The impact of obesity on left ventricular mass and left ventricular systolic function in children

2016 ◽  
Vol 45 (4) ◽  
pp. 171
Author(s):  
Ria Nova ◽  
Bambang Madiyono ◽  
Sudigdo Sastroasmoro ◽  
Damayanti R Sjarif
Keyword(s):  
Wall Thickness ◽  
Systolic Function ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Internal Diameter ◽  
Obese Children ◽  
Normal Children ◽  
Posterior Wall Thickness ◽  
Lv Mass ◽  
Lv Systolic Function

Background Obesity causes cardiovascular disturbances. Theincidence of cardiovascular disease is higher even in mildly obesepatients than in lean subjects.Objectives The purpose of this study was to compare left ven-tricular (LV) mass, LV internal dimensions, and LV systolic func-tion between obese and normal children; and to determine the as-sociation of the degree of obesity with LV mass and LV systolicfunction.Methods This cross-sectional study was conducted on elemen-tary school students in Jakarta from February to April 2003. Wemeasured the subjects’ body weight and height, and performedlipid profile and echocardiography examinations. Measurementsof LV mass, LV internal dimensions with regard to septum thick-ness, LV internal diameter, and LV posterior wall thickness; andLV systolic function as indicated by shortening fraction and ejec-tion fraction, were performed echocardiographically. The differ-ences in measurements between obese and normal children aswell as between obese children with and without lipid abnormalitywere analyzed. The correlation between the degree of obesity withLV size and systolic function was determined.Results Twenty-eight normal children and 62 obese children wereenrolled in the study. Mean LV mass was 35.7 (SD 5.16) g/cm 3 inobese children versus 24.0 (SD 3.80) g/cm 3 in normal children(P<0.0001). Mean septum thickness was 0.8 (SD 0.14) mm inobese children versus 0.6 (SD 7.90) mm in normal children (P<0.0001). Mean posterior wall thickness was 0.9 (SD 0.14) mm inobese children versus 0.6 (SD 9.97) mm in normal children(P<0.0001). Mean LV internal diameter was 4.0 (SD 0.34) mm inobese children versus 3.9 (SD 0.29) mm in normal children(P=0.300). There was strong correlation between the degree ofobesity and LV mass (r=0.838, P<0.0001). LV systolic function(shortening fraction) was 37.1 (SD 4.20) percent in obese childrenversus 35.8 (SD 4.99) percent in normal children (P=0.19). Ejec-tion fraction was 67.4 (SD 5.32) percent in obese children versus65.5 (SD 6.29) percent in normal children (P=0.13). There wasweak correlation between LV systolic function and the degree ofobesity (shortening fraction r=0.219, P=0.038; ejection fractionr=0.239, P=0.023).Conclusions Obese children had significantly greater LV mass,septum thickness, and posterior wall thickness than normal chil-Backgrounddren. Such significant difference was absent for LV internal diam-eter and measures of LV systolic function. There was no signifi-cant difference in LV mass and LV systolic function between obesechildren with or without abnormality of lipid profile. A strong corre-lation exists between the degree of obesity and LV mass, but thecorrelation between degree of obesity and LV systolic function wasweak

Abstract 11093: Layer-specific Quantification of Myocardial Deformation by Strain Echocardiography May Reveal the Mechanism of Preserved Left Ventricular Ejection Fraction in Patients With Hypertrophic Cardiomyopathy

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Jing Ping Sun ◽  
Xianda Ni ◽  
Tingyan Xu ◽  
Min Xu ◽  
Xing Sheng Yang ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Ejection Fraction ◽  
Wall Thickness ◽  
Radial Strain ◽  
Left Ventricular ◽  
Relative Wall Thickness ◽  
Left Ventricular Ejection ◽  
Compensatory Mechanisms ◽  
Ventricular Ejection Fraction ◽  
Bull's Eye

Purpose: We aimed to evaluate compensatory mechanisms in hypertrophic cardiomyopathy (HCM) patients (pts) with preserved left-ventricular (LV) ejection fraction (EF). Methods: Speckle-tracking echocardiography (Vivid E9, GE) was performed in 50 HCM with preserved LV EF (38 m; 49± 14 y, all LV EF > 55%) and 50 age, gender matched controls (38 m; 49±12 y). The global and segmental longitudinal (LS), circumferential (CS) and radial strain (RS) strains of endocardia (End), mid-wall and epicardia layers were analyzed using a novel layer-specific TTE. The ratio of End to epicardia strain (End/Epi) was calculated. Results: The LV EF were similar in pts and controls (64±8 vs 64±7 %, p=0.95). The diastolic function was significantly impaired in HCM pts compared with controls (E/E’:18.4±8.4 vs 8.6 ±2.4, p<0.0001). The absolute value of LS and CS was reserved at apical End layers (-34±7 vs -35±6, p=0.44); the remaining segments and LV global LS and CS of three layers were significantly smaller (LS,-16±5 vs -22±3; CS -24±8 vs -33±7; p<0.0001), and LS and CS End/Epi (1.7±0.3 vs 1.3±0.1, 3.4±1.1 vs 1.7±0.2 respectively, P <0.0001) was significantly higher in HCM pts than in controls. The RS and LV twist were preserved in all LV segments (27±10 vs 24±12, p=0.19; 20±8 vs 18±5, p=0.33; respectively). In HCM pts, the LV LS value at basal and middle levels revealed significant negative correlations with LV relative wall thickness (r=–0.65, –0.59 and –0.60, –0.54, respectively , p< 0.0001); and mild negative correlations (r=-0.33,-0.29, p<0.0001). The LV CS value at all levels revealed mild correlations with relative wall thickness (r=-0.22, p<0.05) . The LS were significantly reduced at the hypertrophic segments (Figure). Conclusions: In HCM patients with preserved LVEF, LV GLS was impaired, but apical End LS and basal End CS, LV RS as well as LV twist were maintained as the compensation for reduction LV LS and CS. The Bull’s eye of LS may help us to localize the lesion segments and define the type of HCM.

