Search

Recently, small-molecule covalent inhibitors have been accepted as a practical tool for targeting previously "undruggable" proteins. The high target selectivity of modern covalent inhibitors is now alleviating toxicity concerns regarding the covalent modifications of proteins. However, despite the tremendous clinical success of current covalent inhibitors, there are still unmet medical needs that covalent inhibitors have not yet addressed. This review categorized representative covalent inhibitors based on their mechanism of covalent inhibition: conventional covalent inhibitors, targeted covalent inhibitors (TCIs), and expanded TCIs. By reviewing both Food and Drug Administration (FDA)-approved drugs and drug candidates from recent literature, we provide insight into the future direction of covalent inhibitor development. [ABSTRACT FROM AUTHOR]

Purpose. To determine the incidence of keratoconus and to determine its possible association with common systemic diseases using a nationwide cohort. Methods. This retrospective nationwide cohort study included 1,025,340 subjects from the Korean National Health Insurance Service-National Sample Cohort database from 2004 to 2013. Estimates for incidence rates of keratoconus were identified. After 1 : 5 matching using propensity scores, associations between keratoconus and certain systemic comorbidities were determined using multivariate logistic regression analysis. Results. The incidence during the same period was 15.1 cases per 100,000 person-years. Adjusted logistic regression analysis after propensity score matching revealed significant associations between keratoconus and allergic rhinitis (odds ratio (OR): 1.86; 95% confidence interval (CI): 1.63–2.13; p < 0.001), asthma (OR: 1.20; 95% CI: 1.06–1.36; p < 0.001), atopic dermatitis (OR: 1.33; 95% CI: 1.13–1.56; p < 0.001), and diabetes mellitus (DM) (OR: 1.35; 95% CI: 1.15–1.58; p < 0.001). Conclusion. Estimates of the incidence of keratoconus may help in the planning of eye-care policies, and the results of this study determined the associations between allergic diseases and keratoconus. Conflicting results regarding the association between keratoconus and DM should be further evaluated. [ABSTRACT FROM AUTHOR]

Although progressive cardiac dysfunction is the leading cause of death in patients with Duchenne muscular dystrophy (DMD), their cardiac function measured by conventional echocardiography has been generally interpreted as normal at a young age. We aimed to determine whether two-dimensional speckle tracking echocardiography (STE) or tissue Doppler imaging (TDI) could be used for early identification and detection of cardiac dysfunction in young patients with DMD. Thirteen pediatric patients (mean age, 9.69 ± 2.2 years) with DMD and 26 age-matched healthy children (mean age, 9.65 ± 2.2 years) were included in the study. All patients were examined via conventional echocardiography, TDI, and STE. Standard echocardiographic measurements of left ventricular (LV) systolic and diastolic function were obtained. Myocardial velocities including peak-systolic and early- and late-diastolic myocardial velocities were calculated in longitudinal direction in the interventricular septum, using TDI. Speckle tracking analyses were performed by acquiring apical four-, three-, and two-chamber views with the highest possible frame rates. Conventional parameters were similar between the two groups, but heart rates were higher in patients with DMD than in controls. The results of LV diastolic function evaluated using TDI showed that annular peak velocity during early diastole (e′; 10.9 ± 1.7 vs. 14.6 ± 1.7 cm/s), e′/a′ ratio (2.0 ± 0.5 vs. 3.0 ± 0.5), E/e′ ratio (9.4 ± 1.4 vs. 7.3 ± 0.8), and myocardial performance index (0.46 ± 0.05 vs. 0.36 ± 0.06) of the mitral septal annulus among patients with DMD differed significantly from those of healthy children. A significant decrease in global longitudinal systolic strain was found in patients with DMD (− 16.6 ± 3.7 vs. − 21.2 ± 2.1), with a marked decrease in the LV basal inferolateral and basal inferior walls. In young patients with DMD who have global normal systolic function, reductions in systolic deformation parameters as well as reduced early diastolic myocardial velocities can be detected particularly in the basal inferolateral LV walls. The prognostic significance of these findings warrants further longitudinal follow-up. [ABSTRACT FROM AUTHOR]

The presence of fragmented QRS is a known marker of heterogeneous ventricular activation around the myocardial scar area. We validated whether fragmented QRS shows any association with ventricular dysfunction, fibrosis, or ventricular arrhythmias in patients with Duchenne muscular dystrophy (DMD). Thirty-seven patients with DMD were evaluated using electrocardiography (ECG), echocardiography, cardiac magnetic resonance, and 24-h Holter monitoring. Associations between fragmented QRS and ventricular dysfunction, fibrosis, or ventricular arrhythmia were investigated. Fragmented QRS complexes were present in 31 of 37 (83.7%) patients, and they were associated with a significantly lower left ventricular ejection fraction along with an increased left ventricular Tei index as evaluated by echocardiography, and more frequent ventricular arrhythmia as indicated using 24-hour Holter monitoring compared with patients without fragmented QRS. The number of leads with fragmented QRS correlated negatively with left ventricular ejection fraction both using echocardiography ( r = −0.616) and CMR ( r = −0.516). Further, the number of leads with fragmented QRS showed a significant correlation with several other echocardiographic measurements (mitral Em and Sm, and left ventricular Tei index), and 2-dimensional speckle-tracking echocardiography derived global left ventricular longitudinal strain. The frequency of ventricular arrhythmia observed using Holter monitoring showed a significant positive correlation with the frequency of fragmented QRS on ECG ( r = 0.674). There was a positive trend of correlation between fragmented QRS and the amount of myocardial fibrosis as assessed by late gadolinium enhancement using CMR, but the statistical significance of the relationship was low ( r = 0.433, p = 0.056). Fragmentation of QRS complexes is associated with degrees of left ventricular dysfunction, fibrosis, and ventricular arrhythmias in patients with DMD. [ABSTRACT FROM AUTHOR]