scholarly journals P955 left ventricle cardiac remodeling among lithuanian football versus basketball players

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
A Aldujeli ◽  
J Laukaitiene ◽  
R Unikas
Keyword(s):  
Left Ventricle ◽  
Wall Thickness ◽  
Cardiac Remodeling ◽  
Interventricular Septum ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Relative Wall Thickness ◽  
Football Players ◽  
Basketball Players ◽  
Lv Mass

Abstract Background Regular physical exercise causes a continuous gradual increase of the cardiac left ventricular (LV) mass known as physiological adaptive hypertrophy. The extent of LV remodeling depends on the type, amount, and intensity of the exercise. Purpose The aim of this study was to compare structural changes of the heart among Lithuanian football, basketball players and unathletic controls. Methods A total of 50 Lithuanian males aged between 20-29 years volunteered to participate in the study. Football players (n = 15) playing for local II league football clubs,and Basketball players (n = 15) playing for local minor league basketball teams. All athletes had been regularly engaged in their sport for at least three years. Inactive healthy volunteers (n = 20) of similar age served as controls. Routine transthoracic echocardiographic examinations to measure end-diastolic LV dimensions were performed by cardiology fellow under the supervision of a fully licensed cardiologist. Statistical analyses were performed using the SPSS 20.0 software. The value of p &lt; 0,05 was considered as statistically significant. Results No structural or functional pathologies were evident during the echocardiographic examination in any of the subjects. Absolute interventricular septum (IVS) thickness and LV posterior wall thickness, but not LV diameter, were higher in athletes than in inactive controls (P &lt; 0,001). Indexed LV diameter was higher in football players as compared with non-athlete controls and basketball players (P &lt; 0,05). Left ventricular mass of all athletes were higher as compared with controls (p &lt; 0.001). Relative wall thickness was not increased in football players but was higher in basketball players as compared with controls (p &lt; 0.05). Conclusion Cardiac remodeling in Lithuanian football players resulted in left ventricle eccentric hypertrophy due to the LV dilation, increased LV mass and relatively normal relative wall thickness. However in Lithuanian basketball players we noticed an increase in both relative wall thickness and LV mass resulting in LV concentric hypertrophy. Echocardiographic characteristics Groups n End-diastolic LV diameter(mm) End-diastolic Interventricular septum (mm) End-diastolic LV posterior wall LV mass Football Players 15 56.9 10.8 10.8 242 Basketball players 15 53.6 11.5 11.3 254 Inactive individuals 20 53.2 9.1 9.5 182 P value 0.01 &lt;0.001 &lt;0.001 &lt;0.01 Abstract P955 Figure.

Cardiovascular genetics: the role of genetic testing in diagnosis and management of patients with hypertrophic cardiomyopathy

Heart ◽  
2020 ◽  
pp. heartjnl-2020-316798
Author(s):  
Monica Ahluwalia ◽  
Carolyn Y Ho
Keyword(s):  
At Risk ◽  
Clinical Practice ◽  
Genetic Testing ◽  
Hypertrophic Cardiomyopathy ◽  
Clinical Manifestations ◽  
Left Ventricular ◽  
Family Management ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing

Genetic testing in hypertrophic cardiomyopathy (HCM) is a valuable tool to manage patients and their families. Genetic testing can help inform diagnosis and differentiate HCM from other disorders that also result in increased left ventricular wall thickness, thereby directly impacting treatment. Moreover, genetic testing can definitively identify at-risk relatives and focus family management. Pathogenic variants in sarcomere and sarcomere-related genes have been implicated in causing HCM, and targeted gene panel testing is recommended for patients once a clinical diagnosis has been established. If a pathogenic or likely pathogenic variant is identified in a patient with HCM, predictive genetic testing is recommended for their at-risk relatives to determine who is at risk and to guide longitudinal screening and risk stratification. However, there are important challenges and considerations to implementing genetic testing in clinical practice. Genetic testing results can have psychological and other implications for patients and their families, emphasising the importance of genetic counselling before and after genetic testing. Determining the clinical relevance of genetic testing results is also complex and requires expertise in understanding of human genetic variation and clinical manifestations of the disease. In this review, we discuss the genetics of HCM and how to integrate genetic testing in clinical practice.

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